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Inhibitory Effects of the Arabinosides of 6-Mercaptopurine and Cytosine on Purine and Pyrimidine Metabolism¹

Life Sciences Research, Stanford Research Institute, Menlo Park, California

The influences on metabolism in ascites tumor cells of azaserine, 1-ß-D-arabinofuranosylcytosine (ara-C),² and 9-ß-D-arabinofuranosyl-9-H-purine-6-thiol (ara-6-MP) were studied and compared. Either ara-C or azaserine blocked the incorporation of purine and pyrimidine precursors into DNA. Survival studies indicated that a combination of the 2 gave an additive response. Either ara-C or ara-6-MP blocked the conversion of cytidylate to deoxycytidylate. Treatment of tumor-bearing mice with a combination of ara-C and ara-6-MP gave an additive response. Azaserine blocked the conversion of uridylate to cytidylate. Combination therapy with azaserine and ara-6-MP gave a synergistic response. The drug synergism given by combinations of azaserine and ara-6-MP suggests that a sequential block occurs in the formation of deoxycytidylate from uridylate.

¹ This work was supported by Contract PH 43-65-575 with the Cancer Chemotherapy National Service Center, National Cancer Institute, NIH.

² Abbreviations used: ara-C, 1-ß-D-arabinofuranosylcytosine; ara-6-MP, 9-ß-D-arabinofuranosyl-9-H-purine-6-thiol; 6-MP, 6-metcaptopurine; TPNH, reduced triphosphopyridine nucleotide; ATP, adenosine-5'-triphosphate; AMP, adenosine-5'-monophosphate; dAMP, 5'-deoxyadenylate; GMP, 5'-guanylate; dGMP; 5'-deoxyguanylate; UMP, 5'-uridylate; dUMP, 5'-deoxyuridylate; TMP, 5'-thymidylate; CMP, 5'-cytidylate; dCMP, 5'-deoxycytidylate; aza, azaserine.

Received 10/22/65.