Biochemical modulation of cytosine arabinoside

1-beta-D arabinofuranosylcytosine (ara-C) is an analog of the naturally occurring nucleoside 2'-deoxycytidine which is a potent antileukemic agent in man. Because the metabolism (and, ultimately, the effectiveness) of this agent is regulated by multiple processes involved in pyrimidine biosynthesis, attempts to improve its efficacy through biochemical modulation have been the focus of intense interest. These approaches have included combination of ara-C with inhibitors of de novo pyrimidine biosynthesis, deaminase inhibitors, nucleoside transport blockers, nucleosides, and more recently, hematopoietic growth factors. Although potentiation of ara-C metabolism and cytotoxicity has been documented in multiple experimental in vitro and in vivo experimental systems, clinical studies in humans have thus far failed to document definitive improvements in ara-C selectivity and efficacy through biochemical modulation. It is likely that such improvements will require the identification of more optimal schedules, sequences and dose relationships, and possibly combined modality approaches.