Increased sensitivity to oxanosine, a novel nucleoside antibiotic, of rat kidney cells upon expression of the integrated viral src gene.
The mechanism of antitumor action of oxanosine was studied using a strain of rat kidney cells infected with a mutant Rous sarcoma virus, the src gene of which was temperature sensitive. Oxanosine inhibited cell growth in vitro, as well as nucleic acid synthesis in these cells, 10 times more strongly at a permissive temperature (33 degrees C) than at a non-permissive temperature (39 degrees C). Protein synthesis was inhibited only slightly at either temperature. The inhibition of cell growth and nucleic acid synthesis was reversed by guanosine, GMP, and to a lesser extent by adenosine and inosine. Oxanosine inhibited the conversion of [14C]hypoxanthine to guanine nucleotides in cells and again in the same temperature-related fashion. The conversion to adenine nucleotides was not inhibited. Oxanosine-5'-monophosphate was found to be a potent nearly competitive inhibitor, with respect to IMP, of IMP dehydrogenase (EC 1.2.1.14; IMP:NAD+ oxidoreductase) isolated from cells grown either at 33 degrees C or at 39 degrees C; with the former and the latter enzyme preparations, KmS for IMP were 6.0 X 10(-6) M and 5.3 X 10(-6) M, respectively, while Kis for oxanosine-5'-monophosphate were 1-3 X 10(-6) M and 5.2 X 10(-6) M, as well.
Uehara
Y
Y
Hasegawa
M
M
Hori
M
M
Umezawa
H
H
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001358:Avian Sarcoma Viruses / Q000235:genetics; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D005814:Genes, Viral / Q000187:drug effects*; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors; D007668:Kidney / Q000187:drug effects; D009857:Oncogenes; D011687:Purines / Q000494:pharmacology; D012313:RNA / Q000096:biosynthesis; D051381:Rats; D012263:Ribonucleosides / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D011687:Purines; D012263:Ribonucleosides; D012313:RNA; C032886:oxanosine; D004247:DNA; D007168:IMP Dehydrogenase