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The Role of Phosphohydrolases in the Mechanism of Resistance of Neoplastic Cells to 6-Thiopurines¹

Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510

Phosphohydrolase activity was examined in cell-free extracts of Sarcoma 180 and a subline (Sarcoma 180/TG) resistant to both 6-mercaptopurine and 6-thioguanine as well as their respective nucleosides. Acid phosphohydrolase and soluble 5'-nucleotidase activities were identical in the two cell lines, whereas alkaline phosphohydrolase activity was 8 times greater in Sarcoma 180/TG. Alkaline phosphohydrolase activity was localized predominantly in particulate fractions from Sarcoma 180/TG, showed a pH optimum of 9.2, and hydrolyzed a wide variety of phosphate esters, including p-nitrophenylphosphate and 5'-nucleotides, such as 6-thioinosine 5'-phosphate. It is suggested that enhanced breakdown of the active nucleotide form of the 6-thiopurines by alkaline phosphohydrolase is at least partially responsible for the insensitivity of Sarcoma 180/TG to these agents.

¹ This study was supported by Grant CA-02817 from the National Cancer Institute, USPHS, and Grant T-23 from the American Cancer Society.

² Present address: Departments of Oral Biology and Pharmacology, School of Dentistry, The University of Michigan, Ann Arbor, Mich. 48104.

³ Present address: Department of Medicine, University of Washington School of Medicine, Seattle, Wash. 98125.

Received 5/28/71. Accepted 6/30/71.