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Chlorodeoxyadenosine and arabinosylcytosine in patients with acute
myelogenous leukemia: pharmacokinetic, pharmacodynamic, and molecular
interactions
V Gandhi, E Estey, MJ Keating, A Chucrallah and W Plunkett
Department of Clinical Investigation, University of Texas M.D. Anderson
Cancer Center, Houston 77030, USA.
The effectiveness of arabinosylcytosine (ara-C) for the treatment of acute
myelogenous leukemia (AML) depends on the formation of its active
metabolite, the triphosphate of ara-C (ara-CTP). Using biochemical
modulation strategies to increase the accumulation of ara-CTP in leukemia
blasts, a clinical protocol was designed combining 2- chlorodeoxyadenosine
(CdA), an inhibitor of ribonucleotide reductase, and ara-C for adults with
AML. The protocol stipulated an infusion of 1 g/m2 of ara-C over 2 hours on
day 1. A continuous infusion of CdA (12 mg/m2/d) begun 24 hours later and
continued for 5 days. Identical doses of ara-C were administered on days 3,
4, 5, and 6. Pharmacokinetic and pharmacodynamic interactions between CdA
and ara-C during therapy were investigated. To complement these studies,
molecular actions of the triphosphate of ara-C and CdA on DNA extension by
human DNA polymerase alpha in an in vitro model system was conducted. In
the circulating leukemia blasts of 7 of the 9 patients studied, ara-CTP
pharmacokinetics showed a median 40% increase in the rate of ara-CTP
accumulation after 24 hours of CdA infusion. The ex vivo effect of CdA on
accumulation of ara-CTP in AML blasts was similar to that during therapy
except that the enhancement was less. The DNA synthetic capacity of the
circulating blasts was inhibited to a greater extent by administration of
CdA and ara-C in combination than by either one alone. Additionally the
lowered level of DNA synthesis was maintained until the next infusion of
ara-C. Endogenous levels of deoxynucleotides increased 24 hours after ara-C
infusion. Administration of CdA in general lowered the concentrations of
all dNTPs. DNA pol alpha incorporated CdATP and ara-CTP with high affinity
in a DNA primer extending over an oligonucleotide template of defined
sequence. Human DNA polymerase alpha extended DNA primers terminated by CdA
monophosphate (CdAMP) at its 3'-end by incorporating ara-C monophosphate
(ara-CMP). The tandem incorporation of CdAMP and ara-CMP resulted in nearly
complete inhibition of DNA primer extension. The insertion of two analogs
in sequence, inhibition of ribonucleotide reductase, and the metabolic
potentiation of ara-CTP by CdA infusion may be responsible for sustained
inhibition of DNA synthesis in the circulating leukemia blasts during
therapy with this combination regimen.
Volume 87,
Issue 1,
pp. 256-264,
01/01/1996
Copyright © 1996 by The American Society of Hematology
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