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Enhancement of the Differentiation-inducing Properties of 6-Thioguanine by Hypoxanthine and Its Nucleosides in HL-60 Promyelocytic Leukemia Cells¹

Department of Pharmacology and Developmental Therapeutics Program, Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06510

Previous work has shown that 6-thioguanine (TGua) is an effective inducer of differentiation of Friend and HL-60 leukemia cells which lack hypoxanthine-guanine phosphoribosyltransferase but is at best only weakly active in inducing maturation in parental wild-type cells. Studies in wild-type and mutant HL-60 cells have provided evidence that the free-base TGua is the form of this drug that induces differentiation, while the formation of TGua nucleotides leads to cytotoxicity and inhibits differentiation. To attempt to increase the potential of TGua to serve as an inducer of parental HL-60 leukemia cells, physiological purine and pyrimidine nucleosides were tested for their ability to protect HL-60 cells against TGua-induced cytotoxicity. Adenosine, deoxyadenosine, inosine, and deoxyinosine completely prevented the toxic action of the purinethiol, while guanosine and deoxyguanosine were only partially effective. The capacity of adenosine and deoxyadenosine to prevent the cytotoxicity of TGua was abolished by the inhibitor of adenosine deaminase, deoxycoformycin, implying that inosine and deoxyinosine were the active forms of the protecting agents. The protective activities of inosine and deoxyinosine appeared to depend on phosphorolysis catalyzed by purine nucleoside phosphorylase, since exogenously added hypoxanthine was as effective as inosine in reducing the cytotoxicity of the purine antimetabolite. Accumulation of TGua nucleotides in the acid-soluble fraction of HL-60 cells treated with TGua was significantly decreased by the presence of inosine. Inosine also served under these circumstances as a D-ribose 1-phosphate donor to TGua, as evidenced by its increased conversion to 6-thioguanosine. The prevention of the cytotoxicity of TGua by the simultaneous administration of hypoxanthine or its nucleosides resulted in an expression of the differentiation-inducing properties of TGua in HL-60 cells, as measured by the accumulation of nitroblue tetrazolium-positive cells. These findings support the concept that the processes of cytotoxicity and differentiation are separable events produced by different metabolic forms of the purine antimetabolite.

¹ This research was supported in part by USPHS Grants CA-02817 and CA-28852 from the National Cancer Institute.

² To whom requests for reprints should be addressed.

Received 7/24/84. Accepted 9/13/84.