ANTI-INFLAMMATORY, ANTIRHEUMATOID AND RELATED AGENTS. ANTISEPTIC AND DISINFECTANTS. IMMUNOSUPPRESSANT. IMMUNIZING AGENTS. IMMUNOMODULATING AGENTS. ANTINEOPLASTIC AGENTS
The Immune Response
The immune response occurs when immunologically competent cells are activated in response to foreign organisms or antigenic substances liberated during the acute or chronic inflammatory response. The outcome of the immune response for the host may be beneficial, as when it causes invading organisms to be phagocytosed or neutralized. On the other hand, the outcome may be deleterious if it leads to chronic inflammation without resolution of the underlying injurious process. Chronic inflammation involves the release of a number of mediators that are not prominent in the acute response.
One of the most important conditions involving these mediators is rheumatoid arthritis, in which chronic inflammation results in pain and destruction of bone and cartilage that can lead to severe disability and in which systemic changes occur that can result in shortening of life.
The cell damage associated with inflammation acts on cell membranes to cause leukocytes to release lysosomal enzymes; arachidonic acid is then liberated from precursor compounds, and various eicosanoids are synthesized. Compounds, the cyclooxygenase pathway of arachidonate metabolism produces prostaglandins, which have a variety of effects on blood vessels, oerve endings, and on cells involved in inflammation. The discovery of cyclooxygenase (COX) isoforms (COX-1 and COX-2) led to the concepts that the constitutive COX-1 isoform tends to be homeostatic in function, while COX-2 is induced during inflammation and tends to facilitate the inflammatory response. On this basis, highly selective COX-2 inhibitors have been developed and marketed on the assumption that such selective inhibitors would be safer thaonselective COX-1 inhibitors but without loss of efficacy. The lipoxygenase pathway of arachidonate metabolism yields leukotrienes, which have a powerful chemotactic effect on eosinophils, neutrophils, and macrophages and promote bronchoconstriction and alterations in vascular permeability. Kinins, neuropeptides, and histamine are also released at the site of tissue injury, as are complement components, cytokines, and other products of leukocytes and platelets. Stimulation of the neutrophil membranes produces oxygen-derived free radicals.
Superoxide anion is formed by the reduction of molecular oxygen, which may stimulate the production of other reactive molecules such as hydrogen peroxide and hydroxyl radicals. The interaction of these substances with arachidonic acid results in the generation of chemotactic substances, thus perpetuating the inflammatory process.
Reduction of inflammation with nonsteroidal anti-inflammatory drugs (NSAIDs) often results in relief of pain for significant periods. Furthermore, most of the nonopioid analgesics (aspirin, etc) also have anti-inflammatory effects, so they are appropriate for the treatment of both acute and chronic inflammatory conditions.
Another important group of agents are characterized as slow-acting antirheumatic drugs (SAARDs) or disease-modifying antirheumatic drugs (DMARDs). They may slow the bone damage associated with rheumatoid arthritis and are thought to affect more basic inflammatory mechanisms than do the NSAIDs. Unfortunately, they may also be more toxic than the nonsteroidal anti-inflammatory agents.
Nonsteroidal Anti-Inflammatory Drugs
Salicylates and other similar agents used to treat rheumatic disease share the capacity to suppress the signs and symptoms of inflammation. These drugs also exert antipyretic and analgesic effects, but it is their anti-inflammatory properties that make them most useful in the management of disorders in which pain is related to the intensity of the inflammatory process.
Although all NSAIDs are not FDA-approved for the whole range of rheumatic diseases, all are probably effective in rheumatoid arthritis, seronegative spondyloarthropathies (eg, psoriatic arthritis and arthritis associated with inflammatory bowel disease), osteoarthritis, localized musculoskeletal syndromes (eg, sprains and strains, low back pain), and gout (except tolmetin, which appears to be ineffective in gout). Since aspirin, the original NSAID, has a number of adverse effects, many other NSAIDs have been developed in attempts to improve upon aspirin’s efficacy and decrease its toxicity.
Chemistry & Pharmacokinetics
The NSAIDs are grouped in several chemical classes, some of which are shown in Figure 36–1.
This chemical diversity yields a broad range of pharmacokinetic characteristics (Table 36–1). Although there are many differences in the kinetics of NSAIDs, they have some general properties in common. All but one of the NSAIDs are weak organic acids as given; the exception, nabumetone, is a ketone prodrug that is metabolized to the acidic active drug. Most of these drugs are well absorbed, and food does not substantially change their bioavailability. Most of the NSAIDs are highly metabolized, some by phase I followed by phase II mechanisms and others by direct glucuronidation (phase II) alone. Metabolism of most NSAIDs proceeds, in part, by way of the CYP3A or CYP2C families of P450 enzymes in the liver. While renal excretion is the most important route for final elimination, nearly all undergo varying degrees of biliary excretion and reabsorption (enterohepatic circulation). In fact, the degree of lower gastrointestinal tract irritation correlates with the amount of enterohepatic circulation. Most of the NSAIDs are highly proteinbound ( 98%), usually to albumin. Some of the NSAIDs (eg, ibuprofen) are racemic mixtures, while one, naproxen, is provided as a single enantiomer and a few have no chiral center (eg, diclofenac). Figure 36–1.
Pharmacodynamics
The anti-inflammatory activity of the NSAIDs is mediated chiefly through inhibition of biosynthesis of prostaglandins. Various NSAIDs have additional possible mechanisms of action, including inhibition of chemotaxis, down-regulation of interleukin-1 production, decreased production of free radicals and superoxide, and interference with calcium-mediated intracellular events. Aspirin irreversibly acetylates and blocks platelet cyclooxygenase, while most non-COXselective NSAIDs are reversible inhibitors. Selectivity for COX-1 versus COX-2 is variable and incomplete for the older members, but highly selective COX-2 inhibitors (celecoxib, rofecoxib, and valdecoxib) are now available and other highly selective coxibs are being developed. The highly selective COX-2 inhibitors do not affect platelet function at their usual doses. In testing using human whole blood, aspirin, indomethacin, piroxicam, and sulindac were somewhat more
effective in inhibiting COX-1; ibuprofen and meclofenamate inhibited the two isozymes about equally. The efficacy of COX-2-selective drugs equals that of the older NSAIDs, while gastrointestinal safety may be improved. On the other hand, highly selective COX-2 inhibitors may increase the incidence of edema and hypertension.
The NSAIDs decrease the sensitivity of vessels to bradykinin and histamine, affect lymphokine production from T lymphocytes, and reverse vasodilation. To varying degrees, all newer NSAIDs are analgesic, anti-inflammatory, and antipyretic, and all (except the COX-2-selective agents and the nonacetylated salicylates) inhibit platelet aggregation. NSAIDs are all gastric irritants as well, though as a group the newer agents tend to cause less gastric irritation than aspirin. Nephrotoxicity has been observed for all of the drugs for which extensive experience has been reported, and hepatotoxicity can also occur with any NSAID.
Although these drugs effectively inhibit inflammation, there is no evidence that—in contrast to drugs such as methotrexate and gold—they alter the course of an arthritic disorder.
Aspirin
Aspirin’s long use and availability without prescription diminishes its glamour compared to that of the newer NSAIDs. Aspirin is now rarely used as an anti-inflammatory medication; it has been replaced by ibuprofen and naproxen, since they are effective, are also available over the counter, and have good to excellent safety records.
Pharmacokinetics
Salicylic acid is a simple organic acid with a pKa of 3.0. Aspirin (acetylsalicylic acid; ASA) has a pKa of 3.5 (see Table 1–1). Sodium salicylate and aspirin (Figure 36–2) are equally effective anti-inflammatory drugs, though aspirin may be more effective as an analgesic. The salicylates are rapidly absorbed from the stomach and upper small intestine, yielding a peak plasma salicylate level within 1–2 hours. Aspirin is absorbed as such and is rapidly hydrolyzed (serum half-life 15 minutes) to acetic acid and salicylate by esterases in tissue and blood. Salicylate is bound to albumin, but the binding is saturable so that the unbound fraction increases as total concentration increases. Ingested salicylate and that generated by the hydrolysis of aspirin may be excreted unchanged, but the metabolic pathways for salicylate disposition become saturated when the total body load of salicylate exceeds 600 mg. Beyond this amount, increases in salicylate dosage increase salicylate concentration disproportionately. As doses of aspirin increase, salicylate elimination halflife increases from 3–5 hours (for 600 mg/d dosage) to 12–16 hours (dosage > 3.6 g/d).
Alkalinization of the urine increases the rate of excretion of free salicylate and its water-soluble conjugates.
Figure 36–2.
Mechanisms of Action
Anti-Inflammatory Effects
Aspirin is a nonselective inhibitor of both COX isoforms (Figure 36–3), but salicylate is much less effective in inhibiting either isoform. Nonacetylated salicylates may work as oxygen radical scavengers. Aspirin irreversibly inhibits COX and inhibits platelet aggregation, while nonacetylated salicylates do not.
Figure 36–3.
Aspirin also interferes with the chemical mediators of the kallikrein system, thus inhibiting granulocyte adherence to damaged vasculature, stabilizing lysosomes, and inhibiting the chemotaxis of polymorphonuclear leukocytes and macrophages.
Analgesic Effects
Aspirin is most effective in reducing pain of mild to moderate intensity through its effects on inflammation and because it probably inhibits pain stimuli at a subcortical site.
Antipyretic Effects
Aspirin reduces elevated temperature, whereas normal body temperature is only slightly affected.
Aspirin’s antipyretic effect is probably mediated by both COX inhibition in the central nervous system and inhibition of IL-1 (which is released from macrophages during episodes of inflammation).
Antiplatelet Effects
Single low doses of aspirin (81 mg daily) produce a slightly prolonged bleeding time, which doubles if administration is continued for a week. The change is due to irreversible inhibition of platelet COX, so that aspirin’s antiplatelet effect lasts 8–10 days (the life of the platelet).
Clinical Uses
Analgesia, Antipyresis, and Anti-Inflammatory Effects
Aspirin is employed for mild to moderate pain of varied origin but is not effective for severe visceral pain. Aspirin and other NSAIDs have been combined with opioid analgesics for treatment of cancer pain, where their anti-inflammatory effects act synergistically with the opioids to enhance analgesia. High-dose salicylates are effective for treatment of rheumatic fever, rheumatoid arthritis, and other inflammatory joint conditions.
Other Effects
Aspirin decreases the incidence of transient ischemic attacks, unstable angina, coronary artery thrombosis with myocardial infarction, and thrombosis after coronary artery bypass grafting .
Epidemiologic studies suggest that long-term use of aspirin at low dosage is associated with a lower incidence of colon cancer, possibly related to its COX-inhibiting effects.
Dosage
The optimal analgesic or antipyretic dose of aspirin is less than the 0.6–0.65 g oral dose commonly used. Larger doses may prolong the effect. The usual dose may be repeated every 4 hours. The anti-inflammatory dose for children is 50–75 mg/kg/d in divided doses and the average starting anti-inflammatory dose for adults is 45 mg/kg/d in divided doses. The relationship of salicylate blood levels to therapeutic effect and toxicity is illustrated in Figure 36–4.
Adverse Effects
At the usual dosage, aspirin’s main adverse effects are gastric upset (intolerance) and gastric and duodenal ulcers, while hepatotoxicity, asthma, rashes, and renal toxicity occur less frequently.
Upper gastrointestinal bleeding associated with aspirin use is usually related to erosive gastritis. A 3 mL increase in fecal blood loss is routinely associated with aspirin administration; the blood loss is greater for higher doses. On the other hand, some mucosal adaptation occurs in many patients, so that blood loss declines back to baseline over 4–6 weeks; ulcers have been shown to heal while aspirin was taken concomitantly.
With higher doses, patients may experience “salicylism“—vomiting, tinnitus, decreased hearing, and vertigo—reversible by reducing the dosage. Still larger doses of salicylates cause hyperpnea through a direct effect on the medulla. At toxic salicylate levels, respiratory alkalosis followed by metabolic acidosis (salicylate accumulation), respiratory depression, and even cardiotoxicity and glucose intolerance can occur (Figure 36–4). Two grams or less of aspirin daily usually increases serum uric acid levels, whereas doses exceeding
The antiplatelet action of aspirin contraindicates its use by patients with hemophilia. Although previously not recommended during pregnancy, aspirin may be valuable in treating preeclampsiaeclampsia. When overdosing occurs, gastric lavage is advised and an alkaline, high urine output state should be maintained. Hyperthermia and electrolyte abnormalities should be treated. In severe toxic reactions, ventilatory assistance may be required.
Sodium bicarbonate infusions may be employed to alkalinize the urine, which will increase the amount of salicylate excreted.
Nonacetylated Salicylates
These drugs include magnesium choline salicylate, sodium salicylate, and salicylsalicylate. All nonacetylated salicylates are effective anti-inflammatory drugs, though they may be less effective analgesics than aspirin. Because they are much less effective than aspirin as cyclooxygenase inhibitors, they may be preferable when cyclooxygenase inhibition is undesirable, such as in patients with asthma, those with bleeding tendencies, and even (under close supervision) those with renal dysfunction.
The nonacetylated salicylates are administered in the same dosage as aspirin and can be monitored using serum salicylate measurements.
COX-2 Selective Inhibitors
COX-2 selective inhibitors, or coxibs, were developed in an attempt to inhibit prostacyclin synthesis by the COX-2 isoenzyme induced at sites of inflammation without affecting the action of the constitutively active “housekeeping” COX-1 isoenzyme found in the gastrointestinal tract, kidneys, and platelets. Coxibs selectively bind to and block the active site of the COX-2 enzyme much more effectively than that of COX-1. COX-2 inhibitors have analgesic, antipyretic, and anti-inflammatory effects similar to those of nonselective NSAIDs but with fewer gastrointestinal side effects. Likewise, COX-2 inhibitors have been shown to have no impact on platelet aggregation, which is mediated by the COX-1 isoenzyme. As a result, COX-2 inhibitors do not offer the cardioprotective effects of traditional nonselective NSAIDs, which has resulted in some patients taking low-dose aspirin in addition to a coxib regimen to maintain this effect. Unfortunately, because COX-2 is constitutively active within the kidney, recommended doses of COX-2 inhibitors cause renal toxicities similar to those associated with traditional NSAIDs. They are not recommended for patients with severe renal insufficiency. Furthermore, some clinical data have suggested a higher incidence of cardiovascular thrombotic events associated with COX-2 inhibitors such as rofecoxib, but this issue has not yet been settled. Data from animal studies have also pointed to the role of the COX-2 enzyme in bone repair, resulting in a recommendation for short-term use of different drugs in postoperative patients and those undergoing bone repair. COX-2 inhibitors have been recommended mainly for treatment of osteoarthritis and rheumatoid arthritis, but other indications include primary familial adenomatous polyposis, dysmenorrhea, acute gouty arthritis, acute musculoskeletal pain, and perhaps ankylosing spondylitis.
Celecoxib
Celecoxib is a highly selective COX-2 inhibitor—about 10–20 times more selective for COX-2 thanfor COX-1. Pharmacokinetic and dosage considerations are given in Table 36–1.
Celecoxib is as effective as other NSAIDs in rheumatoid arthritis and osteoarthritis, and in trials it has caused fewer endoscopic ulcers than most other NSAIDs. Because it is a sulfonamide, celecoxib may cause rashes. It does not affect platelet aggregation. It interacts occasionally with warfarin—as would be expected of a drug metabolized via CYP2C9.
The coxibs continue to be investigated to determine whether their effect on prostacyclin production could lead to a prothrombotic state. The frequency of other adverse effects approximates that of other NSAIDs. Celecoxib causes no more edema or renal effects than other members of the NSAID group, but edema and hypertension have been documented.
Etoricoxib
Etoricoxib, a bipyridine derivative, is a second-generation COX-2-selective inhibitor with the highest selectivity ratio of any coxib for inhibition of COX-2 relative to COX-1. It is extensively metabolized by hepatic P450 enzymes followed by renal excretion and has an elimination half-life of 22 hours. Etoricoxib is approved in the United Kingdom for acute treatment of the signs and symptoms of osteoarthritis (60 mg once daily) and rheumatoid arthritis (90 mg once daily), for treatment of acute gouty arthritis (120 mg once daily), and for relief of acute musculoskeletal pain (60 mg once daily). Approval in the
Meloxicam
Meloxicam is an enolcarboxamide related to piroxicam that has been shown to preferentially inhibit COX-2 over COX-1, particularly at its lowest therapeutic dose of 7.5 mg/d. It is not as selective as the other coxibs. The drug is popular in Europe and many other countries for most rheumatic diseases and has recently been approved for treatment of osteoarthritis in the
Diclofenac
Diclofenac is a phenylacetic acid derivative that is relatively nonselective as a cyclooxygenase inhibitor. Pharmacokinetic and dosage characteristics are set forth in Table 36–1.
Adverse effects occur in approximately 20% of patients and include gastrointestinal distress, occult gastrointestinal bleeding, and gastric ulceration, though ulceration may occur less frequently than with some other NSAIDs. A preparation combining diclofenac and misoprostol decreases upper gastrointestinal ulceration but may result in diarrhea. Another combination of diclofenac and omeprazole was also effective with respect to the prevention of recurrent bleeding, but renal adverse effects were common in high-risk patients. Diclofenac at a dosage of 150 mg/d appears to impair renal blood flow and glomerular filtration rate. Elevation of serum aminotransferases may occur more commonly with this drug than with other NSAIDs. A 0.1% ophthalmic preparation is recommended for prevention of postoperative ophthalmic
inflammation and can be used after intraocular lens implantation and strabismus surgery. A topical gel containing 3% diclofenac is effective for solar keratoses. Diclofenac in rectal suppository form can be considered a drug of choice for preemptive analgesia and postoperative nausea.
In
Other adverse effects of fenoprofen include nausea, dyspepsia, peripheral edema, rash, pruritus, central nervous system and cardiovascular effects, tinnitus, and drug interactions. However, the latter effects are less common than with aspirin.
Ibuprofen
Ibuprofen is a simple derivative of phenylpropionic acid. In doses of about 2400 mg daily, ibuprofen is equivalent to
Pharmacokinetic characteristics
are given in table 36–1. Oral ibuprofen is often prescribed in lower doses (< 2400 mg/d), at which it has analgesic but not anti-inflammatory efficacy. It is available over the counter in low-dose forms under several trade names. A topical cream preparation appears to be absorbed into fascia and muscle; an (S)(–) formulation has been tested. Ibuprofen cream was more effective than placebo cream for the
treatment of primary knee osteoarthritis. A liquid gel preparation of ibuprofen 400 mg provided faster relief and superior overall efficacy in postsurgical dental pain. In comparison with indomethacin, ibuprofen decreases urine output less and also causes less fluid retention than indomethacin. Ibuprofen has been shown to be effective in closing patent ductus arteriosus in preterm infants, with much the same efficacy and safety as indomethacin. Oral ibuprofen is as effective as intravenous administration in this condition.
Gastrointestinal irritation and bleeding occur, though less frequently than with aspirin. The use of ibuprofen concomitantly with aspirin may decrease the total anti-inflammatory effect. The drug is relatively contraindicated in individuals with nasal polyps, angioedema, and bronchospastic reactivity to aspirin. In addition to the gastrointestinal symptoms (which can be modified by ingestion with meals), rash, pruritus, tinnitus, dizziness, headache, aseptic meningitis (particularly in patients with systemic lupus erythematosus), and fluid retention have been reported. Interaction with anticoagulants is uncommon.
The concomitant administration of ibuprofen antagonizes the irreversible platelet inhibition induced by aspirin. Thus, treatment with ibuprofen in patients with increased cardiovascular risk may limit the cardioprotective effects of aspirin. Rare hematologic effects include agranulocytosis and aplastic anemia. Effects on the kidney (as with all NSAIDs) include acute renal failure, interstitial nephritis, and nephrotic syndrome, but these occur very rarely. Finally, hepatitis has been reported.
Indomethacin
Indomethacin, introduced in 1963, is an indole derivative (Figure 36–1). It is a potent nonselective COX inhibitor and may also inhibit phospholipase A and C, reduce neutrophil migration, and decrease T cell and B cell proliferation. Probenecid prolongs indomethacin’s half-life by inhibiting both renal and biliary clearance.
Clinical Uses
Indomethacin enjoys the usual indications for use in rheumatic conditions and is particularly popular for gout and ankylosing spondylitis. In addition, it has been used to treat patent ductus arteriosus. Indomethacin has been tried iumerous small or uncontrolled trials for many conditions, including Sweet’s syndrome, juvenile rheumatoid arthritis, pleurisy, nephritic syndrome, diabetes insipidus, urticarial vasculitis, postepisiotomy pain, and prophylaxis of heterotopic ossification in arthroplasty, and many others. An ophthalmic preparation seems to be efficacious for conjunctival inflammation (alone and in combination with gentamicin) to reduce pain after traumatic corneal abrasion. Gingival inflammation is reduced after administration of indomethacin oral rinse. Epidural injections produce a degree of pain relief similar to that achieved with methylprednisolone in postlaminectomy syndrome.
Adverse Effects
At higher dosages, at least a third of patients have reactions to indomethacin requiring discontinuance. The gastrointestinal effects may include abdominal pain, diarrhea, gastrointestinal hemorrhage, and pancreatitis. Headache is experienced by 15–25% of patients and may be associated with dizziness, confusion, and depression. Rarely, psychosis with hallucinations has been reported. Hepatic abnormalities are rare. Serious hematologic reactions have beeoted, including thrombocytopenia and aplastic anemia. Hyperkalemia has been reported and is related to inhibition of the synthesis of prostaglandins in the kidney. Renal papillary necrosis has also been observed.
Ketoprofen
Ketoprofen is a propionic acid derivative that inhibits both cyclooxygenase (nonselectively) and lipoxygenase. Its pharmacokinetic characteristics are given in Table 36–1. Concurrent administration of probenecid elevates ketoprofen levels and prolongs its plasma half-life.
The effectiveness of ketoprofen at dosages of 100–300 mg/d is equivalent to that of other NSAIDs in the treatment of rheumatoid arthritis, osteoarthritis, gout, dysmenorrhea, and other painful conditions. In spite of its dual effect on prostaglandins and leukotrienes, ketoprofen is not superior to other NSAIDs. Its major adverse effects are on the gastrointestinal tract and the central nervous system.
Ketorolac
Ketorolac is an NSAID promoted for systemic use mainly as an analgesic, not as an anti-inflammatory drug (though it has typical NSAID properties). Pharmacokinetics are presented in Table 36–1. The drug does appear to have significant analgesic efficacy and has been used successfully to replace morphine in some situations involving mild to moderate postsurgical pain. It is most often given intramuscularly or intravenously, but an oral dose formulation is available. When used with an opioid, it may decrease the opioid requirement by 25–50%. An ophthalmic preparation is available for anti-inflammatory applications. Toxicities are similar to those of other NSAIDs, although renal toxicity may be more common with chronic use.
Meclofenamate & Mefenamic Acid
Meclofenamate and mefenamic acid (Table 36–1) inhibit both COX and phospholipase A2.
Meclofenamate appears to have adverse effects similar to those of other NSAIDs, though diarrhea and abdominal pain may be more common; it has no advantages over other NSAIDs. This drug enhances the effect of oral anticoagulants. Meclofenamate is contraindicated in pregnancy; its efficacy and safety have not been established for young children.
Mefenamic acid is probably less effective than aspirin as an anti-inflammatory agent and is clearly more toxic. It should not be used for longer than 1 week and should not be given to children.
Naproxen
Naproxen is a naphthylpropionic acid derivative. It is the only NSAID presently marketed as a single enantiomer, and it is a nonselective COX inhibitor. Naproxen’s free fraction is 41% higher in women than in men, though albumin binding is very high in both sexes (Table 36–1). Naproxen is effective for the usual rheumatologic indications and is available both in a slow-release formulation and as an oral suspension. A topical preparation and an ophthalmic solution are also available.
The incidence of upper gastrointestinal bleeding in OTC use is low but still double that of OTC ibuprofen (perhaps due to a dose effect). Rare cases of allergic pneumonitis, leukocytoclastic vasculitis, and pseudoporphyria as well as the more common NSAID-associated adverse effects have beeoted.
Piroxicam
Piroxicam, an oxicam (Figure 36–1), is a nonselective COX inhibitor but at high concentrations also inhibits polymorphonuclear leukocyte migration, decreases oxygen radical production, and inhibits lymphocyte function. Its long half-life (Table 36–1) permits once-daily dosing.
Piroxicam can be used for the usual rheumatic indications. Toxicity includes gastrointestinal symptoms (20% of patients), dizziness, tinnitus, headache, and rash. When piroxicam is used in dosages higher than 20 mg/d, an increased incidence of peptic ulcer and bleeding is encountered.
Clinical Pharmacology of the NSAIDs
All NSAIDs, including aspirin, are about equally efficacious with a few exceptions—tolmetin seems not to be effective for gout, and aspirin is less effective than other NSAIDs (eg, indomethacin) for ankylosing spondylitis. Thus, NSAIDs tend to be differentiated on the basis of toxicity and cost-effectiveness. For example, the gastrointestinal and renal side effects of ketorolac limit its use. Fries et al (1993), using a toxicity index, estimated that indomethacin, tolmetin, and meclofenamate were associated with the greatest toxicity, while salsalate, aspirin, and ibuprofen were least toxic. The selective COX-2 inhibitors were not included in this analysis.
For patients with renal insufficiency, nonacetylated salicylates may be best. Fenoprofen is less used because of its rare association with interstitial nephritis. Diclofenac and sulindac are associated with more liver function test abnormalities than other NSAIDs. The relatively expensive and selective COX-2 inhibitors are probably safest for patients at high risk for gastrointestinal bleeding. These drugs or a nonselective NSAID plus omeprazole or misoprostol may be appropriate in those patients at highest risk for gastrointestinal bleeding; in this subpopulation of patients, they are cost-effective despite their high acquisition costs.
The choice of an NSAID thus requires a balance of efficacy, cost-effectiveness, safety, and numerous personal factors (eg, other drugs also being used, concurrent illness, compliance, medical insurance coverage), so that there is no “best” NSAID for all patients. There may, however, be one or two best NSAIDs for a specific person.
Agents That Affect Bone Mineral Homeostasis
Calcium and phosphate, the major mineral constituents of bone, are also two of the most important minerals for general cellular function. Accordingly, the body has evolved a complex set of mechanisms by which calcium and phosphate homeostasis are carefully maintained (Figure 42–1).
Approximately 98% of the 1–2 kg of calcium and 85% of the
VItamin D
Vitamin D is a secosteroid produced in the skin from 7-dehydrocholesterol under the influence of ultraviolet irradiation. Vitamin D is also found in certain foods and is used to supplement dairy products. Both the natural form (vitamin D3, cholecalciferol) and the plant-derived form (vitamin D2, ergocalciferol) are present in the diet. These forms differ in that ergocalciferol contains a double bond (C22–23) and an additional methyl group in the side chain (Figure 42–2).
Vitamin D is a prohormone that serves as precursor to a number of biologically active metabolites (Figure 42–2). Vitamin D is first hydroxylated in the liver to form 25-hydroxyvitamin D (25[OH]D). This metabolite is further converted in the kidney to a number of other forms, the beststudied of which are 1,25-dihydroxyvitamin D (1,25[OH]2D) and 24,25-dihydroxyvitamin D (24,25[OH]2D). Of the natural metabolites, only vitamin D, 25(OH)D (as calcifediol), and 1,25(OH)2D (as calcitriol) are available for clinical use. Moreover, a number of analogs of 1,25(OH)2 are being synthesized in an effort to extend the usefulness of this metabolite to a variety of nonclassic conditions. Calcipotriene (calcipotriol), for example, is currently being used to treat psoriasis, a hyperproliferative skin disorder. Doxercalciferol and paricalcitol have recently been approved for the treatment of secondary hyperparathyroidism in patients with renal failure. Other analogs are being investigated for the treatment of various malignancies.
The regulation of vitamin D metabolism is complex, involving calcium, phosphate, and a variety of hormones, the most important of which is PTH, which stimulates the production of 1,25(OH)2D by the kidney. mechanism of action of the vitamin D metabolites remains under active investigation. However, calcitriol is well established as the most potent agent with respect to stimulation of intestinal calcium and phosphate transport and bone resorption. Calcitriol appears to act on the intestine both by induction of new protein synthesis (eg, calcium-binding protein) and by modulation of calcium flux across the brush border and basolateral membranes by a means does not require new protein synthesis. The molecular action of calcitriol on bone has received less attention. However, like PTH, calcitriol can induce RANK ligand in osteoblasts and proteins such as osteocalcin, which may regulate the mineralization process. The metabolites 25(OH)D and 24,25(OH)2D are far less potent stimulators of intestinal calcium and phosphate transport or bone resorption. However, 25(OH)D appears to be more potent than 1,25(OH)2D in stimulating renal reabsorption of calcium and phosphate and may be the major metabolite regulating calcium flux and contractility in muscle. Specific receptors for 1,25(OH)2D exist in target issues. However, the role and even the existence of receptors for 25(OH)D and 24,25(OH)2D remain controversial.
A summary of the principal actions of PTH and vitamin D on the three main target tissues— intestine, kidney, and bone—is presented in Table 42–2. The net effect of PTH is to raise serum calcium and reduce serum phosphate; the net effect of vitamin D is to raise both. Regulation of calcium and phosphate homeostasis is achieved through a variety of feedback loops. Calcium is the principal regulator of PTH secretion. It binds to a novel ion recognition site that is part of a Gq protein–coupled receptor and links changes in intracellular free calcium concentration to changes in the extracellular calcium.
As serum calcium levels rise and bind to this receptor, intracellular calcium levels increase and inhibit PTH secretion. Phosphate regulates PTH secretion indirectly by forming complexes with calcium in the serum. Since it is the ionized concentration of calcium that is detected by the parathyroid gland, increases in serum phosphate levels reduce the ionized calcium and lead to enhanced PTH secretion. Such feedback regulation is appropriate to the net effect of PTH to raise serum calcium and reduce serum phosphate levels. Likewise, both calcium and phosphate at high levels reduce the amount of 1,25(OH)2D produced by the kidney and increase the amount of 24,25(OH)2D produced. Since 1,25(OH)2D raises serum calcium and phosphate, whereas 24,25(OH)2D has less effect, such feedback regulation is again appropriate. 1,25(OH)2D itself directly inhibits PTH secretion (independently of its effect on serum calcium) by a direct action on PTH gene transcription. This provides yet another negative feedback loop, because PTH is a major stimulus for 1,25(OH)2D production. This ability of 1,25(OH)2D to inhibit PTH secretion directly is being exploited using calcitriol analogs that have less effect on serum calcium.
Such drugs are proving useful in the management of secondary hyperparathyroidism accompanying renal failure and may be useful in selected cases of primary hyperparathyroidism.
A number of hormones modulate the actions of PTH and vitamin D in regulating bone mineral homeostasis. Compared with that of PTH and vitamin D, the physiologic impact of such secondary regulation on bone mineral homeostasis is minor. However, in pharmacologic amounts, a number of these hormones have actions on the bone mineral homeostatic mechanisms that can be exploited therapeutically.
Calcitonin
The calcitonin secreted by the parafollicular cells of the mammalian thyroid is a single-chain peptide hormone with 32 amino acids and a molecular weight of
British Medical Research Council (MRC) and expressed as MRC units. Human calcitonin monomer has a half-life of about 10 minutes with a metabolic clearance of 8–9 mL/kg/min. Salmon calcitonin has a longer half-life and a reduced metabolic clearance (3 mL/kg/min), making it more attractive as a therapeutic agent. Much of the clearance occurs in the kidney, although little intact calcitonin appears in the urine.
The principal effects of calcitonin are to lower serum calcium and phosphate by actions on bone and kidney. Calcitonin inhibits osteoclastic bone resorption. Although bone formation is not impaired at first after calcitonin administration, with time both formation and resorption of bone are reduced.
Thus, the early hope that calcitonin would prove useful in restoring bone mass has not been realized. In the kidney, calcitonin reduces both calcium and phosphate reabsorption as well as reabsorption of other ions, including sodium, potassium, and magnesium. Tissues other than bone and kidney are also affected by calcitonin. Calcitonin in pharmacologic amounts decreases gastrin secretion and reduces gastric acid output while increasing secretion of sodium, potassium, chloride, and water in the gut. Pentagastrin is a potent stimulator of calcitonin secretion (as is hypercalcemia), suggesting a possible physiologic relationship between gastrin and calcitonin. In the adult human, no readily demonstrable problem develops in cases of calcitonin deficiency (thyroidectomy) or excess (medullary carcinoma of the thyroid). However, the ability of calcitonin to block bone resorption and lower serum calcium makes it a useful drug for the treatment of Paget’s disease, hypercalcemia, and osteoporosis.
Clinical Pharmacology
Disorders of bone mineral homeostasis generally present with abnormalities in serum or urine calcium levels (or both), often accompanied by abnormal serum phosphate levels. These abnormal mineral concentrations may themselves cause symptoms requiring immediate treatment (eg, coma in malignant hypercalcemia, tetany in hypocalcemia). More commonly, they serve as clues to an underlying disorder in hormonal regulators (eg, primary hyperparathyroidism), target tissue response (eg, chronic renal failure), or drug misuse (eg, vitamin D intoxication). In such cases, treatment of the underlying disorder is of prime importance.
Since bone and kidney play central roles in bone mineral homeostasis, conditions that alter bone mineral homeostasis usually affect either or both of these tissues secondarily. Effects on bone can result in osteoporosis (abnormal loss of bone; remaining bone histologically normal), osteomalacia (abnormal bone formation due to inadequate mineralization), or osteitis fibrosa (excessive bone resorption with fibrotic replacement of resorption cavities). Biochemical markers of skeletal involvement include changes in serum levels of the skeletal isoenzyme of alkaline phosphatase and
osteocalcin (reflecting osteoblastic activity) and urine levels of hydroxyproline and pyridinoline cross-links (reflecting osteoclastic activity). The kidney becomes involved when the calcium-timesphosphate product in serum exceeds the point at which ectopic calcification occurs (nephrocalcinosis) or when the calcium-times-oxalate (or phosphate) product in urine exceeds saturation, leading to nephrolithiasis. Subtle early indicators of such renal involvement include polyuria, nocturia, and hyposthenuria. Radiologic evidence of nephrocalcinosis and stones is not generally observed until later. The degree of the ensuing renal failure is best followed by monitoring the decline in creatinine clearance.
Abnormal Serum Calcium & Phosphate Levels
Hypercalcemia
Hypercalcemia causes central nervous system depression, including coma, and is potentially lethal. Its major causes (other than thiazide therapy) are hyperparathyroidism and cancer with or without bone metastases. Less common causes are hypervitaminosis D, sarcoidosis, thyrotoxicosis, milkalkali syndrome, adrenal insufficiency, and immobilization. With the possible exception of hypervitaminosis D, these latter disorders seldom require emergency lowering of serum calcium. A number of approaches are used to manage the hypercalcemic crisis.
Calcitonin
Calcitonin has proved useful as ancillary treatment in a large number of patients. Calcitonin by itself seldom restores serum calcium to normal, and refractoriness frequently develops. However, its lack of toxicity permits frequent administration at high doses (200 MRC units or more). An effect on serum calcium is observed within 4–6 hours and lasts for 6–10 hours. Calcimar (salmon calcitonin) is available for parenteral and nasal administration.
Calcium
A number of calcium preparations are available for intravenous, intramuscular, and oral use.
Calcium gluceptate (0.9 meq calcium/mL), calcium gluconate (0.45 meq calcium/mL), and calcium chloride (0.68–1.36 meq calcium/mL) are available for intravenous therapy. Calcium gluconate is the preferred form because it is less irritating to veins. Oral preparations include calcium carbonate (40% calcium), calcium lactate (13% calcium), calcium phosphate (25% calcium), and calcium citrate (21% calcium). Calcium carbonate is often the preparation of choice because of its high percentage of calcium, ready availability (eg, Tums), low cost, and antacid properties. In achlorhydric patients, calcium carbonate should be given with meals to increase absorption or the patient switched to calcium citrate, which is somewhat better absorbed. Combinations of vitamin D and calcium are available, but treatment must be tailored to the individual patient and individual disease, a flexibility lost by fixed-dosage combinations. Treatment of severe symptomatic hypocalcemia can be accomplished with slow infusion of 5–20 mL of 10% calcium gluconate.
Rapid infusion can lead to cardiac arrhythmias. Less severe hypocalcemia is best treated with oral forms sufficient to provide approximately 400–800 mg of elemental calcium (1–2 g calcium carbonate) per day. Dosage must be adjusted to avoid hypercalcemia and hypercalciuria.
Vitamin D
When rapidity of action is required, 1,25(OH)2D3 (calcitriol), 0.25–1 g daily, is the vitamin D metabolite of choice, since it is capable of raising serum calcium within 24–48 hours. Calcitriol also raises serum phosphate, though this action is usually not observed early in treatment. The combined effects of calcitriol and all other vitamin D metabolites and analogs on both calcium and phosphate make careful monitoring of these mineral levels especially important to avoid ectopic calcification secondary to an abnormally high serum calcium x phosphate product. Since the choice of the
levels of high-energy organic
Vitamin D deficiency, once thought to be rare in this country, is being recognized more often, especially in the pediatric and geriatric populations on vegetarian diets and with reduced sunlight exposure. This problem can be avoided by daily intake of 400–800 units of vitamin D and treated by higher dosages (4000 units per day). No other metabolite is indicated. The diet should also
contain adequate amounts of calcium and phosphate.
Use of Vitamin D Preparations
The choice of vitamin D preparation to be used in the setting of chronic renal failure in the dialysis patient depends on the type and extent of bone disease and hyperparathyroidism. No consensus has been reached regarding the advisability of using any vitamin D metabolite in the predialysis patient. 1,25(OH)2D3 (calcitriol) will rapidly correct hypocalcemia and at least partially reverse the secondary hyperparathyroidism and osteitis fibrosa. Many patients with muscle weakness and bone pain gain an improved sense of well-being.
Dihydrotachysterol, an analog of 1,25(OH)2D, is also available for clinical use, though it is used much less frequently than calcitriol. Dihydrotachysterol appears to be as effective as calcitriol, differing principally in its time course of action; calcitriol increases serum calcium in 1–2 days, whereas dihydrotachysterol requires 1–2 weeks. For an equipotent dose (0.2 mg dihydrotachy-sterol versus
Calcifediol (25[OH]D3) may also be used to advantage. Calcifediol is less effective than calcitriol in stimulating intestinal calcium transport, so that hypercalcemia is less of a problem with calcifediol.
Like dihydrotachysterol, calcifediol requires several weeks to restore normocalcemia in hypocalcemic individuals with chronic renal failure. Presumably because of the reduced ability of the diseased kidney to metabolize calcifediol to more active metabolites, high doses (50–100 g daily) must be given to achieve the supraphysiologic serum levels required for therapeutic effectiveness.
Vitamin D has been used in treating renal osteodystrophy. However, patients with a substantial degree of renal failure who are thus unable to convert vitamin D to its active metabolites usually are refractory to vitamin D. Its use is decreasing as more effective alternatives become available.
Two analogs of calcitriol, doxercalciferol and paricalcitol, are approved for the treatment of secondary hyperparathyroidism of chronic renal failure. Their principal advantage is that they are less likely than calcitriol to induce hypercalcemia. Their biggest impact will be in patients in whom the use of calcitriol may lead to unacceptably high serum calcium levels.
Regardless of the drug employed, careful attention to serum calcium and phosphate levels is required. Calcium supplements (dietary and in the dialysate) and phosphate restriction (dietary and with oral ingestion of phosphate binders) should be employed along with the use of vitamin D metabolites. Monitoring serum PTH and alkaline phosphatase levels is useful in determining whether therapy is correcting or preventing secondary hyperparathyroidism.
Although not generally available, percutaneous bone biopsies for quantitative histomorphometry may help in choosing appropriate therapy and following the effectiveness of such therapy. Unlike the rapid changes in serum values, changes in bone morphology require months to years. Monitoring serum levels of the vitamin D metabolites is useful to determine compliance, absorption, and metabolism.
The common features that appear to be important in this group of diseases are malabsorption of calcium and vitamin D. Liver disease may, in addition, reduce the production of 25(OH)D from vitamin D, though the importance of this in all but patients with terminal liver failure remains in dispute. The malabsorption of vitamin D is probably not limited to exogenous vitamin D. The liver secretes into bile a substantial number of vitamin D metabolites and conjugates that are reabsorbed in (presumably) the distal jejunum and ileum. Interference with this process could deplete the body of endogenous vitamin D metabolites as well as limit absorption of dietary vitamin D.
In mild forms of malabsorption, vitamin D (25,000–50,000 units three times per week) should suffice to raise serum levels of 25(OH)D into the normal range. Many patients with severe disease do not respond to vitamin D. Clinical experience with the other metabolites is limited, but both calcitriol and calcifediol have been used successfully in doses similar to those recommended for treatment of renal osteodystrophy. Theoretically, calcifediol should be the drug of choice under these conditions, since no impairment of the renal metabolism of 25(OH)D to 1,25(OH)2D and 24,25(OH)2D exists in these patients. Both calcitriol and 24,25(OH)2D may be of importance in reversing the bone disease. As in the other diseases discussed, treatment of intestinal osteodystrophy with vitamin D and its metabolites should be accompanied by appropriate dietary calcium supplementation and monitoring of serum calcium and phosphate levels.
Cromolyn sodium (disodium cromoglycate) and nedocromil sodium are stable but extremely insoluble salts (see structures below). When used as aerosols (metered-dose inhalers), they effectively inhibit both antigen- and exercise-induced asthma, and chronic use (four times daily) slightly reduces the overall level of bronchial reactivity. However, these drugs have no effect on airway smooth muscle tone and are Cromolyn is poorly absorbed from the gastrointestinal tract and must be inhaled as a microfine
powder or aerosolized solution. Nedocromil also has a very low bioavailability and is available only in metered-dose aerosol form. ineffective in reversing asthmatic bronchospasm; they are only of value when taken prophylactically.
Mechanism of Action
Cromolyn and nedocromil differ structurally but are thought to share a common mechanism of action, an alteration in the function of delayed chloride channels in the cell membrane, inhibiting cellular activation. This action on airway nerves is thought to be responsible for nedocromil’s inhibition of cough; on mast cells, for inhibition of the early response to antigen challenge; and on eosinophils, for inhibition of the inflammatory response to inhalation of allergens. The inhibitory effect on mast cells appears to be specific for cell type, since cromolyn has little inhibitory effect on mediator release from human basophils. It may also be specific for different organs, since cromolyn inhibits mast cell degranulation in human and primate lung but not in skin.
This in turn may reflect known differences in mast cells found in different sites, as in their neutral protease content.
Until recently, the idea that cromolyn inhibits mast cell degranulation was so well accepted that the inhibition of a response by cromolyn was thought to indicate the involvement of mast cells in the response. This simplistic idea has been overturned in part by the finding that cromolyn and nedocromil inhibit the function of cells other than mast cells and in part by the finding that nedocromil inhibits appearance of the late response even when given after the early response to antigen challenge, ie, after mast cell degranulation has occurred.
Clinical Use of Cromolyn & Nedocromil
In short-term clinical trials, pretreatment with cromolyn or nedocromil blocks the bronchoconstriction caused by antigen inhalation, by exercise, by aspirin, and by a variety of causes of occupational asthma. This acute protective effect of a single treatment makes cromolyn useful for administration shortly before exercise or before unavoidable exposure to an allergen.
When taken regularly (two to four puffs two to four times daily) by patients with perennial asthma, both agents reduce symptomatic severity and the need for bronchodilator medications. These drugsare neither as potent nor as predictably effective as inhaled corticosteroids. In general, young patients with extrinsic asthma are most likely to respond favorably. At present, the only way of determining whether a patient will respond is by a therapeutic trial for 4 weeks. The addition of nedocromil to a standard dose of an inhaled corticosteroid appears to improve asthma control.
Cromolyn solution is also useful in reducing symptoms of allergic rhinoconjunctivitis.
Because the drugs are so poorly absorbed, adverse effects of cromolyn and nedocromil are minor and are localized to the sites of deposition. These include such symptoms as throat irritation, cough, mouth dryness, chest tightness, and wheezing. Some of these symptoms can be prevented by inhaling a 2-adrenoceptor agonist before cromolyn or nedocromil treatment. Serious adverse effects are rare. Reversible dermatitis, myositis, or gastroenteritis occurs in fewer than 2% of patients, and a very few cases of pulmonary infiltration with eosinophilia and anaphylaxis have
been reported. This lack of toxicity accounts for cromolyn’s widespread use in children, especially those at ages of rapid growth. For children who have difficulty coordinating the use of the inhaler device, cromolyn may be given by aerosol of a 1% solution.
Immunosuppressant. Immunizing Agents. Immunomodulating Agents. Antineoplastic Agents
Immunosuppressive therapy is necessary for all transplant recipients in order to prevent immune system rejection of foreign tissue present in grafts. In the case of islet cell transplantation for the treatment of Type 1 Diabetes, there is the added complication of preventing autoimmune rejection of the new cells. In view of this issue and of the unfortunate diabetogenicity of many immunosuppressive medications, it is no wonder that it took 36 years from the discovery of the first effective immunosuppressant for researchers to determine how to reliably prevent the rejection of islet transplants.
Type 1 diabetes is an autoimmune disease which causes the body to attack healthy islet cells, a problem that can continue with transplanted islets. This process should be distinguished from allogeneic immune responses, which occur when the body’s immune system attacks tissue grafts because it does not recognize the surface antigens on the foreign cells.
This difference is highlighted by cases of identical twin donors and recipients. Normally, a graft recipient will not need immunosuppressants when he receives an organ from his identical twin because the cells in the graft will express the same surface antigens as the cells in his own body. However, a diabetic patient’s immune system will still reject islet cells taken from his twin due to the autoimmune nature of the disease. In fact, researchers strongly suspect that the majority of islet cell graft rejections are autologous rather than allogeneic.
In order to be effective, islet cell transplantations must be accompanied by medications that prevent autologous and allogeneic immune rejection and that do not have diebetogeneic or, ideally, nephrotoxic side effects. The failure of the immunosuppressants used in early islet transplant trials to meet these criteria ultimately played a crucial role in their failure.
In the early days of transplantation, surgeons relied on a combination of azathioprine, an anti-mitotic agent, and corticosteroids, which disrupt T-cell activation. In 1974, these medications were used during the first islet transplants. Not surprisingly, the trials were failures; not a single patient managed to achieve insulin independence. Later trials were able to realize some degree of success by improving islet purification methods and by switching from azathioprine to cyclosporine, which is much less toxic. However, the continued problem of autoimmunity, combined with the transplanted islets’ vulnerability to the toxic effects of immunosuppression, kept these gains modest.
The
There are two main problems with this method of treatment. One is the often serious side effects of sirolimus, which include mouth ulcerations, cholesterol and lipid problems, bone marrow damage, and pneumonia. The second is tacrolimus toxicity, which is believed, over time, to destroy the islet cells. For these reasons, many investigators are testing new medication protocols in an attempt to offer islet transplants with fewer complications.
Some researchers are also examining a technique called immunoisolation as a means to prevent immune rejection without the use of immunosuppressants. This approach entails isolating the transplanted cells in semipermeable membrane capsules. In theory this is an ideal solution, as the membrane would allow nutrients and insulin to pass in and out of the capsule while preventing the recipient’s antibodies from coming into contact with the islets. In practice, however, these capsules typically fail within months of transplantation due to cell overgrowth and to macrophages produced by the overgrowth. At the present time, immunoisolation does not present a viable alternative to immunosuppression. Further research in this area is needed to determine the plausibility of this approach being a solution for islet rejection in the future.
Fig. 1 Mechanisms of rejection of transplanted islets
Immunosuppression vs. insulin therapy in the treatment of type I diabetes: examining the trade-off
It is unfortunate that most researchers studying islet transplantation have failed to address the question of whether the advantage of insulin independence is worth the side effects of immunosuppression. In early trials, recipients of islet transplants included only those who had also received kidney transplants and would require immunosuppression anyway. However, the Edmonton Protocol has focused on patients who are not receiving kidney transplants.
All three immunosuppressant medications used for islet transplantation can cause severe side effects, including diarrhea, vomiting, fever, nausea, tremors, swelling of the limbs, weakness, and numerous other problems. In addition, the immunosuppressant daclizumab must be injected, so patients who achieve insulin independence are not completely free from needles.
A major advantage of islet transplantation is that patients need not constantly monitor their blood sugar levels, as the transplanted cells will adjust their insulin output in response to changes in blood sugar levels. Each immunosuppressive medication is taken once a day, while patients on insulin therapy often must test their blood and inject insulin several times a day.
However, on the whole, insulin therapy is effective for most type 1 diabetics. Although this population can suffer from hyperglycemia, high blood pressure, and coronary problems, the side effects of immunosuppression are often worse. It is possible that the immunosuppressive regimens of the future will have fewer side effects, tipping the scales in favor of islet transplantation, but for now, this new therapy should be reserved for type 1 diabetics who are either suffering severe symptoms that insulin therapy cannot alleviate or who are receiving immunosuppressive drugs for some other reason.
Acronyms
ABVD: Doxorubicin (adriamycin), bleomycin, vinblastine, dacarbazine
CHOP: Cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (oncovin),
prednisone
CMF: Cyclophosphamide, methotrexate, fluorouracil
COP: Cyclophosphamide, vincristine (oncovin), prednisone
FAC: Fluorouracil, doxorubicin (adriamycin), cyclophosphamide
FEC: Fluorouracil, epirubicin, cyclophosphamide
IFL: Irinotecan, fluorouracil, leucovorin
MP: Melphalan, prednisone
MOPP: Mechlorethamine, vincristine (oncovin), procarbazine, prednisone
PCV: Procarbazine, lomustine, vincristine
PEB: Cisplatin (platinum), etoposide, bleomycin
VAD: Vincristine, doxorubicin (adriamycin), dexamethasone
General
Cancer is basically a disease of cells characterized by a shift in the control mechanisms that govern cell proliferation and differentiation.
Cells that have undergone neoplastic transformation usually express cell surface antigens that may be of normal fetal type, may display other signs of apparent immaturity, and may exhibit qualitative or quantitative chromosomal abnormalities, including various translocations and the appearance of amplified gene sequences. Such cells proliferate excessively and form local tumors that can compress or invade adjacent normal structures. A small subpopulation of cells within the tumor can be described as tumor stem cells. They retain the ability to undergo repeated cycles of proliferation as well as to migrate to distant sites in the body to colonize various organs in the process called metastasis. Such tumor stem cells thus can express clonogenic or colony-forming capability. Tumor stem cells often have chromosome abnormalities reflecting their genetic instability, which leads to progressive selection of subclones that can survive more readily in the multicellular environment of the host. Quantitative abnormalities in various metabolic pathways and cellular components accompany this neoplastic progression. The invasive and metastatic processes as well as a series of metabolic abnormalities resulting from the cancer cause illness and eventual death of the patient unless the neoplasm can be eradicated with treatment.
Causes of Cancer
The incidence, geographic distribution, and behavior of specific types of cancer are related to multiple factors, including sex, age, race, genetic predisposition, and exposure to environmental carcinogens. Of these factors, environmental exposure is probably most important. Chemical carcinogens (particularly those in tobacco smoke) as well as azo dyes, aflatoxins, asbestos, and benzene have been clearly implicated in cancer induction in humans and animals. Identification of potential carcinogens in the environment has been greatly simplified by the widespread use of the Ames test for mutagenic agents. Ninety percent of carcinogens can be shown to be mutagenic with this assay. Ultimate identification of potential human carcinogens, however, requires testing in at least two animal species.
Certain herpes and papilloma group DNA viruses and type C RNA viruses have also been implicated as causative agents in animal cancers and are responsible for some human cancers as well. Oncogenic RNA viruses all appear to contain a reverse transcriptase enzyme that permits translation of the RNA message of the tumor virus into the DNA code of the infected cell. Thus, the information governing transformation can become a stable part of the genome of the host cell.
Expression of virus-induced neoplasia probably also depends on additional host and environmental factors that modulate the transformation process. A specific human retrovirus (HTLV-I) has been identified as being the causative agent for a specific type of human T cell leukemia. The virus that causes AIDS (HIV-1) is closely related. Cellular genes are known that are homologous to the transforming genes of the retroviruses, a family of RNA viruses, and induce oncogenic transformation. These mammalian cellular genes, known as oncogenes, have been shown to code for specific growth factors and their receptors and may be amplified (increased number of gene copies) or modified by a single nucleotide in malignant cells. The bcl-2 oncogene may be a generalized cell death suppressor gene that directly regulates apoptosis, a pathway of programmed cell death.
Another class of genes, tumor suppressor genes, may be deleted or damaged, with resulting neoplastic change. A single gene in this class, the p53 gene, has been shown to have mutated from a tumor suppressor gene to an oncogene in a high percentage of cases of several human tumors, including liver, breast, colon, lung, cervix, bladder, prostate, and skin. The normal wild form of this gene appears to play an important role in suppressing neoplastic transformation; mutations in this gene place the cell at high risk.
Cancer Therapeutic Modalities
Cancer is the second most common cause of death in the
Cancer chemotherapy, as currently employed, can be curative in certain disseminated neoplasms that have undergone either gross or microscopic spread by the time of diagnosis. These cancers include testicular cancer, non-Hodgkin’s lymphoma, Hodgkin’s disease, and choriocarcinoma as well as childhood cancers such as acute lymphoblastic leukemia, Burkitt’s lymphoma, Wilms’ tumor, and embryonal rhabdomyosarcoma. There are also growing numbers of cancers in which the use of chemotherapy combined with initial surgery can increase the cure rate in locally advanced early-stage breast cancer, esophageal cancer, rectal cancer, and osteogenic sarcoma.
For many other forms of disseminated cancer, chemotherapy provides palliative rather than curative therapy at present. Effective palliation results in temporary improvement of the symptoms and signs of cancer and enhancement in the overall quality of life. In the past decade, advances in cancer chemotherapy have also begun to provide evidence that chemical control of neoplasia may become a reality for many forms of cancer. This will probably be achieved through a combined-modality approach in which optimal combinations of surgery, radiotherapy, and chemotherapy are used to eradicate both the primary neoplasm and its occult micrometastases before gross spread can be detected on physical or x-ray examination. Use of hormonal agents to modulate tumor growth is playing an increasing role in hormone-responsive tumors thanks to the development of hormone antagonists and partial agonists. Several recombinant biologic agents have been identified as being active for cancer therapy, including interferon alfa and interleukin-2.
Anticancer Drug Development
A major effort to develop anticancer drugs through both empiric screening and rational design of new compounds has been under way for over 3 decades. Recent advances in this field have included the synthesis of peptides and proteins with recombinant DNA techniques and monoclonal antibodies. The drug development program has employed testing in a few well-characterized transplantable animal tumor systems. Simple in vitro assays for measuring drug sensitivity of a battery of human tumor cells augment and shorten the testing program and are used currently as the primary screening tests for new agents by the National Cancer Institute and many pharmaceutical firms. After new drugs with potential anticancer activity are identified, they are subjected to preclinical toxicologic and limited pharmacologic studies in animals. Other features of clinical testing are similar to the procedure for other drugs but may be accelerated. Ideal anticancer drugs would eradicate cancer cells without harming normal tissues. Unfortunately, no currently available agents meet this criterion, and clinical use of these drugs involves a weighing of benefits against toxicity in a search for a favorable therapeutic index.
Classes of drugs that have recently entered clinical development include signal transduction inhibitors, focused on critical signaling pathways essential for cell growth and proliferation; microtubule inhibitors, directed against the mitotic spindle apparatus; differentiation agents, intended to force neoplastic cells past a maturation block to form end-stage cells with little or no proliferative potential; antimetastatic drugs, designed to perturb surface properties of malignant cells and thus alter their invasive and metastatic potential; antiangiogenic agents, designed to inhibit the formation of tumor vasculature; hypoxic tumor stem cell-specific agents, designed to exploit the greater capacity for reductive reactions in these often therapeutically resistant cells; tumor radiosensitizing and normal tissue radioprotecting drugs, aimed at increased therapeutic effectiveness of radiation therapy; cytoprotective agents, focused on protecting certaiormal tissues against the toxic effects of chemotherapy; and biologic response modifiers, which alter tumor-host metabolic and immunologic relationships.
Importance of Neoplastic Cell Burden
Patients with widespread cancer may have up to 1012 tumor cells throughout the body at the time of diagnosis (Figure 55–1). If tolerable dosing of an effective drug is capable of killing 99.99% of clonogenic tumor cells, treatment would induce a clinical remission of the neoplasm associated with symptomatic improvement. However, there would still be up to 8 logs of tumor cells (108) remaining in the body, including those that might be inherently resistant to the drug because of tumor heterogeneity. There may also be other tumor cells that reside in pharmacologic sanctuary sites (eg, the central nervous system, testes), where effective drug concentrations may be difficult to achieve. When cell cycle-specific drugs are used, the tumor stem cells must also be in the sensitive phase of the cell cycle (not in G0). For this reason, scheduling of these agents is particularly important. In common bacterial infections, a three-log reduction in microorganisms might be curative because host resistance factors can eliminate residual bacteria through immunologic and microbicidal mechanisms; however, host mechanisms for eliminating even moderate numbers of cancer cells appear to be generally ineffective.
Combinations of agents with differing toxicities and mechanisms of action are often employed to overcome the limited log kill of individual anticancer drugs. If drugs display nonoverlapping toxicities, they can be used at almost full dosage, and at least additive cytotoxic effects can be achieved with combination chemotherapy; furthermore, subclones resistant to only one of the agents can potentially be eradicated. Some combinations of anticancer drugs also appear to exert true synergism, wherein the effect of the two drugs is greater than additive. The efficacy of combination chemotherapy has now been validated in many forms of human cancer, and the scientific rationale appears to be sound. As a result, combination chemotherapy is now the standard approach to curative treatment of testicular cancer and lymphomas and to palliative treatment of many other tumor types. This important therapeutic approach was first formulated by Skipper and Schabel and described as the log-kill hypothesis (Figure 55–1).
Growth of acute leukemias and aggressive lymphomas closely follows exponential cell kinetics. In contrast, most human solid tumors do not grow in such a manner; instead, they follow a Gompertzian model of tumor growth and regression. Under Gompertzian kinetics, the growth fraction of the tumor is not constant and peaks when the tumor is about one third of its maximum size.
Importance of Cell Cycle Kinetics
Information on cell and population kinetics of cancer cells explains, in part, the limited effectiveness of most available anticancer drugs. A schematic summary of cell cycle kinetics is presented in Figure 55–2. This information is relevant to the mode of action, indications, and scheduling of cell cycle-specific (CCS) and cell cycle-nonspecific (CCNS) drugs. Agents falling into these two major classes are summarized.
In general, CCS drugs are most effective in hematologic malignancies and in solid tumors in which a relatively large proportion of the cells are proliferating or are in the growth fraction. CCNS drugs (many of which bind to cellular DNA and damage these macromolecules) are particularly useful in low growth fraction solid tumors as well as in high growth fraction tumors. In all instances, effective agents sterilize or inactivate tumor stem cells, which are often only a small fraction of the cells within a tumor. Non-stem cells (eg, those that have irreversibly differentiated) are considered sterile by definition and are not a significant component of the cancer problem.
Resistance to Cytotoxic Drugs
A major problem in cancer chemotherapy is drug resistance. Some tumor types, eg, malignant melanoma, renal cell cancer, and brain cancer, exhibit primary resistance, ie, absence of response on the first exposure, to currently available standard agents. The presence of inherent drug resistance is felt to be tightly associated with the genomic instability associated with the development of most cancers. Acquired resistance develops in a number of drug-sensitive tumor types. Experimentally, drug resistance can be highly specific to a single drug and usually is based on a change in the genetic apparatus of a given tumor cell with amplification or increased expression of one or more specific genes. In other instances, a multidrug-resistant phenotype occurs—resistance to a variety of natural product anticancer drugs of differing structures developing after exposure to a single agent. This form of multidrug resistance is often associated with increased expression of a normal gene (the MDR1 gene) for a cell surface glycoprotein (Pglycoprotein) involved in drug efflux. This transport molecule requires ATP to expel a variety of foreign molecules (not limited to antitumor drugs) from the cell. It is expressed constitutively in normal tissues such as the epithelial cells of the kidney, large intestine, and adrenal gland as well as in a variety of tumors. Multidrug resistance can be reversed experimentally by calcium channel blockers, such as verapamil, and a variety of other drugs, which inhibit the transporter. Other mechanisms of multiple drug resistance involve overexpression of the multidrug resistance protein 1 (MRP1), a member of the ATP-binding cassette transmembrane transporter superfamily that now consists of nine members (MRP1-MRP9). MRP1, the most extensively studied, increases resistance to natural product drugs such as anthracyclines, vinca alkaloids, taxanes, and epipodophyllotoxins by functioning as a drug export pump.
Basic Pharmacology of Cancer Chemotherapeutic Drugs
Polyfunctional Alkylating Agents
The major clinically useful alkylating agents (Figure 55–3) have a structure containing a bis- (chloroethyl)amine, ethyleneimine, or nitrosourea moiety. Among the bis(chloroethyl)amines, cyclophosphamide, mechlorethamine, melphalan, and chlorambucil are the most useful. Ifosfamide is closely related to cyclophosphamide but has a somewhat different spectrum of activity and toxicity. Thiotepa and busulfan are used for specialized purposes for ovarian cancer and chronic myeloid leukemia, respectively. The major nitrosoureas are carmustine (BCNU), lomustine (CCNU), and semustine (methyl-CCNU). A variety of investigational alkylating agents have been synthesized that link various carrier molecules such as amino acids, nucleic acid bases, hormones, or sugar moieties to a group capable of alkylation; however, successful site-directed alkylation has not been achieved to date.
As a class, the alkylating agents exert cytotoxic effects via transfer of their alkyl groups to various cellular constituents. Alkylations of DNA within the nucleus probably represent the major interactions that lead to cell death. However, these drugs react chemically with sulfhydryl, amino, hydroxyl, carboxyl, and phosphate groups of other cellular nucleophiles as well. The general mechanism of action of these drugs involves intramolecular cyclization to form an ethyleneimonium ion that may directly or through formation of a carbonium ion transfer an alkyl group to a cellular constituent. In addition to alkylation, a secondary mechanism that occurs with nitrosoureas involves carbamoylation of lysine residues of proteins through formation of isocyanates.
The major site of alkylation within DNA is the N7 position of guanine (Figure 55–4); however, other bases are also alkylated to lesser degrees, including N1 and N3 of adenine, N3 of cytosine, and O6 of guanine, as well as phosphate atoms and proteins associated with DNA. These interactions can occur on a single strand or on both strands of DNA through cross-linking, as most major alkylating agents are bifunctional, with two reactive groups. Alkylation of guanine can result in miscoding through abnormal base pairing with thymine or in depurination by excision of guanine residues. The latter effect leads to DNA strand breakage through scission of the sugar-phosphate backbone of DNA. Cross-linking of DNA appears to be of major importance to the cytotoxic action of alkylating agents, and replicating cells are most susceptible to these drugs. Thus, although alkylating agents are not cell cycle-specific, cells are most susceptible to alkylation in late G1 and S phases of the cell cycle and express block in G2.
Drug Resistance
The mechanism of acquired resistance to alkylating agents may involve increased capability to repair DNA lesions, decreased permeability of the cell to the alkylating drug, and increased production of glutathione, which inactivates the alkylating agent through conjugation or through increased glutathione S-transferase activity, which catalyzes the conjugation.
Pharmacologic Effects
Active alkylating agents have direct vesicant effects and can damage tissues at the site of injection as well as produce systemic toxicity. Toxicities are generally dose-related and occur particularly in rapidly growing tissues such as bone marrow, the gastrointestinal tract, and the reproductive system.
After intravenous injection, nausea and vomiting usually occur within 30–60 minutes with mechlorethamine, cyclophosphamide, or carmustine. The emetogenic effects are mediated by the central nervous system and can be reduced by pretreatment with 5-HT3 (serotonin) receptor antagonists such as ondansetron or granisetron. Subcutaneous injection of mechlorethamine or carmustine leads to tissue necrosis and sloughing.
Cyclophosphamide in its parent form does not have direct cytotoxic effects, and it must be activated to cytotoxic forms by microsomal enzymes (Figure 55–5). The liver microsomal cytochrome P450 mixed-function oxidase system converts cyclophosphamide to 4-hydroxycyclophosphamide, which is in equilibrium with aldophosphamide. These active metabolites are believed to be delivered by the bloodstream to both tumor and normal tissue, where nonenzymatic cleavage of aldophosphamide to the cytotoxic forms—phosphoramide mustard and acrolein—occurs. The liver appears to be protected through the enzymatic formation of the inactive metabolites 4- ketocyclophosphamide and carboxyphosphamide.
Oral administration of alkylating agents has been of great value, and this approach has been developed using relatively less reactive alkylating drugs. Cyclophosphamide, melphalan, chlorambucil, busulfan, and, more recently, temozolomide are those most commonly given via the oral route, and their cytotoxic effects are similar to those observed with parenteral administration. In general, if a tumor is resistant to one alkylating agent, it will be relatively resistant to other agents of this class (though not necessarily to nitrosoureas); however, there are exceptions to this rule depending on the specific tumor. Cyclophosphamide is the most widely used alkylating agent. The oral drug busulfan has a major degree of specificity for the granulocyte series and is therefore of particular value in therapy of chronic myelogenous leukemia. With all oral alkylating agents, some degree of leukopenia is necessary to provide evidence that the drug has been absorbed adequately.
Frequent monitoring of blood counts is essential during administration of these agents as the development of severe leukopenia or thrombocytopenia necessitates immediate interruption of therapy.
Nitrosoureas
These drugs appear to be non-cross-resistant with other alkylating agents; all require biotransformation, which occurs by nonenzymatic decomposition, to metabolites with both alkylating and carbamoylating activities. The nitrosoureas are highly lipid-soluble and cross the blood-brain barrier, making them useful in the treatment of brain tumors. The nitrosoureas appear to function by cross-linking through alkylation of DNA. The drugs may be more effective against plateau phase cells than exponentially growing cells, though within a cycling cell population these agents appear to slow cell progression through the DNA synthetic phase.
After oral administration of lomustine, peak plasma levels of metabolites appear within 1–4 hours; central nervous system concentrations reach 30–40% of the activity present in the plasma. While the initial plasma half-life is in the range of 6 hours, a second half-life is in the range of 1–2 days. Urinary excretion appears to be the major route of elimination from the body. One naturally occurring sugar-containing nitrosourea, streptozocin, is interesting because it has minimal bone marrow toxicity. This agent has activity in the treatment of insulin-secreting islet cell carcinoma of the pancreas.
Related Drugs Probably Acting As Alkylating Agents
A variety of other compounds have mechanisms of action that involve alkylation. These include procarbazine, dacarbazine, altretamine (hexamethylmelamine), cisplatin, and carboplatin. Dosages and major toxicities are listed in Table 55–2.
Dacarbazine
Dacarbazine is a synthetic compound that functions as an alkylating agent following metabolic activation by liver microsomal enzymes by oxidative N-demethylation to the monomethyl derivative. This metabolite spontaneously decomposes to 5-aminoimidazole-4-carboxamide, which is excreted in the urine, and diazomethane. The diazomethane generates a methyl carbonium ion that is believed to be the likely cytotoxic species. Dacarbazine is administered parenterally and is not schedule-dependent. It produces marked nausea, vomiting, and myelosuppression. Its major applications are in melanoma, Hodgkin’s disease, and soft tissue sarcomas.
Altretamine (Hexamethylmelamine)
Altretamine is structurally similar to triethylenemelamine. It is relatively insoluble and available only in oral form. It is rapidly biotransformed in the liver by demethylation to the pentamethylmelamine and tetramethylmelamine metabolites. This agent is approved for use in ovarian cancer patients who have progressed despite treatment with a regimen based on platinum or an alkylating agent (or both). The main dose-limiting toxicities include nausea, vomiting, and myelosuppression. Neurotoxicity in the form of somnolence, mood changes, and peripheral neuropathy is also observed.
Cisplatin, Carboplatin, & Oxaliplatin
Cisplatin (cis-diamminedichloroplatinum [II]) is an inorganic metal complex discovered through the serendipitous observation that neutral platinum complexes inhibited division and induced filamentous growth of Escherichia coli. Several platinum analogs have been subsequently synthesized. While the precise mechanism of action of cisplatin is still undefined, it is thought to act in somewhat the same way as alkylating agents. It kills cells in all stages of the cell cycle, inhibits DNA biosynthesis, and binds DNA through the formation of interstrand cross-links. The primary binding site is the N7 of guanine, but covalent interaction with adenine and cytosine also occurs. The platinum complexes appear to synergize with certain other anticancer drugs. Aggressive hydration with intravenous saline infusion alone or with saline and mannitol or other diuretics appears to significantly reduce the incidence of nephrotoxicity.
Cisplatin has major antitumor activity in a broad range of solid tumors, including non-small cell and small cell lung cancer, esophageal and gastric cancer, head and neck cancer, and genitourinary cancers, particularly testicular, ovarian, and bladder cancer. When used in combination regimens with vinblastine and bleomycin or etoposide and bleomycin, cisplatin-based therapy has led to the cure of nonseminomatous testicular cancer.
Carboplatin is a second-generation platinum analog that exerts its cytotoxic effects exactly as cisplatin and has activity against the same spectrum of solid tumors. Its main dose-limiting toxicity is myelosuppression, and it has significantly less renal toxicity and gastrointestinal toxicity than cisplatin. Moreover, vigorous intravenously hydration is not required. As a result, carboplatin is now being used in place of cisplatin in combination chemotherapy.
Oxaliplatin is a third generation diaminocyclohexane platinum analog. Its mechanism of action is identical to that of cisplatin and carboplatin. However, it is not cross-resistant to cancer cells that are resistant to cisplatin or carboplatin on the basis of mismatch repair defects. This agent was recently approved for use as second-line therapy in metastatic colorectal cancer following treatment with the combination of fluorouracil-leucovorin and irinotecan, and it is now widely used as firstline therapy of this disease as well. Neurotoxicity is dose-limiting and characterized by a peripheral sensory neuropathy, often triggered or worsened upon exposure to cold. While this neurotoxicity is cumulative, it tends to be reversible—in contrast to cisplatin-induced neurotoxicity.
Clinical Uses of the Alkylating Agents
The alkylating agents are used in the treatment of a wide variety of hematologic and solid cancers, generally as part of a combination regimen. They are discussed along with various specific tumors (below).
Antimetabolites (Structural Analogs)
The development of drugs with actions on intermediary metabolism of proliferating cells has been important both clinically and conceptually. While biochemical properties unique to all cancer cells have yet to be discovered, neoplastic cells do have a number of quantitative differences in metabolism from normal cells that render them more susceptible to a number of antimetabolites or structural analogs. Many of these agents have been rationally designed and synthesized based on knowledge of cellular processes, and a few have been discovered as antibiotics.
Mechanisms of Action
The biochemical pathways that have thus far proved to be most vulnerable to antimetabolites have been those relating to nucleotide and nucleic acid synthesis. In a number of instances, when an enzyme is known to have a major effect on pathways leading to cell replication, inhibitors of the reaction it catalyzes have proved to be useful anticancer drugs.
These drugs and their doses and toxicities are shown in Table 55–3. The principal drugs are discussed below.
Methotrexate
Methotrexate (MTX) is a folic acid antagonist that binds to the active catalytic site of dihydrofolate reductase (DHFR), interfering with the synthesis of the reduced form that accepts one-carbon units.
Lack of this cofactor interrupts the synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine, thereby interfering with the formation of DNA, RNA, and proteins.
The enzyme binds methotrexate with high affinity, and at pH 6.0, virtually no dissociation of the enzyme-inhibitor complex occurs (inhibition constant about 1 nmol/L). At physiologic pH, reversible competitive kinetics occur (inhibition constant about 1 mol/L). Intracellular formation of polyglutamate derivatives appears to be important in the therapeutic action of methotrexate. The polyglutamates of methotrexate are selectively retained within cancer cells and have increased inhibitory effects on enzymes involved in folate metabolism, making them important determinants of the duration of action of methotrexate.
Drug Resistance
Tumor cell resistance to methotrexate has been attributed to (1) decreased drug transport, (2) decreased polyglutamate formation, (3) synthesis of increased levels of DHFR through gene amplification, and (4) altered DHFR with reduced affinity for methotrexate. Recent studies have also suggested that decreased accumulation of drug through activation of the multidrug resistance P170 glycoprotein transporter may also result in drug resistance.
Dosage & Toxicity
Methotrexate is administered by the intravenous, intrathecal, or oral route. Up to 90% of an oral dose is excreted in the urine within 12 hours. The drug is not subject to metabolism, and serum levels are therefore proportionate to dose as long as renal function and hydration status are adequate. Dosages and toxic effects are listed in Table 55–3. The effects of methotrexate can be reversed by administration of leucovorin (citrovorum factor). Leucovorin rescue has been used with accidental overdose or experimentally along with high-dose methotrexate therapy in a protocol intended to rescue normal cells while still leaving the tumor cells subject to its cytotoxic action.
Other Applications
Methotrexate is also used in the treatment of rheumatoid arthritis (Chapter 36: Nonsteroidal Anti- Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout) and psoriasis.
Purine Antagonists
6-Thiopurines
Mercaptopurine (6-MP) was the first of the thiopurine series found useful as an anticancer drug. Like other thiopurines, it must be metabolized by hypoxanthine-guanine phosphoribosyl transferase (HGPRT) to the nucleotide form (6-thioinosinic acid), which in turn inhibits a number of the enzymes of purine nucleotide interconversion. Significant amounts of thioguanylic acid and 6- methylmercaptopurine ribotide (MMPR) are also formed from 6-MP. These metabolites may also contribute to the action of the mercaptopurine. Mercaptopurine is used primarily in the treatment of childhood acute leukemia, and a closely related analog, azathioprine, is used as an immunosuppressive agent.
Thioguanine (6-TG) inhibits several enzymes in the purine nucleotide pathway. A variety of metabolic lesions are associated with the cytotoxic action of the purinethiols. These include inhibition of purine nucleotide interconversion; decrease in intracellular levels of guanine nucleotides, which leads to inhibition of glycoprotein synthesis; interference with the formation of DNA and RNA; and incorporation of thiopurine nucleotides into both DNA and RNA. 6-TG has a synergistic action when used together with cytarabine in the treatment of adult acute leukemia.
Drug Resistance
Resistance to both 6-MP and 6-TG occurs most commonly by decrease in HGPRT activity; an alternative mechanism in acute leukemia involves elevation of levels of alkaline phosphatase, which results in dephosphorylation of thiopurine nucleotide and cellular loss of the resulting ribonucleoside.
Dosage & Toxicity
Mercaptopurine and thioguanine are both given orally (Table 55–3) and excreted mainly in the urine. However, 6-MP is converted to an inactive metabolite (6-thiouric acid) by an oxidation catalyzed by xanthine oxidase, whereas 6-TG requires deamination before it is metabolized by this enzyme. This factor is important because the purine analog allopurinol, a potent xanthine oxidase inhibitor, is frequently used with chemotherapy in hematologic cancers to prevent hyperuricemia after tumor cell lysis. It does this by blocking purine oxidation, allowing excretion of cellular purines that are relatively more soluble than uric acid. Nephrotoxicity and acute gout produced by excessive uric acid are thereby prevented. Simultaneous therapy with allopurinol and 6-MP results in excessive toxicity unless the dose of mercaptopurine is reduced to 25% of the usual level.
This effect does not occur with 6-TG, which can be used in full doses with allopurinol.
Pyrimidine Antagonists
Fluorouracil
5-Fluorouracil (5-FU) is a prodrug and undergoes a complex series of biotransformation reactions to ribosyl and deoxyribosyl nucleotide metabolites. One of these metabolites, 5-fluoro-2′- deoxyuridine-5′-monophosphate (FdUMP), forms a covalently bound ternary complex with the enzyme thymidylate synthase and the reduced folate N5,10- methylenetetrahydrofolate, a reaction critical for the synthesis of thymidylate. This results in inhibition of DNA synthesis through
“thymineless death.” 5-FU is converted to 5-fluorouridine-5′-triphosphate (FUTP), which is then incorporated into RNA, where it interferes with RNA processing and mRNA translation. In addition, 5-FU is converted to 5-fluorodeoxyuridine-5′-triphosphate (FdUTP), which can be incorporated into cellular DNA, resulting in inhibition of DNA synthesis and function. Thus, the cytotoxicity of fluorouracil is felt to be the result of effects on both DNA- and RNA-mediated events.
Fluorouracil is normally given intravenously (Table 55–3) and has a short metabolic half-life on the order of 15 minutes. It is not administered by the oral route because its bioavailability is erratic due to the high levels of the breakdown enzyme dihydropyrimidine dehydrogenase present in the gut mucosa. Floxuridine (5-fluoro-2′-deoxyuridine, FUDR) has an action similar to that of fluorouracil, and it is only used for hepatic artery infusions. A cream incorporating fluorouracil is used topically for treating basal cell cancers of the skin.
Fluorouracil is the most widely used agent for the treatment of colorectal cancer, both as adjuvant therapy as well as for advanced disease. In addition, it has activity against a wide variety of solid tumors, including cancers of the breast, stomach, pancreas, esophagus, liver, head and neck, and anus. Its major toxicities are listed in Table 55–3.
Plant Alkaloids
VInblastine
Vinblastine is an alkaloid derived from Vinca rosea, the periwinkle plant. Its mechanism of action involves depolymerization of microtubules, which are an important part of the cytoskeleton and the mitotic spindle. The drug binds specifically to the microtubule protein tubulin in dimeric form; the drug-tubulin complex adds to the forming end of the microtubules to terminate assembly, and depolymerization of the microtubules then occurs. This results in mitotic arrest at metaphase, dissolution of the mitotic spindle, and interference with chromosome segregation. Toxicity includes nausea and vomiting, bone marrow suppression, and alopecia. It has clinical activity in the treatment of Hodgkin’s disease, non-Hodgkin’s lymphomas, breast cancer, and germ cell cancer. See clinical section below and Table 55–4.
VIncristine
Vincristine is also an alkaloid derivative of Vinca rosea and is closely related in structure to vinblastine. Its mechanism of action is considered to be identical to that of vinblastine in that it functions as a mitotic spindle poison leading to arrest of cells in the M phase of the cell cycle. Despite these similarities to vinblastine, vincristine has a strikingly different spectrum of clinical activity and qualitatively different toxicities.
Vincristine has been effectively combined with prednisone for remission induction in acute lymphoblastic leukemia in children. It is also active in various hematologic malignancies such as Hodgkin’s and non-Hodgkin’s lymphoma and
multiple myeloma and in several pediatric tumors including rhabdomyosarcoma, neuroblastoma, Ewing’s sarcoma, and Wilms’ tumor. The main doselimiting toxicity is neurotoxicity, usually expressed as a peripheral sensory neuropathy, although autonomic nervous system dysfunction—with orthostatic hypotension, sphincter problems, and paralytic ileus—cranial nerve palsies, ataxia, seizures, and coma have been observed. While myelosuppression can occur, it is generally milder and much less significant than with vinblastine.
The other potential side effect that can develop is the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).
VInorelbine
Vinorelbine is a semisynthetic vinca alkaloid whose mechanism of action is identical to that of vinblastine and vincristine, ie, inhibition of mitosis of cells in the M phase through inhibition of tubulin polymerization. Despite its similarities in mechanism of action, vinorelbine has activity ion-small cell lung cancer and in breast cancer. Myelosuppression with neutropenia is the doselimiting toxicity, but nausea and vomiting, transient elevations in liver function tests, neurotoxicity, and SIADH are also reported.
Epipodophyllotoxins
Two compounds, VP-16 (etoposide) and a related drug, VM-26 (teniposide), are semisynthetic derivatives of podophyllotoxin, which is extracted from the mayapple root (Podophyllum peltatum).
Both an intravenous and an oral formulation of etoposide are approved for clinical use in the USA. Etoposide and teniposide are similar in chemical structure and in their effects—they block cell division in the late S-G2 phase of the cell cycle. Their primary mode of action involves inhibition of topoisomerase II, which results in DNA damage through strand breakage induced by the formation of a ternary complex of drug, DNA, and enzyme. The drugs are water-insoluble and need to be formulated in a Cremophor vehicle for clinical use. These agents are administered via the intravenous route (Table 55–4) and are rapidly and widely distributed throughout the body except for the brain. Up to 90–95% of drug is protein-bound, mainly to albumin. Dose reduction is required in the setting of renal dysfunction. Etoposide has clinical activity in germ cell cancer, small cell and non-small cell lung cancer, Hodgkin’s and non-Hodgkin’s lymphomas, and gastric cancer and as high-dose therapy in the transplant setting for breast cancer and lymphomas. Teniposide’s use is limited to acute lymphoblastic leukemia.
Antitumor Antibiotics
Screening of microbial products has led to the discovery of a number of growth inhibiting compounds that have proved to be clinically useful in cancer chemotherapy. Many of these antibiotics bind to DNA through intercalation between specific bases and block the synthesis of RNA, DNA, or both; cause DNA strand scission; and interfere with cell replication. All of the anticancer antibiotics now being used in clinical practice are products of various strains of the soil microbe Streptomyces. These include the anthracyclines, dactinomycin, bleomycin, and mitomycin.
Anthracyclines
The anthracycline antibiotics, isolated from Streptomyces peucetius var caesius, are among the most widely used cytotoxic anticancer drugs. Two congeners, doxorubicin and daunorubicin, are FDAapproved, and their structures are shown below. Several other anthracycline analogs have entered clinical practice, including idarubicin, epirubicin, and mitoxantrone. Daunorubicin was the first agent in this class to be isolated, and it is still used in the treatment of acute myeloid leukemia.
Doxorubicin has a broad spectrum of clinical activity against hematologic malignancies as well as a wide range of solid tumors. The entire class of anthracyclines exert their cytotoxic action through four major mechanisms. These are (1) inhibition of topoisomerase II; (2) high-affinity binding to DNA through intercalation, with consequent blockade of the synthesis of DNA and RNA, and DNA strand scission; (3) binding to cellular membranes to alter fluidity and ion transport; and (4) generation of semiquinone free radicals and oxygen free radicals through an enzyme-mediated reductive process. This latter mechanism has now been established as being the cause of the drug’s cardiac toxicity.
In the clinical setting, anthracyclines are administered via the intravenous route (Table 55–4). The anthracyclines are metabolized extensively in the liver, with reduction and hydrolysis of the ring substituents. The hydroxylated metabolite is an active species, whereas the aglycone is inactive. Up to 50% of drug is eliminated in the feces via biliary excretion, and for this reason dose reduction is required in the setting of liver dysfunction. Although anthracyclines are usually administered on an every-3-week schedule, alternative schedules of administration such as low-dose weekly or 72–96 hour continuous infusions have been shown to yield equivalent clinical efficacy with reduced overall toxicity.
Doxorubicin is one of the most important anticancer drugs, with major clinical activity in carcinomas of the breast, endometrium, ovary, testicle, thyroid, stomach, bladder, liver, and lung; in soft tissue sarcomas; and in several childhood cancers, including neuroblastoma, Ewing’s sarcoma, osteosarcoma, and rhabdomyosarcoma. It is also widely used in hematologic malignancies, including acute lymphoblastic leukemia, multiple myeloma, and Hodgkin’s and non-Hodgkin’s lymphomas. It is generally used in combination with other anticancer agents (eg, cyclophosphamide, cisplatin, and fluorouracil), and responses and remission duration tend to be improved with combination regimens as opposed to single-agent therapy. Daunorubicin has a far narrower spectrum of activity than doxorubicin. Daunorubicin has been mainly used for the treatment of acute myeloid leukemia, although there has been a shift in clinical practice toward using idarubicin, an analog of daunorubicin. Its efficacy in solid tumors appears to be limited.
Idarubicin is a semisynthetic anthracycline glycoside analog of daunorubicin and is approved for use in combination with cytarabine for induction therapy of acute myeloid leukemia. When combined with cytarabine, idarubicin appears to be more active than daunorubicin in producing complete remissions and in improving survival in patients with acute myelogenous leukemia.
Epirubicin is a doxorubicin analog whose mechanism of action is identical to that of all other anthracyclines. It was initially approved for use as a component of adjuvant therapy of early-stage, node-positive breast cancer but is now also used for the treatment of metastatic breast cancer.
The main dose-limiting toxicity of all anthracyclines is myelosuppression, with neutropenia more commonly observed than thrombocytopenia. In some cases, mucositis is dose-limiting. Two forms of cardiotoxicity are observed. The acute form occurs within the first 2–3 days and presents as arrhythmias or conduction abnormalities, other electrocardiographic changes, pericarditis, and myocarditis. This form is usually transient and is asymptomatic in most cases. The chronic form
results in a dose-dependent, dilated cardiomyopathy associated with heart failure. The chronic cardiac toxicity appears to result from increased production of free radicals within the myocardium.
This effect is rarely seen at total doxorubicin dosages below 500–550 mg/m2. Use of lower weekly doses or continuous infusions of doxorubicin appear to reduce the incidence of cardiac toxicity. In addition, treatment with the iron-chelating agent dexrazoxane (ICRF-187) is currently approved to prevent or reduce anthracycline-induced cardiotoxicity in women with metastatic breast cancer who have received a total cumulative dose of doxorubicin of 300 mg/m2. All anthracyclines can produce “radiation recall reaction,” with erythema and desquamation of the skin observed at sites of prior radiation therapy.
Mitoxantrone
Mitoxantrone (dihydroxyanthracenedione, DHAD) is an anthracene compound whose structure resembles the anthracycline ring. It binds to DNA to produce strand breakage and inhibits both DNA and RNA synthesis. It is currently used for treatment of advanced, hormone-refractory prostate cancer and low-grade non-Hodgkin’s lymphoma. It is also indicated in breast cancer as well as in pediatric and adult acute myeloid leukemias. The plasma half-life of mitoxantrone in patients is approximately 75 hours, and it is predominantly excreted via the hepatobiliary route in feces.
Myelosuppression with leukopenia is the dose-limiting toxicity, and mild nausea and vomiting, mucositis, and alopecia also occur. While the drug is felt to be less cardiotoxic than doxorubicin, both acute and chronic cardiac toxicity are reported. A blue discoloration of the fingernails, sclera, and urine can be observed up to 1–2 days after drug therapy.
Dactinomycin
Dactinomycin is an antitumor antibiotic isolated from a Streptomyces organism. It binds tightly to double-stranded DNA through intercalation between adjacent guanine-cytosine base pairs and inhibits all forms of DNA-dependent RNA synthesis, with ribosomal RNA formation being most sensitive to drug action.
Dactinomycin is mainly used to treat pediatric tumors such as Wilms’ tumor, rhabdomyosarcoma, and Ewing’s sarcoma, but it has activity also against germ cell tumors and gestational trophoblastic disease. Dactinomycin can also induce a “radiation recall reaction.” See Table 55–4 for other toxicities.
Hormonal Agents
Steroid Hormones & Antisteroid Drugs
The relationship between hormones and hormone-dependent tumors was initially demonstrated in 1896 when Beatson showed that oophorectomy produced improvement in women with advanced breast cancer. Sex hormones and adrenocortical hormones are employed in the management of several other types of cancer. Since sex hormones are actively involved in the stimulation and control of proliferation and function of certain tissues, including the mammary and prostate glands, cancers arising from these tissues may be inhibited or stimulated by appropriate changes in hormonal balance. Cancer of the breast and cancer of the prostate can be effectively treated with sex hormone therapy or ablation of appropriate endocrine organs.
Corticosteroids have been useful in the treatment of acute leukemia, lymphoma, multiple myeloma, and other hematologic malignancies as well as in advanced breast cancer. In addition, they are effective as supportive therapy in the management of cancer-related hypercalcemia. The steroid hormones and related agents most useful in cancer therapy are listed in Table 55–5.
The mechanisms of action of steroid hormones on lymphoid, mammary, and prostatic cancer have been partially clarified. Specific cell surface receptors have been identified for estrogen, progesterone, corticosteroids, and androgens ieoplastic cells in these tissues. As iormal cells,
steroid hormones also form an intracellular steroid-receptor complex that ultimately binds directly to nuclear proteins associated with DNA to activate transcription of a broad range of cellular genes involved in cell growth and proliferation.
Most steroid-sensitive cancers express specific cell surface receptors. Prednisone-sensitive lymphomas, estrogen-sensitive breast cancers, and prostatic cancers express specific receptors for corticosteroids, estrogens, and androgens, respectively. It is now possible to assay tumor specimens for steroid receptor content and to identify which individual patients are likely to benefit from hormonal therapy. Measurement of the estrogen receptor (ER) and progesterone receptor (PR) proteins in breast cancer tissue is now standard clinical practice. ER or PR positivity predicts response to hormonal therapy, whereas patients whose tumors are ER-negative generally fail to respond to such treatment.
The sex hormones are used in the treatment of cancers of the breast, prostate, and endometrium. With replacement doses, estrogen can stimulate the growth of breast and endometrial cancer. Surprisingly, high-dose estrogen is useful therapeutically in metastatic breast cancer but has been largely replaced by antiestrogen therapy. In prostate cancer, androgens stimulate growth while estrogen administration results in suppression of androgen production. Drugs that reduce androgen secretion or block the effect of androgens at the receptor level are also effective in prostate cancer.
Hormones & Inhibitors.
Estrogen & Androgen Inhibitors
The antiestrogen tamoxifen has proved to be extremely useful for the treatment of both early-stage and metastatic breast cancer. It is now approved as a chemopreventive agent in women at high risk for breast cancer. In addition, this hormonal agent has activity in endometrial cancer.
Tamoxifen functions as a competitive partial agonist-inhibitor of estrogen and binds to the estrogen receptors of estrogen-sensitive tumors. However, tamoxifen has a tenfold lower affinity for ER than does estradiol, indicating the importance of ablation of endogenous estrogen for optimal antiestrogen effect. In addition to its direct antiestrogen effects on tumor cells, tamoxifen also suppresses serum levels of insulin-like growth factor-1 and up-regulates local production of transforming growth factor-beta (TGF- ).
Tamoxifen is given orally and is rapidly and completely absorbed. High plasma levels of tamoxifen are obtained within 4–6 hours after oral administration, and the agent has a much longer biologic half-life than estradiol—on the order of 7–14 days. It is extensively metabolized by the liver P450 system, and the main metabolites also possess antitumor activity similar to that of the parent drug. Tamoxifen is well tolerated, and its side effects are generally quite mild (Table 55–5). Flutamide and bicalutamide are nonsteroidal antiandrogen agents that bind to the androgen receptor and inhibit androgen effects. They are administered orally and are rapidly and completely absorbed by the gastrointestinal tract. At present they are used in combination with radiation therapy for the treatment of early-stage prostate cancer and in the setting of metastatic prostate cancer. Toxicities are listed in
Gonadotropin-Releasing Hormone Agonists
Leuprolide and goserelin are synthetic peptide analogs of naturally occurring gonadotropinreleasing hormone (GnRH, LHRH). Leuprolide and goserelin are indicated in the treatment of advanced prostate cancer and more
recently these agents have been incorporated as part of neoadjuvant therapy of early-stage prostate cancer. Leuprolide and goserelin are now formulated in long-acting depot forms, which allows for administration once every 3 months. The main side effects include hot flushes, impotence, and gynecomastia. Other toxicities are given in Table 55–5. Aromatase Inhibitors
Aminoglutethimide is a nonsteroidal inhibitor of corticosteroid synthesis at the first step involving the conversion of cholesterol to pregnenolone Aminoglutethimide also inhibits the extra-adrenal synthesis of estrone and estradiol. Aside from its direct effects on adrenal steroidogenesis, aminoglutethimide is an inhibitor of an aromatase enzyme that converts the adrenal androgen androstenedione to estrone (Figure 40–2). This aromatization of an androgenic precursor into an estrogen occurs in body fat.
Since estrogens promote the growth of breast cancer, estrogen synthesis in adipose tissue can be important in breast cancer growth in postmenopausal women.
Aminoglutethimide is primarily used in the treatment of metastatic breast cancer in women whose tumors express significant levels of estrogen or progesterone receptors. It also has activity in advanced prostate cancer that is hormone-responsive. Aminoglutethimide is normally administered with hydrocortisone to prevent symptoms of adrenal insufficiency. Hydrocortisone is preferable to dexamethasone because the latter agent accelerates the rate of catabolism of aminoglutethimide.
Adverse effects of aminoglutethimide are listed in Table 55–5.
Anastrozole is a selective nonsteroidal inhibitor of aromatase that has no inhibitory effect on adrenal glucocorticoid or mineralocorticoid synthesis. It is presently approved for first-line treatment of postmenopausal women with metastatic breast cancer that is ER-positive, for treatment of postmenopausal women with metastatic breast cancer that is ER-positive and has progressed while on tamoxifen therapy, and as adjuvant therapy of postmenopausal women with hormonepositive, early-stage breast cancer. Letrozole is a nonsteroidal competitive inhibitor of aromatase that is significantly more potent than aminoglutethimide and acts in the same way as anastrozole. It is also indicated for first-line treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer and for second-line treatment of postmenopausal women with advanced breast cancer after progression on tamoxifen therapy. Exemestane is a steroidal hormonal agent that binds to and irreversibly inactivates aromatase. There appears to be a lack of cross-resistance between exemestane and nonsteroidal aromatase inhibitors. This agent is indicated for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed on tamoxifen therapy. Each of these aromatase inhibitors exhibits a similar side effect profile (Table 55–5).
Miscellaneous Anticancer Drugs
Asparaginase
Asparaginase (L-asparagine amidohydrolase) is an enzyme that is isolated from various bacteria for clinical use. The drug is used to treat childhood acute lymphocytic leukemia. It hydrolyzes circulating L-asparagine to aspartic acid and ammonia. Because tumor cells lack asparagines synthetase, they require an exogenous source of L-asparagine. Thus, depletion of L-asparagine results in effective inhibition of protein synthesis. In contrast, normal cells can synthesize Lasparagine and thus are less susceptible to the cytotoxic action of asparaginase. The main side effect of this agent is a hypersensitivity reaction manifested by fever, chills, nausea and vomiting, skin rash, and urticaria. Severe cases can present with bronchospasm, respiratory failure, and hypotension. Other toxicities include an increased risk of both clotting and bleeding as a result of alterations in various clotting factors, pancreatitis, and neurologic toxicity with lethargy, confusion, hallucinations, and coma.
Hydroxyurea
Hydroxyurea (HONHCONH2) is an analog of urea whose mechanism of action involves the inhibition of DNA synthesis in the S phase by inhibiting the enzyme ribonucleotide reductase, resulting in depletion of deoxynucleoside triphosphate pools. The drug is administered orally and has nearly 100% oral bioavailability. It is mainly used in chronic myelogenous leukemia and treatment of the blast crisis of acute myeloid leukemia. However, it is also effective as an adjunct with radiation therapy for head and neck cancer and in treating essential thrombocytosis and polycythemia vera. Myelosuppression is the dose-limiting toxicity, but nausea and vomiting, mucositis and diarrhea, headache and increased lethargy, and a maculopapular skin rash with pruritus are also observed. The development of secondary malignancies is a late complication of some types of cancer chemotherapy. The most frequent secondary malignancy is acute myelogenous leukemia (AML).
The alkylating agents, procarbazine, etoposide, and ionizing radiation are all considered to be leukemogenic. AML has been observed in up to 15% of patients with Hodgkin’s disease who have received radiotherapy plus MOPP chemotherapy and in patients with multiple myeloma, ovarian carcinoma, or breast carcinoma treated with melphalan. The risk of AML is observed as early as 2–4 years after the initiation of chemotherapy and peaks at 5 and 9 years. With improvements in the clinical efficacy of various combination chemotherapy regimens resulting in prolonged survival and in some cases actual cure of cancer, the issue of how second cancers may affect long-term survival assumes greater importance. There is already evidence that certain alkylating agents (eg, cyclophosphamide) may be less carcinogenic than others (eg, melphalan). Systematic testing of the carcinogenicity of anticancer drugs in several animal models should allow less toxic agents to be identified and substituted for other more carcinogenic ones in chemotherapy regimens.
1. http://www.youtube.com/watch?v=nudFAzJsTog&feature=related
2. http://www.youtube.com/watch?v=ywdk3BTjK2s&feature=related
3. http://www.youtube.com/watch?v=tbumdvae2SE&feature=related
4. http://www.youtube.com/watch?v=ywdk3BTjK2s&feature=related
5. http://www.youtube.com/watch?v=9OCQzHl960Q&feature=related
6. http://www.youtube.com/watch?v=EDrzDpsK7WY&feature=related
7. http://www.youtube.com/watch?v=NFTL51FvX4Q&feature=related
8. http://www.youtube.com/watch?v=76b7icmEoOA&feature=related
9. http://www.youtube.com/watch?v=tASI4UrS2T0&feature=related
10. http://www.youtube.com/watch?v=3iKFaXIKUrM&feature=related
11. http://www.youtube.com/watch?v=r9rYXk5pHxc&feature=channel
12. http://www.youtube.com/watch?v=R2MfczL8_mk&feature=list_related&playnext=1&list=PL7CC5BD5F10523844
13. http://www.youtube.com/watch?v=qVmu8aXDSMQ&feature=related
14. http://www.youtube.com/watch?v=1WHF0Gq5Wps&feature=related
15. http://www.youtube.com/watch?v=rpVwurEbv5c&feature=related
16. http://www.youtube.com/watch?v=KdeW9mHBTBw&feature=related
17. http://www.youtube.com/watch?v=olFD1R5Gu–A&feature=related
18. http://www.youtube.com/watch?v=z2N1LJ8A5_Q&feature=related
19. http://www.youtube.com/watch?v=G9D–Vfmbt4s&feature=related
20. http://www.youtube.com/watch?v=ejq99wLEMTw&feature=related
