Mechanisms of action of 6-thioguanine, 6-mercaptopurine, and 8-azaguanine.
The effects of 6-thioguanine on purine biosynthesis and cell viability have been examined in H.Ep. 2 cells grown in culture. Toxicity is not reversed by aminoimidazolecarboxamide, suggesting that inhibition of purine biosynthesis de novo is not the sole mechanism of toxicity. Also, 6-(methylmercapto)purine ribonucleoside, a potent inhibitor of purine biosynthesis de novo, produces more marked reductions in cellular pools of purines than does 6-thioguanine without killing cells. There is no apparent inhibition by 6-thioguanosine 5'-monophosphate of other enzymes leading to the synthesis of guanosine 5'-triphosphate as determined in whole cells by measurements of radioactive hypoxanthine or guanine incorporation. Inhibition of DNA synthesis by 1 mM thymidine protects cells from 6-mercaptopurine or 6-thioguanine but fails to protect cells from 8-azaguanine toxicity. On the other hand, inhibition of RNA synthesis by 6-azauridine plus deoxycytidine protects cells against 8-azaguanine but does not protect against 6-thioguanine or 6-mercaptopurine toxicity. In agreement with the in vitro data, arabinosylcytosine (a potent inhibitor of DNA synthesis) fails to protect mice against 8-azaguanine but has previously been shown to protect mice from 6-mercaptopurine or 6-thioguanine toxicity. The results support the hypotheses of others that incorporation into DNA (as 6-thioguanine nucleotide) is a mechanism of toxicity for these thiopurines, whereas 8-azaguanine is toxic due to its incorporation into RNA.
D001375:Azaguanine / Q000494:pharmacology*; D001380:Azauridine / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000096:biosynthesis; D003841:Deoxycytidine / Q000494:pharmacology; D006147:Guanine / Q000378:metabolism; D007042:Hypoxanthines / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D015122:Mercaptopurine / Q000494:pharmacology*; D008778:Methylthioinosine / Q000494:pharmacology; D011687:Purines / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013866:Thioguanine / Q000494:pharmacology*; D013936:Thymidine / Q000494:pharmacology
D004273:DNA, Neoplasm; D007042:Hypoxanthines; D007093:Imidazoles; D011687:Purines; D012334:RNA, Neoplasm; D003561:Cytarabine; D003841:Deoxycytidine; D008778:Methylthioinosine; D006147:Guanine; D001380:Azauridine; D015122:Mercaptopurine; D013866:Thioguanine; D001375:Azaguanine; D013936:Thymidine