Purine analogs revisited: interference in protein formation.
We have examined in L1210 cells in vitro the effects of three guanine analogs (8-azaguanine, 3-deazaguanine, and 6-thioguanine) on protein biosynthesis and have compared this action with respect to effects on macromolecular synthesis and mechanisms of tumor growth inhibition and cell viability. The major site of action of azaG was the inhibition of protein synthesis. TG seemed to inhibit RNA synthesis more than DNA and protein synthesis. In contrast, DG inhibited both protein and DNA synthesis but not RNA synthesis. Whereas the LD50 and ID50 for macromolecular synthesis for DG and also for azaG were quite similar, for TG the LD50 was one-tenth that of the ID50 for macromolecular synthesis. Since azaG, DG, and TG had different effects on protein and RNA synthesis, the effects of the analogs on the process of translation were examined. DG and azaG, but not TG, altered the polyribosome sedimentation profile, increasing the numbers of monosomes and smaller polysomes and decreasing the number of larger polysomes. This shift in the polysome profile was reversed by low concentrations of cycloheximide, suggesting that DG and azaG inhibited the initiation of translation. This was examined directly by the incorporation of 35S-met-tRNA into the initiation complexes. DG and azaG inhibited the formation of the 43S and 80S initiation complexes and this inhibition correlated closely with the inhibition of total protein synthesis. It is likely that the inhibition of tumor growth by azaG is due to the inhibition of initiation of translation, perhaps through actions on mRNA. The mechanism of growth inhibition for DG is not yet known but may similarly involve actions at this level.
D000818:Animals; D001375:Azaguanine / Q000494:pharmacology; D002478:Cells, Cultured; D004273:DNA, Neoplasm / Q000096:biosynthesis; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis; D011132:Polyribosomes / Q000378:metabolism; D014176:Protein Biosynthesis; D011687:Purines / Q000494:pharmacology*; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013866:Thioguanine / Q000494:pharmacology
D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D011687:Purines; D012334:RNA, Neoplasm; D006147:Guanine; C010567:3-deazaguanine; D013866:Thioguanine; D001375:Azaguanine