Pharmacokinetic parameters of 1-beta-D-arabinofuranosylcytosine (ara-C) and their relationship to intracellular metabolism of ara-C, toxicity, and response of patients with acute nonlymphocytic leukemia treated with conventional and high-dose ara-C.

Abstract

1 $I-ARABINOFURANOSY L cytosine (araC) is a deoxycytidine analogue, an agent most commonly used in the treatment of patients with acute nonlymphocytic leukemia (ANLL) alone and in combination with other agents.‘T2 Following its transport into cells, ara-C is activated to ara-CTP, which is a potent inhibitor of DN.4 synthesis,3.4 and is also incorporated into cellular DNA.5,6 The extent of this incorporation has been correlated with the inhibition of DNA synthesis and the loss of colonogenic potential of human cells. Skipper et al’ demonstrated the schedule dependency of ara-C against mice bearing leukemia L1210 cells. The basis for this schedule dependency was directly related to the differential intracellular retention of the biological active form of ara-C, ara-CTP, between normal and tumor cells.*s9 Thus to maintain an effective differential concentration of ara-CTP between tumor and normal tissues, ara-C has to be administered according to specified time intervals (eg, every 3 or 4 hours).‘,’ This is due in part to the rapid distribution half-life of ara-C in blood and more importantly to the differences observed in the intracellular retention of araCTP among different tumor cell types. To circumvent these pharmacologic limitations, ara-C was employed clinically by three modes: (1) by daily continuous infusion of low doses of ara-C’,” (2) by multiple high doses,“-‘4 and (3) by the combination of ara-C with an inhibitor of deoxycytidine deaminase tetrahydrouracil (THU).“-” Studies carried out to date indicate that highdose ara-C is efficacious in both previously untreated and relapsed patients with ANLL. The optimal doses, schedule, and mode of administration of this agent have not been clearly defined. Studies by many groups are underway to define determinants of responses to lowand high-dose ara-C so that this active agent can best be utilized under optimal conditions for achieving therapeutic selectivity.‘s-25 In this presentation the relationship between the pharmacokinetics of ara-C, administered by conventional low doses (100 mg/m2/d) and by high dose (1 to 3 g/m2/12 hours), and the simultaneous measurement of ara-CTP will be evaluated. Furthermore, the importance of pharmacokinetic properties of ara-C in the prediction of toxicity and efficacy in patients with ANLL will also be discussed,