Evidence for a relationship between intracellular GTP levels and the induction of HL-60 leukemia cell differentiation by 5,10-dideazatetrahydrofolic acid (DDATHF).
5,10-Dideazatetrahydrofolic acid (DDATHF) is an inhibitor of glycinamide ribonucleotide transformylase, the first of two tetrahydrofolate requiring enzymes in the de novo purine nucleotide biosynthetic pathway, and is a potent inducer of the maturation of HL-60 promyelocytic leukemia cells. The inhibition of cellular growth by DDATHF was effectively prevented by adenosine or deoxyadenosine, whereas guanosine or deoxyguanosine only partially prevented the growth inhibition produced by this folate antimetabolite, implying that the depletion of both ATP and GTP, which occurs with this agent, was responsible for its growth inhibitory effects. In contrast, the induction of differentiation by DDATHF was completely abolished by the presence of guanosine or deoxyguanosine, suggesting that the depletion of intracellular guanine nucleotides by DDATHF represents the event that is essential to the induction of differentiation by this folate analog. This possibility was supported by the observation that the concentration of dGTP was not decreased in cells treated with DDATHF under the conditions employed. Both guanine nucleosides selectively restored intracellular GTP pools depleted by the treatment with DDATHF to their normal level, whereas only adenine nucleosides completely restored the levels of both ATP and GTP to their normal intracellular concentrations. The relationship between guanine nucleotide pools and the induction of HL-60 differentiation by DDATHF was further supported by the finding that maturation and the depletion of intracellular GTP by DDATHF were not reversed by guanine nucleosides in HL-60 cells deficient in hypoxanthine-guanine phosphoribosyltransferase activity. The findings provide support for the hypothesis that the terminal differentiation of these leukemic cells by DDATHF is the result of the depletion of intracellular GTP pools.
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510.
J A
JA
Sokoloski
G
G
Pizzorno
G P
GP
Beardsley
A C
AC
Sartorelli
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D006160:Guanosine Triphosphate / Q000378:metabolism*; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D011685:Purine Nucleotides / Q000378:metabolism; D013763:Tetrahydrofolates / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D011685:Purine Nucleotides; D013763:Tetrahydrofolates; C045894:lometrexol; D006160:Guanosine Triphosphate