Although 1-Beta-D-arabinofuranosyl cytosine (ara-C) has been widely used in the treatment of leukemia in man, its effectiveness is limited primarily because of the rapid inactivation of this agent by enzymatic deamination. Efforts to use deaminase inhibitors in combination with ara-C or to use high doses of ara-C in an attempt to increase therapeutic levels of the drug by saturating the deaminases have not been very successful largely because of a concomitant increase in drug related toxicities. An alternative approach to increase the effectiveness of a deoxycytine analog is to find a cytotoxic derivative that is resistant to deamination. Such an agent would enable the clinician to titrate the therapeutic concentration for each individual patient without regard to drug inactivation by serum, liver and tissue deaminases. This is important because key metabolic enzyme levels vary depending on such parameters as the age and condition of the patient, the type of tissue, and the stage of the disease. The overall purpose of this proposal is to investigate the potential use of a new deaminase resistant analog, 3'-amino-2',3'-dideoxycytidine (3'-NH2-dCyd), as a substitute for ara-C in certain types of treatment protocols. This will be accomplished by 1) comparing ara-C and 3'NH2-dCyd as single agents with regard to treatment effectiveness, cell specific metabolism and resistance development. Preliminary results revealed that these agents are metabolized differently in cells. Treatment comparison of varius neoplastic cell types showed extensive variation in the effective concentrations of ara-C with little change in 3'-NH2-dCyd sensitivity. This suggests that cells which are resistant to ara-C therapy are not necessarily cross-resistant to 3'-NH2-dCyd. 2) Cells treated with these agents will be monitored for resistance development with emphasis on identification of the drug-induced alterations which lead to a decreased treatment response. 3) Double agent combinations containing 3'NH2-dCyd will be compared to those containing ara-C in an attempt to identify the treatment protocol that not only is more efficacious for a particular neoplastic celll but also, which is more effective in the prevention or delay of resistance development. In summary, this study will compare ara-C and 3'NH2-dCyd with emphasis on elucidation of the cell type specific metabolic and treatment differences that can be taken advantage of chemotherapeutically. Findings from the proposed research may lead to new effective treatment protocols and may identify new targets for rational chemotherapy.
| Mancini, W R; Williams, M S; Lin, T S (1988) Specific inhibition of DNA biosynthesis induced by 3'-amino-2',3'-dideoxycytidine. Biochemistry 27:8832-9 |
