Tolerance to methylnitrosourea-induced DNA damage is associated with 6-thioguanine resistance in CHO cells.
Clones (13 and B) of O6-methylguanine-DNA-methyl-transferase-proficient (MT+) CHO cells showing different levels of resistance to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) but similar MT activity, were found to be sensitive to methyl methanesulphonate and resistant to N-methyl-N-nitrosourea (MNU). A 2.8-fold increase in resistance to MNU-induced cytotoxicity was observed in clone 13 and a 16-fold increase in clone B. A slight increase in survival (1.5-fold) after N-ethyl-N-nitrosourea treatment was observed in clone B. These data indicate that the resistant phenotype is specific for agents that preferentially methylate O atoms in DNA. The survival of MNNG- and MNU-resistant clones as well as of the parental CHO cell line was analysed after exposure to purine analogues substituted in different positions, 8-azaguanine (8-AG), 8-azaadenine (8-AA) and 6-thioguanine (6-TG). A 6-fold increase in resistance to 6-TG was found in clone B, although the hypoxanthine guanine phosphoribosyltransferase gene is functional in these cells. The same cytotoxicity was found in all the lines after treatment with 8-AG and 8-AA. These data are in agreement with the previous observation that clone 13 and clone B belong to two different classes of resistance, clone 13 resistance being explained by MT levels. The finding that clone B is cross-resistant to 6-TG is discussed in the light of a mechanism of tolerance to modifications at specific positions of guanine.
Aquilina
G
G
Laboratory of Comparative Toxicology and Ecotoxicology, Istituto Superiore di Sanita', Roma, Italy.
Zijno
A
A
Moscufo
N
N
Dogliotti
E
E
Bignami
M
M
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002999:Clone Cells; D006224:Cricetinae; D003412:Cricetulus; D004249:DNA Damage; D004351:Drug Resistance; D005260:Female; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D008770:Methylnitrosourea / Q000494:pharmacology*; D008780:Methyltransferases / Q000378:metabolism; D019853:O(6)-Methylguanine-DNA Methyltransferase; D010053:Ovary; D013866:Thioguanine / Q000494:pharmacology*
D008770:Methylnitrosourea; D008741:Methyl Methanesulfonate; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D013866:Thioguanine