Augmentation by thymidine of the incorporation and distribution of 5-fluorouracil in ribosomal RNA

The syndrome of 5-fluorouracil cardiotoxicity. An elusive cardiopathy

“…37-39 It potently inhibits thymidylate synthetase by competitive binding, resulting in a thymine-depleted state ("thymine-less death").40-43 This is enhanced by folate c o f a~t o r s .~~,~~ Cytotoxic effects also are mediated through incorporation of fluorodeoxyuridine triphosphate into DNA and of fluorouridine-5' triphosphate (FUTP) and 5-fluorocytosine into RNA.37,46-48 5-FU incorporation into human breast carcinoma RNA has been correlated with cytotoxicity, but it is difficult to determine whether DNA or RNA effects form the major mode of toxicity in a given cell line. 37,[49][50][51] Many other modes of action have been postulated and include alteration of membrane function (effects on calcium channels), interference with mitochondria1 metabolism (energy failure from disruption of the highenergy phosphate balance), inhibition of ribosomal RNA, alteration of macromolecule characteristics (such a s of contractile elements), oxidative damage (pyrimidines are thought to play a role in favism), release of vasoactive substances (histamine and catecholamines are known to cause ultrastructural changes similar to FUTP -RNA( FU) t I…”

Evidence for distinct DNA‐ and RNA‐based mechanisms of 5‐fluorouracil cytotoxicity in Saccharomyces cerevisiae

“…Other experiments also showed a good correlation between the incorporation of 5FU into RNA and cytotoxicity (Greenhalgh and Parish, 1990; Parker and Cheng, 1990). The suggested effects of 5FU on RNA include inhibition of mRNA splicing and polyadenylation, tRNA, snRNA and rRNA base modifications, rRNA processing and self‐splicing of group I introns (Carrico and Glazer, 1979; Doong and Dolnick, 1988; Fang et al , 2004; Lenz et al , 1994; Patton, 1993; Randerath et al , 1983; Samuelsson, 1991; Santi and Hardy, 1987; Zhao and Yu, 2007; Mercure et al , 1993, 1997). However, the significance of these observed effects and their contribution to the cytotoxicity of 5FU remain unclear.…”

Fluorinated Pyrimidines and Their Nucleosides

“…However, production of the initial 45 S rRNA precursor was only slightly inhibited (182). Likewise, rRNA synthesis in regenerating rat liver was severely diminished by FU at doses that were without effect on poly (A) RNA synthesis (185,186). Again, 18 and 28 S rRNA species were depleted in these studies with the accumulation of 38 S precursor rRNA.…”

“…Poly(A)RNA apparently incorporates FU to a greater extent than do other species of RNA (185), but its synthesis is not inhibited appreciably at doses that inhibit rRNA maturation (185,186). Gel electrophoretic analysis of FU-containing poly(A)RNA of regenerating rat liver showed a distribution profile similar to that of normal poly(A)RNA (186). This FU-modified RNA had an enhanced (240%) ability to stimulate translation that was associated with an overall increase in quantity of proteins formed, as well as with a preferential increase in five high molecular weight products.…”

“…This FU-modified RNA had an enhanced (240%) ability to stimulate translation that was associated with an overall increase in quantity of proteins formed, as well as with a preferential increase in five high molecular weight products. Because the FUcontaining RNA appeared to interact normally with initiation sites, and because the size of the translation products was unaltered, the stimulatory effect was thought to reside in the elongation process (186). A comparison of the protein translation products obtained using FU-containing poly(A) RNA and the normal counterpart from Ehrlich ascites cells in cell-free rabbit reticulocyte or wheat germ translating systems showed no major qualitative differences (215).…”