Modulation of 6-thioguanine activity by guanine in human promyelocytic leukemia HL-60 cells.
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 microM, 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 microM) fully suppressed the 6-TG (10 microM) 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 (approximately 100 microM). 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.
Cheng
H W
HW
Department of Pharmacy, University of California, San Francisco 94143-0446.
Armstrong
R D
RD
Sadée
W
W
D001711:Biotransformation; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006147:Guanine / Q000494:pharmacology*; D006150:Guanine Nucleotides / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D009696:Nucleic Acids / Q000378:metabolism; D010766:Phosphorylation; D013866:Thioguanine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D006150:Guanine Nucleotides; D009696:Nucleic Acids; D006147:Guanine; D013866:Thioguanine