Studies of ara-C metabolism in acute leukemia.

Abstract

HE EMERGENCE or expansion of a population of cytosine arabinoside (ara-C) resistant cells is probably a major cause of failure to obtain cure with ara-C therapy of acute nonlymphocytic leukemia (ANLL). Therefore, a major goal of the research efforts in our laboratory is the development of methods that enable detection of the frequency and mechanism of ara-C resistance in blast cells present in bone marrow samples from patients with ANLL, to serve as an aid to rational drug development, selection, and dosing. A variety of mechanisms of ara-C resistance have been demonstrated in animal tumor models or in in vitro systems, including enhanced degradation of ara-C or its metabolites,’ diminished activity or levels of deoxycytidine kinase (EC 2.7. I .74),2S3 high intracellular levels of dCTP,435 an altered DNA polymerase insensitive to ara-C triphosphate (ara-CTP) inhibition6v7 and enhanced excision and repair of DNA containing ara-C residues.8 Despite this vast accumulation of knowledge, little data exist that define precise mechanisms of ara-C resistance as they arise in ANLL patients. However, it would be premature to embark on detailed studies of key steps in the ara-C metabolic activation pathway in patient material without first being able to demonstrate quantitative alterations in the major active metabolites and cytotoxic effects of ara-C among groups of patients clinically sensitive or resistant