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Modulation of 6-Thioguanine Activity by Guanine in Human Promyelocytic Leukemia HL-60 Cells¹

Departments of Pharmacy and Pharmaceutical Chemistry [H-W. C., W. S.] and the Cancer Research Institute [R. D. A.], University of California, San Francisco, California 94143-0446

The effects of guanine coadministration on the metabolism and biological activity of 6-thioguanine (6-TG) were studied in human promyelocytic leukemia cells (HL-60). Cell growth, cytotoxicity (cloning assay), and cell differentiation were measured, along with nucleotide metabolism. Guanine was efficiently salvaged by HL-60 cells; at 200 µM, guanine suppressed the formation of 6-TG mononucleotides and abolished 6-TG incorporation into nucleic acids. Similarly, guanine antagonized 6-TG cytotoxicity in a dose dependent fashion. Furthermore, guanine (200 µM) fully suppressed the 6-TG (10 µM) induced HL-60 cell differentiation, which suggests that cell differentiation at pharmacological 6-TG concentrations is dependent on the anabolism of the drug to active nucleotides. 6-TG given alone reduced GTP levels and DNA synthesis rates in HL-60 cells, while a major intracellular 6-TG metabolite, 6-thioguanosine 5'-monophosphate, accumulated to high levels (100 µM). It is suggested that accumulation of 6-thioguanosine 5'-monophosphate and a resultant partial block of the de novo biosynthesis of guanine nucleotides is responsible for 6-TG induced cell differentiation in HL-60 cells.

¹ This work was supported by USPHS Research Grant CA 27866 from the National Cancer Institute and by Grant CH-329 from the American Cancer Society.

² To whom requests for reprints should be addressed, at School of Pharmacy, University of California, San Francisco, CA 94143-0446.

Received 9/22/86. Revised 4/30/87. Revised 1/26/88. Accepted 3/18/88.