6-Methylguanine and 6-methylguanosine inhibit colony-forming ability in a malignant xeroderma pigmentosum cell line but not in other xeroderma pigmentosum and normal human fibroblast strains after treatment with 1-(2-chloroethyl)-1-nitroso-3-(2-hydroxyethyl)-urea.
The XP cell strain XP29MA, its malignant counterpart XP29MAmal and a normal human fibroblast strain were tested for colony-forming ability after treatment with HECNU in the presence of m6G, m6Gua, and he7G. In XP29MAmal, inhibition of post-HECNU colony-forming ability was 35% when 0.25 mM of either m6G or m6Gua were present, whereas in XP29MA and the normal fibroblast strain no inhibition was detected. The he7G caused a similar but smaller inhibitory effect in XP29MAmal, but failed to do so in XP29MA. HECNU predominantly exerts its killing effect by alkylating O-6 of DNA-bound guanine and causing DNA interstrand crosslinks. Alkylation of O-6 of guanine can be repaired by 6-methylguanine-DNA methyltransferase. From our experiments we conclude that in XP29MAmal this methyltransferase was inhibited in the presence of the 6-alkylguanines, thus leaving more 2-chloroethylated sites in DNA unrepaired. This results in sensitization in terms of decreased colony-forming ability observed only in the malignant cell line.
D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D006147:Guanine / Q000031:analogs & derivatives* / Q000633:toxicity; D006151:Guanosine / Q000031:analogs & derivatives* / Q000633:toxicity; D006801:Humans; D008780:Methyltransferases / Q000037:antagonists & inhibitors; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009607:Nitrosourea Compounds / Q000633:toxicity*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D014983:Xeroderma Pigmentosum / Q000201:enzymology / Q000235:genetics* / Q000473:pathology
D009607:Nitrosourea Compounds; D006151:Guanosine; D006147:Guanine; C008449:O-(6)-methylguanine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; C013876:elmustine