FOLINIC ACID AUGMENTATION OF THE EFFECTS OF FLUOROPYRIMIDINES ON MURINE AND HUMAN-LEUKEMIC CELLS
- 1 October 1986
- journal article
- research article
- Vol. 46 (10) , 5229-5235
Abstract
The effects of the fluoropyrimidines on leukemic cells of mouse and human origin have been studied in the presence of folinic acid. This reduced folate enhanced the cytotoxicity and the growth inhibitory potency of 5-fluorouracil (5-FUra) and of 5-fluoro-2''-deoxyuridine (FUdR) against all cell lines examined. The human leukemic cell lines used (two T- and two B-cells) were affected by these fluoropyrimidines only at substantially higher concentrations than were found to be inhibitory to mouse L1210 cells; however, the enhancement of the activity of the fluoropyrimidines occurred over the same range of folinic acid concentrations in mouse and human cells. Whereas the total intracellular folate pool increased continuously with every increment of folinic acid added to the medium, the enhancement of the potency of the fluoropyrimidines was limited. Augmentation of the effects of FUdR exceeded that of 5-fluorouracil in the human leukemic cells studied. The cytotoxicity of the fluoropyrimidines (as defined by cloning efficiency) was enhanced to a greater extent than was growth inhibition so that an impressive lethal synergism was noted; for instance, exposure of L1210 cells to nontoxic concentrations of 5-fluorouracil or FUdR in the presence of folinic acid resulted in a 98 or 99.9% cell kill, respectively. In contrast to previous predictions, the fluoropyrimidines were more inhibitory to mouse leukemic cells containing folate pools that were suboptimal for growth than for folate-replete cells. Growth rate experiments showed that cells exposed to moderate concentrations of FUdR were initially inhibited but recovered with time, whereas in cells exposed to both FUdR and folinic acid, the initial growth inhibitory effects were sustained. We conclude that folinic acid stabilizes the effects of the fluoropyrimidines on thymidylate synthase of both mouse and human leukemic cell populations and that this enhancement is reflected in both inhibition of the growth of and the lethality to these cells. We suggest that only doses of the fluoropyrimidines that are capable of initially inhibiting thymidylate synthase to a high degree will be synergistic with excess reduced folates.This publication has 21 references indexed in Scilit:
- THE EFFECT OF 5-FLUOROURACIL ON THE SYNTHESIS AND METHYLATION OF LOW-MOLECULAR WEIGHT NUCLEAR-RNA IN L1210-CELLS1980
- Biochemical determinants of tumor sensitivity to 5-fluorouracil: Ultrasensitive methods for the determination of 5-fluoro-2′-deoxyuridylate, 2′-deoxyuridylate, and thymidylate synthetaseProceedings of the National Academy of Sciences, 1979
- EFFECT OF 5-FLUOROURACIL ON THE SYNTHESIS OF NUCLEAR-RNA IN L1210 CELLS INVITRO1979
- BASIS FOR NATURAL VARIATION IN SENSITIVITY TO 5-FLUOROURACIL IN MOUSE AND HUMAN CELLS IN CULTURE1979
- Effect of 5,10-methylenetetrahydrofolate on the dissociation of 5-fluoro-2'-deoxyuridylate from thymidylate synthetase: evidence for an ordered mechanismBiochemistry, 1978
- Cytotoxicity of 5-fluoro-2'-deoxyuridine: requirement for reduced folate cofactors and antagonism by methotrexate.Proceedings of the National Academy of Sciences, 1978
- EFFECTS OF 5-FLUOROURACIL ON 5-FLUORODEOXYURIDINE 5'-MONOPHOSPHATE AND 2-DEOXYURIDINE 5'-MONOPHOSPHATE POOLS, AND DNA-SYNTHESIS IN SOLID MOUSE L1210 AND RAT WALKER 256 TUMORS1978
- CLINICAL-PHARMACOLOGICAL EVALUATION OF HEPATIC ARTERIAL INFUSIONS OF 5-FLUORO-2'-DEOXYURIDINE AND 5-FLUOROURACIL1978
- Folate metabolism in mammalian cells in culture. I Partial characterization of the folate derivatives present in L1210 mouse leukemia cells.Journal of Biological Chemistry, 1976
- EFFECTS OF 5-FLUORODEOXYCYTIDINE, 5-FLUORODEOXYURIDINE, AND RELATED COMPOUNDS ON TRANSPLANTED MOUSE LEUKEMIAS1959