CHLORODEOXYADENOSINE AND ARABINOSYLCYTOSINE IN PATIENTS WITH ACUTE MYELOGENOUS LEUKEMIA - PHARMACOKINETIC, PHARMACODYNAMIC, AND MOLECULAR-INTERACTIONS

The effectiveness of arabinosylcytosine (ara-C) for the treatment of a cute myelogenous leukemia (AML) depends on the formation of its active metabolite, the triphosphate of ara-C (ara-CTP). Using biochemical mo dulation strategies to increase the accumulation of ara-CTP in leukemi a blasts, a clinical protocol was designed combining 2-chlorodeoxyaden osine (CdA), an inhibitor of ribonucleotide reductase, and ara-C for a dults with AML. The protocol stipulated an infusion of 1 g/m(2) of ara -C over 2 hours on day 1, a continuous infusion of CdA (12 mg/m(2)/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 pharma codynamic interactions between CdA and ara-C during therapy were inves tigated. To complement these studies, molecular actions of the triphos phate of ara-C and CdA on DMA extension by human DMA 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 showe d a median 40% increase in the rate of ara-CTP accumulation after 24 h ours 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 DMA synthetic capacity of the circulating bl asts was inhibited to a greater extent by administration of CdA and ar a-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 ter minated by CdA monophosphate (CdAMP) at its 3'-end by incorporating ar a-C monophosphate (ara-CMP). The tandem incorporation of CdAMP and ara -CMP resulted in nearly complete inhibition of DNA primer extension. T he insertion of two analogs in sequence, inhibition of ribonucleotide reductase, and the metabolic potentiation of ara-CTP by CdA infusion m ay be responsible for sustained inhibition of DNA synthesis in the cir culating leukemia blasts during therapy with this combination regimen. (C) 1996 by The American Society of Hematology.