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322 Part V: Therapeutic Principles Chapter 22: Pharmacology and Toxicity of Antineoplastic Drugs 323

for consolidation therapy of AML, but lower doses of 1 gm/m or less radiosensitizer and should not be used concurrently with radiation
2
should be used in patients older than 60 years to avoid CNS toxicity. therapy except in clinical trials.
Unlike most drugs, a relatively high concentration of ara-C is achieved Toxicities are acute myelosuppression, mild hepatic enzyme ele-
in the cerebrospinal fluid after intravenous administration, and may vations, uncommonly a reversible pneumonitis, and with prolonged
approach 50 percent of the corresponding plasma concentration. usage, a progressive hemolytic uremic syndrome with capillary leak,
Ara-C is also used intrathecally to treat meningeal leukemia. Doses leading to pleural effusions, ascites, and renal failure. 47
of 50 to 70 mg in adults are usually employed and afford cerebrospinal
fluid levels of the drug near 1 mM, which decline with a half-life of 2
hours. Ara-C (50 mg given every 2 weeks) has been impregnated into a 5-AZACYTIDINE AND
gel matrix, in a formulation called DepoCyt, for sustained release into 5-AZA-2′-DEOXYCYTIDINE
the cerebrospinal fluid, thus avoiding the need for repeated spinal taps.
Initial clinical results in spinal lymphomatous meningitis indicate that Both 5-azacytidine and decitabine (5-aza-2′-deoxycytidine), its closely
it has efficacy equal to that of methotrexate. 43 related deoxy analogue, exhibit cytotoxic activity and also induce differ-
entiation of malignant cells at low doses. The latter action results from
Adverse Effects their incorporation into DNA and their covalent inactivation of DNA
The dose-limiting toxicity for conventional dosing regimens of intra- methyltransferase. The resulting inhibition of methylation of cyto-
venous ara-C, 100 to 150 mg/m per day for 5 to 10 days, is myelosup- sine bases in DNA leads to enhanced transcription of otherwise silent
2
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pression. Nausea and vomiting also occur at these doses, the severity of genes. The differentiating effects of 5-azacytidine are the basis for the
which increases markedly when higher doses are employed, although induction of fetal hemoglobin synthesis in patients with sickle cell ane-
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repeated administration of the drug results in some tolerance. The nadir mia and thalassemia and its approved use in low-dose therapy of mye-
of the white count and platelet count occurs at about days 7 to 10 after lodysplastic syndromes (MDS). The usual doses of 5-azacytidine are 75
2
the last dose of drug. Cerebellar, gastrointestinal, and liver toxicity, as mg/m subcutaneously or intravenously per day for 7 days, repeated
well as conjunctivitis have also been observed when high-dose regimens every 28 days, whereas decitabine is used in doses of 20 mg intrave-
are used. Hepatotoxicity ranges from abnormalities in serum transam- nously every day for 5 days every 4 weeks. Responses become apparent
inase levels to frank jaundice. The severity of these effects increases as in myelodysplasia after two to five courses.
the duration of therapy is prolonged; however, toxic effects rapidly sub- 5-Azacytidine and decitabine are rapidly deaminated to chemically
side upon discontinuation of treatment. Pulmonary infiltrates as a result unstable uridine metabolites that immediately degrade into inactive
of noncardiogenic pulmonary edema, and occasionally associated with products. Pharmacologic activity results from phosphorylation of the
severe pulmonary dysfunction, occur in leukemic patients receiving parent compound by cytidine kinase (for 5-azacytidine) or dCK (for
ara-C, as do gastrointestinal ulcerations with bleeding and infrequently decitabine), with subsequent conversion to a triphosphate nucleotide
perforation. Ara-C treatment is also reported to predispose to Strepto- that becomes incorporated into DNA. The primary clinical toxicities
49
coccus viridans pneumonia. 44 of both 5-azacytidine and decitabine include reversible myelosup-
In patients older than 60 years of age, and in patients with renal pression, nausea and vomiting with higher doses, hepatic dysfunction,
2
dysfunction, intravenous high-dose ara-C (3 g/m every 12 hours, days myalgia, and fever and rash. Resistance likely results from defects in
1, 3, and 5, for six doses) causes a high incidence of cerebellar toxicity, drug activation or alternative mechanisms for gene silencing, such as
45
manifested as ataxia and slurred speech. Confusion and dementia histone methylation or acetylation.
may supervene, leading to a fatal outcome. Cerebellar toxicity is more
frequent in patients with abnormal renal function because of slowed PURINE ANALOGUES
elimination of ara-U, with consequent inhibition of ara-C deamination. Purine analogues (Fig. 22–3) occupy an important role in maintenance
Intrathecal ara-C is usually well tolerated, but neurologic side effects for childhood ALL, and in the past decade newer analogues have shown
have been reported (seizures, alterations in mental status). remarkable activity in chronic leukemias and small cell lymphomas.
With methotrexate, 6-MP is a critical component in the maintenance
phase of curative therapy of childhood ALL. Other purine analogues
GEMCITABINE include azathioprine, a prodrug of 6-MP and potent immunosuppres-
Although primarily used for solid tumors, gemcitabine, a 2′-2′-difluoro sive agent; allopurinol, an inhibitor of xanthine oxidase, useful in the
analogue of deoxycytidine, has significant activity against Hodgkin lym- prevention of uric acid nephropathy; 2-chlorodeoxyadenosine, effective
phoma. Its mechanism of action is similar to ara-C, in that, as a triphos- in the treatment of hairy cell leukemia and other lymphoid malignan-
phate, it competes with deoxycytidine triphosphate for incorporation cies; 6-thioguanine (6-TG), an infrequently used antileukemic agent;
into the elongating DNA strand, where it terminates DNA synthesis. and fludarabine phosphate (2-fluoroara-adenosine monophosphate),
It is also self-potentiating in that at a second site of action, it inhib- an effective agent for chronic lymphocytic leukemia (CLL) and follic-
its ribonucleotide reductase and thereby reduces competitive pools of ular lymphomas, and for suppression of graft-versus-host disease in
deoxycytidine triphosphate (dCTP). It achieves higher nucleotide levels transplantation. A new purine analogue, nelarabine, is an ara-guanine
in tumor cells than does ara-CTP, and has a longer intracellular half- prodrug, with strong activity against T-cell diseases, including lympho-
life. Its clinical pharmacokinetics are determined primarily by its rapid blastic leukemias and lymphomas. The basis for this T-cell sensitivity
50
deamination by cytidine deaminase, yielding a short plasma half-life appears to be the resistance of arabinosylguanine (ara-G) to degrada-
(t ) of 15 to 30 minutes. Standard schedules use 1000 mg/m infused tion by the catabolic enzyme, purine nucleoside phosphorylase. High
2
1/2
over 30 minutes, and produced peak drug concentrations of 20–60 μM levels of arabinosylguanine triphosphate (ara-GTP) accumulate in
in plasma. Longer infusion times may produce higher intracellular tri- T-cell neoplasms, leading to Fas ligand-mediated apoptosis. The most
phosphate concentrations, but the benefit is uncertain. 46 recent addition, clofarabine, also an adenosine analogue, has notable
Resistance in solid tumors arises from low expression of hENT, activity against childhood ALL and adult AML. Deoxycoformycin, a
increased expression of ribonucleotide reductase, and low levels of the potent inhibitor of adenosine deaminase, is also effective in the treat-
initial activating enzyme, dCK. Gemcitabine is an extremely potent ment of T-cell malignancies and hairy cell leukemia.

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