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Further Studies on the Metabolic Effects of 9-ß-D-Arabinofuranosyl-9-H-purine-6-thiol¹

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

9-ß-D-Arabinofuranosyl-9-H-purine-6-thiol(ß-D-arabinosyl-6-mercaptopurine) was found to inhibit the growth of s.c. implants of C3H mammary tumors and Sarcoma 180. Simultaneous treatments with ß-D-arabinosyl-6-mercaptopurine and azaserine effectively inhibited the growth of the Mecca lymphosarcoma and Leukemia 1210. Also, ß-arabinosyl-6-mercaptopurine and azaserine gave a synergistic response in extending the survival of mice bearing the Ehrlich ascites tumor, at one-one hundredth the dosage of ß-D-arabinosyl-6-mercaptopurine that gave minimal evidence of toxicity. Treatment of pregnant Swiss mice with ß-D-arabinosyl-6-mercaptopurine caused skeletal defects in the fetuses or death and resorption of the fetuses. Depression of lymphoid and myeloid blood elements was found only when C3H mice were treated with high, frequent, and prolonged dosages. The effects of ß-D-arabinosyl-6-mercaptopurine on the cytidylate, guanylate, and adenylate reductases from a 6-mercaptopurine-resistant Ca755 ascites tumor were studied in vitro. The cytidylate reductase was the only one of these 3 reductases inhibited by ß-D-arabinosyl-6-mercaptopurine. Evidence was provided that cytidylate reductase may be a regulatory enzyme for DNA synthesis in the Ca755 and Ehrlich ascites tumors. Variable and nonlinear dose responses were found in treating mice bearing tumors differing slightly from their hosts in histocompatibility loci.

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

Received 6/17/66. Accepted 8/18/66.