The target cell determinants of the antitumor actions of 5-FU: does FU incorporation into RNA play a role?
Sufficient evidence has accumulated to permit the conclusion that there are at least two major determinants for the effectiveness of 5-FU against tumors. These are the formation of fluorodeoxyuridylate (FdUMP) and the incorporation of 5-FU into RNA. Either or both of these determinants can be of critical significance in the tumor-inhibitory actions of 5-FU and the sensitivity of normal tissues of this drug, depending on the biological system and the experimental conditions. The critical role for FdUMP and inhibition of DNA synthesis as a cell target determinant is supported by the recognition of "thymineless death;" the time-course correlation of levels of this metabolite (and/or or susceptibility of thymidylate synthetase) with tumor sensitivity to 5-FU and with cytotoxicity to specific organs and tissues; and the reversibility of the actions of 5-Fu by thymidine in vitro. A role for 5-FU incorporated in RNA (FU-RNA) is based on various toxic consequences of the incorporation of the analog, including the inhibition of ribosomal maturation; the occasionally reported lack of rescue from growth inhibition with thymidine, which prevents the 5-FU induced inhibition of DNA synthesis, apparently with increased FU-RNA formation; the activity of uridine as a partial rescue agent, and various studies revealing correlations of FU-RNA with enhanced therapeutic response.
D000818:Animals; D004269:DNA, Bacterial / Q000096:biosynthesis; D004273:DNA, Neoplasm / Q000096:biosynthesis; D005468:Fluorodeoxyuridylate / Q000378:metabolism; D005472:Fluorouracil / Q000378:metabolism* / Q000627:therapeutic use; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D012329:RNA, Bacterial / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000378:metabolism*; D013936:Thymidine / Q000494:pharmacology
D004269:DNA, Bacterial; D004273:DNA, Neoplasm; D012329:RNA, Bacterial; D012334:RNA, Neoplasm; D005468:Fluorodeoxyuridylate; D005472:Fluorouracil; D013936:Thymidine