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326 Part V: Therapeutic Principles Chapter 22: Pharmacology and Toxicity of Antineoplastic Drugs 327

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vinblastine 8 to 9 mg/m . Sequential doses of the drugs are usually formation and a block in the progression through mitosis. They induce
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given at 1- or 2-week intervals. These doses provide peak plasma drug apoptosis in tumor cells irrespective of the p53 status of the cells and kill
concentrations of approximately 1 μM. The plasma pharmacokinetics cells at 10 nM concentrations or less in cell culture in a time-dependent
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of both vinca analogues are characterized by a very rapid initial dis- manner. In experimental settings, resistance is related to increased
position phase followed by a slow terminal phase of decay, with half- drug efflux, mutations in β-tubulin, or increased expression of anti-
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lives of 20 to 85 hours. Almost 70 percent of a dose of vincristine is apoptotic proteins such as survivin, or of the mitosis-related aurora
metabolized by the liver and excreted in the feces. Cytochrome P450 kinase. 88
(CYP)-mediated metabolism is also the major route of inactivation of The taxanes are subject to MDR mediated by the mdr and mrp
vinblastine, producing a variety of inactive metabolic produced in the genes, as well as to β-tubulin mutations. Because they are highly insolu-
liver are excreted in the bile. Inducers of CYP3A4, such as phenylhydan- ble in aqueous solution, paclitaxel and docetaxel are formulated in lipid-
toin, enhance clearance, while inhibitors delay clearance and increase based solvents that cause occasional hypersensitivity reactions. Thus,
toxicity. The dose of vincristine or vinblastine should be reduced in paclitaxel is given after pretreatment with antihistamines (cimetidine,
patients with hepatic impairment. Although specific guidelines for dose diphenhydramine), and dexamethasone. Both drugs are cleared pri-
reduction have not been developed, a 50 percent decrease in dose is marily by hepatic CYP metabolism, although by different isoenzymes
recommended for patients presenting with a bilirubin level of 1.5 to 3 (paclitaxel predominantly by CYP2B6 and docetaxel by CYP3A4) with
mg/dL and a 75 percent reduction for levels greater than 3 mg/dL. Dose terminal plasma half-lives of 10 to 13 hours. Their metabolism is stim-
reduction is not necessary for patients with impaired renal function, as ulated by phenytoin and other CYP-inducing drugs and inhibited by
very little intact drug is excreted in urine. ketoconazole. Their major toxicities, aside from hypersensitivity, are a
sharp but brief leukopenia, milder thrombocytopenia, and mucositis.
Adverse Effects High-dose or repeated cycles of the taxanes cause a sensory and motor
The dose-limiting side effect of vincristine is neurotoxicity, which usu- peripheral neuropathy that is reversible with drug discontinuation.
ally occurs when the total dose received exceeds 6 mg/m . The initial Occasional patients have experienced atrial conduction block or atrial
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signs of neurotoxicity are paresthesia of the fingers and lower extrem- or ventricular arrhythmias after paclitaxel administration, and the com-
ities and loss of deep tendon reflexes. Continued administration may bination of paclitaxel with doxorubicin may produce a greater incidence
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lead to profound loss of motor strength, such as weakness of dorsiflex- of congestive heart failure than seen with doxorubicin alone. A syn-
ion of the foot and extension of the wrists. Elderly patients are partic- drome of progressive fluid retention and peripheral edema occurs in
ularly susceptible to such toxicities. Occasionally, cranial nerve palsies patients receiving multiple cycles of docetaxel and can be at least par-
may lead to vocal cord paralysis or diplopia, and severe jaw pain may tially prevented by pretreatment with glucocorticoids. 90
result from vincristine administration. At high doses of vincristine (>3 The taxanes have not found a valuable role in the treatment of
mg total single dose), autonomic neuropathy may cause obstipation and hematologic malignancy. However, a number of analogues and new
paralytic ileus. Sensory changes and reflex abnormalities slowly improve formulations are under development. Abraxane, consisting of paclitaxel
when the drug is discontinued; motor impairment improves less rapidly bound to albumen microparticles, does not require a lipid solvent, is
and may be irreversible. Inappropriate antidiuretic hormone release virtually free of hypersensitivity as a side effect, and enters cells by a
resulting in symptomatic dilutional hyponatremia has been ascribed to separate albumen-mediated transporter. It is approved for treatment
vincristine. of relapsed breast cancer and pancreatic cancer. Cabazitaxel, approved
While marrow suppression is not common with vincristine admin- for prostate cancer, is a new analogue with decreased susceptibility to
istration, myelosuppression may be noted in patients with impaired MDR. An entirely new class of natural products, the epothilones, have
marrow function as a consequence of prior treatment with other drugs. a similar mechanism of action, are less susceptible to MDR, and have
Platelet counts are relatively unaffected. activity against breast cancer. 91
The primary toxicity of vinblastine is leukopenia. The white count
reaches a nadir at day 7 and reverses rapidly thereafter. Mucositis may
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result from higher doses (>8 mg/m ) of vinblastine or when it is used in TOPOISOMERASE INHIBITORS
combination with other cytotoxic drugs. Neurotoxicity is rare, but ileus
can occur at high doses. CAMPTOTHECINS
Both drugs cause severe pain and local toxicity if extravasated. This group of compounds includes synthetic derivatives of 20 (S)-camp-
Neither drug should ever be given intrathecally. Vincristine adminis- tothecin, a naturally product from the Camptotheca acuminata tree. The
tered inadvertently into the cerebrospinal fluid causes acute neurologic camptothecins interact with a unique target, topoisomerase I, stabilizing
dysfunction, coma, and death. Attempts at replacement of the cerebral the enzyme’s complex with DNA and preventing the resealing of DNA
spinal fluid with an electrolyte solution, Ringer lactate, supplemented single-strand breaks induced by the enzyme. Resistance arises through
with 15 ml/L of fresh-frozen plasma, have been reported to avert a fatal mutation, deletion, or decreased expression of the topoisomerase I gene.
outcome, but do not prevent severe neurologic sequelae. 84 The primary agents in clinical use are irinotecan, which is approved for
treatment of colon cancer, and topotecan, approved for second-line
treatment of ovarian cancer and small cell lung cancer. Irinotecan, most
TAXANES commonly administered intravenously at a dose of 125 mg/m once
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The taxanes, paclitaxel, docetaxel, and Abraxane, are a second class of each week for 4 weeks every 42 days, has shown promise against lym-
antimitotic compounds that differ in mechanism and toxicity profile phomas in phase II trials performed in Japan. Response rates of 42
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from the vinca alkaloids that are primarily used in patients with solid percent in previously treated patients with non-Hodgkin lymphoma,
tumors. Paclitaxel was purified from an extract of the bark of Taxus bre- and of 38 percent in patients with refractory or relapsed adult T-cell
vifolia, whereas docetaxel is a closely related semisynthetic derivative. leukemia-lymphoma, remain to be confirmed. Topotecan has remis-
Abraxane is paclitaxel embedded in an albumin microparticle. The tax- sion-inducing activity in patients with myelodysplasia and chronic
anes bind to the β-tubulin subunit of microtubules and promote the myelomonocytic leukemia, both as a single agent (1.5 mg/m per day
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polymerization of microtubules, leading to disordered mitotic spindle for 5 days) and in combination with ara-C. 93,94 Objective responses have

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