Biochemical modulation of 5-fluoropyrimidine toxicity by dehydroepiandrosterone in human colonic adenocarcinoma cells.
Exposure to dehydroepiandrosterone caused a concentration-dependent accumulation of HT-29 human colonic adenocarcinoma cells in S-phase and sensitization toward the cytotoxic effects of fluorouracil deoxyriboside but not 5-fluorouracil. These effects were synergistic at all tested concentrations of dehydroepiandrosterone (25-100 microM) and fluorouracil deoxyriboside (0.1-10 microM). Sterilization of cultures occurred at a fluorouracil deoxyriboside concentration of 1.0 microM in the presence of 50 microM dehydroepiandrosterone, while sterilization in the absence of dehydroepiandrosterone required nearly a 10-fold higher concentration of drug. Even in HT-29 cells selected for the ability to grow in 50 microM dehydroepiandrosterone, a synergistic response with fluorouracil deoxyriboside was observed. Double label experiments to examine the relative rates of incorporation of [14C]thymidine and [3H]uracil into DNA thymidine indicated that dehydroepiandrosterone exposure preferentially enhanced the de novo pathway for thymidylate synthesis, suggesting that this shift may have contributed to the observed synergism with fluorouracil deoxyriboside. Compared to controls, however, the salvage pathway for thymidylate biosynthesis was also stimulated following exposure to dehydroepiandrosterone. These results and the non-toxic nature of this naturally occurring steroid suggest that dehydroepiandrosterone may be useful as a biochemical modulator of fluorouracil deoxyriboside and, perhaps, other nucleoside analogs in cancer treatment.
Nyce
J
J
Department of Pharmacology, School of Medicine, East Carolina University, Greenville, NC 27858-4354.
Klann
R C
RC
Holbrook
C T
CT
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D002250:Carbon Radioisotopes; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D005472:Fluorouracil / Q000633:toxicity; D006801:Humans; D007399:Interphase / Q000187:drug effects; D011743:Pyrimidines / Q000633:toxicity*; D013936:Thymidine / Q000378:metabolism; D013938:Thymidine Monophosphate / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D014498:Uracil / Q000378:metabolism
D002250:Carbon Radioisotopes; D011743:Pyrimidines; D013938:Thymidine Monophosphate; D003687:Dehydroepiandrosterone; D014498:Uracil; C029269:5-fluoropyrimidine; D005472:Fluorouracil; D013936:Thymidine