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324 Part V: Therapeutic Principles Chapter 22: Pharmacology and Toxicity of Antineoplastic Drugs 325

adult dose is 52 mg/m given as a 2-hour infusion daily for 5 days. Clo- from induction of Hgb F through its activation of a specific promoter
2
farabine has a plasma half-life of 6.5 hours. The primary route of clear- for the γ-globin gene. It may also exert antisickling activity and decrease
ance is through renal excretion, and dose adjustment according to CrCl occlusion of small vessels through its generation of nitric oxide, a
is recommended for patients with abnormal renal function. vasodilator, and through decreased expression of adhesion molecules
Toxicities are myelosuppression; uncommonly, fever, hypotension, such as L-selectin, on neutrophils. Resistance occurs in experimen-
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and pulmonary edema, suggestive of capillary leak caused by cytokine tal tumors as a consequence of amplification of the catalytic subunit of
release; hepatic transaminitis; hypokalemia; and hypophosphatemia. As RNR or through mutations in RNR that lower affinity for the enzyme.
a single agent, the drug is well tolerated as second-line treatment for
AML patients with remission rates of 30 percent. 76 Clinical Pharmacology
Hydroxyurea is well absorbed orally, even when large doses such as
NELARABINE 50 to 75 mg/kg orally are given for rapid lowering of the white blood
(6-METHOXY-ARABINOSYLGUANINE) cell count. In chronic therapy of myeloproliferative neoplasm, starting
doses of 15 mg/kg orally are adjusted upward or downward based on
A guanine nucleoside analogue, nelarabine has useful activity as a sec- neutrophil counts. In managing patients with sickle cell disease, neu-
ondary agent for T-cell lymphoblastic lymphoma and acute T-cell leu- trophils should be maintained above 2000 per mL. Hydroxyurea may
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kemias. Its mode of action is similar to the other purine analogues, in also be given intravenously to rapidly lower the white blood cell count
that it becomes incorporated into DNA and terminates DNA synthe- in patients with extreme leukemic leukocytosis or thrombocytosis. Peak
sis. Its selective action for T cells may relate to the ability of T cells to plasma levels following oral administration are achieved at about 1 hour
activate purine nucleosides and the lack of susceptibility of this drug to and decline with a half-life of 3 to 4 hours thereafter. Renal excretion is
purine nucleoside phosphorylase, a degradative reaction. the major route of drug elimination, and doses should be decreased in
Usual doses are an intravenous 2-hour infusion of 1500 mg/m proportion to the deficit in CrCl.
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for adults on days 1, 3, and 5, and a lower dose of 650 mg/m per day
for 5 days for children. The drug is rapidly demethylated by adenosine Adverse Effects
deaminase after administration, yielding the ara-G, which is cleared by The major toxicities of hydroxyurea are leukopenia and the induction
hydrolysis and has a longer plasma half-life of 3 hours. ara-G is con- of megaloblastic changes. Nausea, drug fever, pneumonitis, macu-
verted intracellularly to its triphosphate which becomes incorporated lopapular skin rash, and painful leg ulcers have been observed with this
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into DNA. The primary toxicities are myelosuppression and abnormal drug, although it is generally well tolerated. Hydroxyurea, like ara-C,
liver function tests, but the drug may cause a spectrum of neurologic is an S-phase–specific agent. Accordingly, single large doses cause lit-
abnormalities, including seizures, delirium, somnolence, and the Guil- tle toxicity other than myelosuppression. The nadir of the leukocyte
lain-Barré syndrome of ascending paralysis. count occurs 3 to 5 days after a single dose of drug, and the leukocyte
count recovers rapidly. It is a potent teratogen and should not be used
in women of childbearing age. Its potential to cause leukemic transfor-
PENTOSTATIN (2′-DEOXYCOFORMYCIN) mation is uncertain, but small cases series suggest this may occur in
Pentostatin contains a unique seven-carbon primary ring system that patients with a myeloproliferative neoplasm. 81
closely resembles the transition-state intermediate of the adenosine
deaminase reaction. As such, pentostatin is a potent inhibitor of the
enzyme, leading to accumulation of intracellular adenosine and deox- ANTITUBULINS
yadenosine nucleotides. In addition, the triphosphate of pentostatin is
incorporated into DNA. The imbalance in purine nucleotide pools pro- VINCA ALKALOIDS
duced by pentostatin probably accounts for its cytotoxicity. Vinblastine and vincristine are commonly used in the treatment of
Although initial trials of pentostatin demonstrated striking renal hematologic neoplasms: vinblastine because of its excellent activity in
and neurologic toxicities at doses of 10 mg/m intravenously per day the treatment of Hodgkin lymphoma and vincristine in lymphomas and
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or greater, lower doses (4 mg/m biweekly) are extremely effective in childhood leukemia. Both drugs have activity in solid-tumor therapy,
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inducing pathologically confirmed complete responses in hairy cell leu- particularly in treating childhood sarcomas (vincristine), and testicular
kemia. At this lower dose, severe depletion of normal T cells occurs and cancer (vinblastine).
may predispose to opportunistic infection. The optimal dose may be
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lower than 4 mg/m biweekly. The drug is eliminated entirely by renal Mechanism of Action
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excretion, necessitating proportional dose reduction in patients with The vinca alkaloids exert their cytotoxic action by their binding to tubu-
reduced CrCl. lin, a structural protein found in the cytoplasm of cells. Microtubules,
assembled through polymerization of tubulin dimers, form the spindle
RIBONUCLEOTIDE REDUCTASE INHIBITOR: along which the chromosomes migrate during mitosis. Microtubules
are an important structural component of neuronal axons. Binding of
HYDROXYUREA the vinca alkaloids to tubulin leads to inhibition of formation of the
Hydroxyurea inhibits RNR, the enzyme that converts ribonucleotide mitotic spindle, arresting cells in metaphase and inducing apoptosis.
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diphosphates to deoxyribonucleotides. It chelates iron, an essential Resistance to the vinca alkaloids may be acquired through the expres-
cofactor in the RNR reaction. In malignant disease, hydroxyurea is sion of the MDR efflux pump. Alternatively, resistant cells may contain
most commonly used for treating polycythemia vera, essential throm- mutant tubulin with decreased avidity of vinca binding. The clinical
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bocythemia, and the chronic phase of CML and to lower the myeloblast importance of these resistance mechanisms, however, is uncertain.
count in patients presenting with AML or blastic crisis of CML. It has
also become the standard agent for preventing painful crisis and reduc- Clinical Pharmacology
ing hospitalization in patients with sickle cell disease and in thalassemia Vincristine and vinblastine are both administered by the intravenous
patients with hemoglobin (Hgb) C/SS. Its antisickling activity results route. The average single dose of vincristine is 1.4 mg/m and that of
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