Inhibition of 2-desamino-2-methyl-10-propagyl-5,8-dideazafolic acid cytotoxicity by 5,10-dideazatetrahydrofolate in L1210 cells with decrease in DNA fragmentation and deoxyadenosine triphosphate pools.
5,10-Dideazatetrahydrofolate (DDATHF) is an antifolate drug, the cytotoxic effects of which can be fully reversed by hypoxanthine, suggesting that DDATHF exerts its effects by inhibiting de novo purine biosynthesis. ICI198583 is a quinazoline based inhibitor of thymidylate synthase. In this study we examine the interaction between treatment of mouse leukaemic L1210 cells with these drugs. The addition of DDATHF with ICI198583 was correlated with a decrease in ICI198583 cytotoxicity in a dose dependent manner. This protection was associated with a decrease in DNA fragmentation, and a drop in intracellular dATP pools. These results support the hypothesis that inhibitory effects on de novo purine biosynthesis by inhibitors of dihydrofolate reductase may limit cytotoxicity, and indicate that a rise in dATP pools may be an important cytotoxic signal.
Kwok
J B
JB
Department of Cancer Medicine, University of Sydney, N.S.W., Australia.
Tattersall
M H
MH
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects*; D003838:Deoxyadenine Nucleotides / Q000096:biosynthesis*; D004336:Drug Antagonism; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D019271:Hypoxanthine; D007042:Hypoxanthines / Q000494:pharmacology; D007939:Leukemia L1210 / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D013763:Tetrahydrofolates / Q000494:pharmacology*; D013942:Thymine Nucleotides / Q000096:biosynthesis; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D003838:Deoxyadenine Nucleotides; D005493:Folic Acid Antagonists; D007042:Hypoxanthines; D013763:Tetrahydrofolates; D013942:Thymine Nucleotides; D019271:Hypoxanthine; C045894:lometrexol; D005492:Folic Acid; C026600:2'-deoxyadenosine triphosphate; C059966:ICI 198583; C024157:thymidine 5'-triphosphate