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320 Part V: Therapeutic Principles Chapter 22: Pharmacology and Toxicity of Antineoplastic Drugs 321

after the infusion of methotrexate, and continuing until plasma con- antibiotics and platinum derivatives, and these or other renal toxins
centrations of the drug fall below 1 μM. In patients receiving high-dose should be avoided in patients during high-dose methotrexate.
methotrexate, drug levels are routinely assayed 24 to 48 hours after dos-
ing to determine the rate of drug elimination and the safety of discontin-
uing leucovorin. Both methotrexate and its hydroxylated metabolite are CYTARABINE (CYTOSINE ARABINOSIDE,
organic acids, which, like uric acid, are much more soluble in alkaline ARABINOSYL CYTOSINE, ARA-C)
urine. In patients receiving such therapy, renal toxicity may result from Ara-C is an antimetabolite analogue of cytidine, differing in the con-
intrarenal precipitation of the parent drug or its 7-OH metabolite, and figuration at the substituent on C ′ position of the sugar, in which the
2
is generally the primary cause of decreased drug clearance and over- C ′-hydroxyl group is cis-oriented relative to the C ′-N-glycosyl bond,
1
2
whelming toxicity. Renal dysfunction can be prevented by alkalinizing in contrast to the trans configuration of the ribose nucleoside. Ara-C is
the urine to pH 7 with intravenous sodium bicarbonate prior to and a mainstay in the induction of remission in patients with acute myelog-
during therapy. Patients should be given intensive hydration, as well. enous leukemia (AML).
If drug concentrations in plasma exceed 1 μM at 48 hours after high- High doses (1 to 3 g/m ) of intravenous ara-C given at 12-hour
2
dose therapy, leucovorin should be continued at higher doses of 50 to intervals for 6 to 12 doses are more effective alone or in a combination
100 mg/m every 6 hours until methotrexate concentrations fall below with anthracyclines than conventional doses (100 to 150 mg/m q12h)
2
2
0.1 μM. The higher doses of leucovorin are necessary to compete with in consolidation therapy of AML, and they confer particular benefit in
methotrexate for transport and polyglutamation. In cases of extreme patients with cytogenetic abnormalities (t[8:21], inv[16], t[9:16], and
renal failure, with stable drug levels in the 10 μM range, leucovorin del[16]) related to the core binding factor that regulates hematopoie-
will not be effective. In this setting, continuous flow hemodialysis may sis. Other subsets of leukemia may have increased sensitivity to ara-C.
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provide a sustained reduction in drug levels. An alternative effective ALL patients with mixed lineage leukemia (MLL) gene translocations
measure in this circumstance is the administration of glucarpidase, a have upregulation of the human equilibrative nucleoside transporter
commercially available bacterial enzyme that instantly degrades anti- (hENT) and have a greater sensitivity to ara-C. AML patients with
36
folates and prevents further toxicity. K-RAS gene mutations seem to derive greater benefit from high-dose
33
ara-C than do patients with wild-type K-RAS in their tumors. 37
Adverse Effects
The dose-limiting toxicities of methotrexate are myelosuppression and Mechanism of Action
gastrointestinal toxicity. Toxic doses of methotrexate can induce throm- Ara-C is converted to the nucleoside triphosphate, cytarabine triphos-
bocytopenia and/or leukopenia, although leukopenia is more common. phate (ara-CTP) intracellularly. The first step is catalyzed by deoxycy-
An early indication of methotrexate toxicity to the gastrointestinal tract tidine kinase (dCK); polymorphisms of the dCK gene may affect the
38
is oral mucositis, whereas more severe toxicity may be manifested as rate of activation, and ultimately response. Ara-CTP is an inhibitor of
diarrhea and gastrointestinal bleeding. Less-common toxic effects of DNA polymerase and is also incorporated into DNA, where it termi-
39
methotrexate are skin rash (10 percent), pneumonitis, and chemical nates strand elongation. If repair is unsuccessful, apoptosis is initiated.
hepatitis. Transaminase elevations are frequently seen after high-dose Ara-C and its mononucleotide are deaminated and inactivated by two
methotrexate but rapidly return to normal in most patients, and with- intracellular enzymes, cytidine deaminase and deoxycytidylate deami-
out sequelae, but low-dose chronic administration, as employed to nase, respectively.
treat psoriasis or rheumatoid arthritis, may lead to portal fibrosis and Acquired ara-C resistance in experimental leukemias consistently
cirrhosis. results from the loss of dCK. Other changes implicated in experimen-
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Methotrexate, given intrathecally in doses of 12 mg every 4 days tal tumors include decreased drug uptake because of decreased expres-
for children older than age 3 years and for adults, is used to prevent or sion of the equilibrative nucleoside transporter, increased deamination,
treat meningeal leukemia and lymphoma. Dose adjustment is required increased pool size of competitive deoxycytidine triphosphate, and
for children younger than age 3 years, and should be made according inhibition of the apoptotic pathway. Some of these changes, particularly
to established protocols. Because the drug distributes poorly into the loss of dCK activity, have been reported in studies of human leukemia,
ventricular system after spinal injection, patients with active meningeal but these results have not been confirmed in definitive trials. 41
leukemia are frequently treated through an indwelling ventricular res-
ervoir. Toxicities caused by intrathecal administration of methotrexate Clinical Pharmacology
include acute arachnoiditis with nuchal rigidity and headache, as well as Ara-C is administered intravenously either as a bolus injection or, more
more chronic CNS toxicities, such as dementia, motor deficits, seizures, commonly, as a continuous infusion. It is not orally bioavailable because
34
and coma. Rarely, these neurotoxicities develop hours after intrathe- of its degradation by cytidine deaminase, which is present in the gastro-
cal drug administration, but more commonly they occur in the days or intestinal epithelium and liver. Two standard schedules of administra-
weeks after initiation of intrathecal treatment, and are most often seen tion are used: (1) rapid infusion of 100 mg/m every 12 hours for 7 days;
2
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in patients with active meningeal leukemia. Leucovorin is ineffective in or (2) continuous infusion of 100 to 200 mg/m per day for up to 7 days.
reversing or preventing these toxicities. Patients with such signs should Ara-C distributes rapidly throughout total-body water and is eliminated
undergo evaluation to rule out progressive CNS tumor, and if malig- from plasma with a biologic half-life of 7 to 20 minutes. Most of the dose
nancy is not found, intrathecal cytarabine should be used for further is excreted as arabinosyluracil (ara-U), an inactive metabolite, which is
therapy. formed in plasma, the liver, granulocytes, and other tissues. Inhibition
Methotrexate and 6-mercaptopurine (6-MP) are synergistic in of ara-C deamination by ara-U may be responsible for the prolongation
their inhibition of purine biosynthesis. L-Asparaginase, an inhibitor of of the biologic half-life of the drug as larger doses are administered.
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protein synthesis, blocks cells from entering DNA synthesis and antag- Single-bolus injections and short infusions (30 minutes to 1 hour dura-
onizes the effects of methotrexate, when used before the antifolate. The tion) at doses as high as 5 g/m produce little myelotoxicity because of
2
two drugs are not used concurrently. the drug’s rapid clearance, whereas continuous intravenous infusion of
2
Nonsteroidal antiinflammatory drugs, which diminish renal only 1 g/m over 48 hours produces severe marrow toxicity. High-dose
2
blood flow, may reduce methotrexate clearance, as may nephrotoxic ara-C (3 g/m q12h for 3 days on days 1, 3, and 5), is routinely used

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