Inhibition of ribonucleotide reductase activity and nucleic acid synthesis in tumor cells by the dialdehyde derivatives of inosine (NSC 118994) and inosinic acid.
Periodate-oxidized inosine (Inox; NSC 118994) and periodate-oxidized 5'-inosinic acid (PI-IMP) were prepared and studied for their effects on ribonucleotide reductase activity in partially purified extracts from Ehrlich tumor cells and on nucleic acid synthesis in intact tumor cells in culture. Ribonucleotide reductase activity in cell-free extracts from Ehrlich tumor cells was inhibited by Inox and PI-IMP. PI-IMP was more inhibitory to the reductase activity than was Inox. Furthermore, the inhibition of ribonucleotide reductase activity by Inox and PI-IMP was greater for cytidine-5'-diphosphate reductase activity than for adenosine-5'-diphosphate reductase activity. The ribonucleotide reductase activity in cell-free extracts prepared from Ehrlich tumor cells treated with Inox or PI-IMP in culture was decreased compared with the activity in the extracts from untreated cells. Incorporation of labeled cytidine into the RNA and DNA of Ehrlich tumor cells in culture was inhibited by both Inox and PI-IMP. The conversion of cytidine to deoxycytidine nucleotides in the acid-soluble pool was likewise inhibited. These data indicate that Inox and PI-IMP inhibit the ribonucleotide reductase step as one of the sites of action of these compounds. However, the inhibition of RNA synthesis indicates that there must be additional sites of action of these nucleoside analogs.
D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D002286:Carcinoma, Ehrlich Tumor / Q000201:enzymology / Q000378:metabolism*; D002478:Cells, Cultured; D004273:DNA, Neoplasm / Q000096:biosynthesis*; D007288:Inosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007291:Inosine Monophosphate / Q000494:pharmacology*; D007292:Inosine Nucleotides / Q000494:pharmacology*; D012334:RNA, Neoplasm / Q000096:biosynthesis*; D012262:Ribonucleoside Diphosphate Reductase / Q000037:antagonists & inhibitors*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D013937:Thymidine Kinase / Q000378:metabolism
D000447:Aldehydes; D004273:DNA, Neoplasm; D007292:Inosine Nucleotides; D012334:RNA, Neoplasm; D007291:Inosine Monophosphate; D007288:Inosine; D012264:Ribonucleotide Reductases; D012262:Ribonucleoside Diphosphate Reductase; D013937:Thymidine Kinase