Carmustine-induced toxicity, DNA crosslinking and O6-methylguanine-DNA methyltransferase activity in two human lung cancer cell lines.
O6-methylguanine-DNA methyltransferase (O6-MT) probably plays an important role in the repair of chloroethylnitrosourea-induced DNA damage. O6-MT was studied as a possible drug resistance factor in two human lung cancer cell lines, one small cell lung cancer (U1690) and one non-small cell lung cancer (U1810), with different sensitivities to carmustine. The U1810 cell line was 3.4-fold more resistant to carmustine than U1690 cells, although the two cell lines were equally sensitive to mustine, melphalan and cisplatin. A 23-fold higher level of DNA interstrand crosslinks was observed following exposure of U1690 cells to carmustine compared with U1810 cells. The O6-MT activity of U1810 cells was 11 times higher than that of U1690 cells. The O6-MT activity in the U1810 cells showed a dose-dependent decrease after exposure to carmustine. These results show a correlation between increased O6-MT activity, decreased drug induced DNA interstrand crosslinking and cellular resistance to carmustine.
Egyházi
S
S
Department of General Oncology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden.
Bergh
J
J
Hansson
J
J
Karran
P
P
Ringborg
U
U
D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology; D018288:Carcinoma, Small Cell / Q000201:enzymology; D002330:Carmustine / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics; D008780:Methyltransferases / Q000378:metabolism*; D009691:Nucleic Acid Denaturation / Q000187:drug effects; D019853:O(6)-Methylguanine-DNA Methyltransferase
D004273:DNA, Neoplasm; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine