Cell cycle effects and increased adduct formation by temozolomide enhance the effect of cytotoxic and targeted agents in lung cancer cell lines.
Temozolomide (TMZ) exerts its cytotoxic effects by methylating guanine in DNA, resulting in a mismatch with thymine. We studied possible enhancement of the cytotoxic activity of several other targeted drugs in four lung cancer cell lines by TMZ. the data are in relation to O(6)-alkylguanine-DNA-alkyltransferase (AGT) expression, gene methylation, cell cycle distribution and adduct formation. Synergism/additivity was found with O(6)-BG), gemcitabine, lonafarnib and paclitaxel, but not with platinum analogs and topoisomerase-inhibitors. O(6)-BG enhanced TMZ-induced accumulation in the G2/m-phase by increasing formation and retention of the O(6)-methyldeoxyguanosine adducts. TMZ combinations with drugs showing a different individual effect on the cell cycle (e.g. gemcitabine-induced S-phase) were most effective. The results show that O(6)-BG enhanced the TMZ effect in all cell lines. TMZ enhanced the cytotoxicity of gemcitabine, paclitaxel and lonafarnib in most cell lines, possibly by affecting the cell cycle, supporting possible application of TMZ in the treatment of lung cancer.
Adema
A D
AD
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
van der Born
K
K
Honeywell
R J
RJ
Peters
G J
GJ
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D018736:DNA Adducts / Q000378:metabolism*; D019175:DNA Methylation; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D003849:Deoxyguanosine / Q000031:analogs & derivatives; D004357:Drug Synergism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics; D017239:Paclitaxel / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D000077204:Temozolomide; D000093542:Gemcitabine; D003986:Dibenzocycloheptenes
D018906:Antineoplastic Agents, Alkylating; D018736:DNA Adducts; D003606:Dacarbazine; D003841:Deoxycytidine; D003849:Deoxyguanosine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D017239:Paclitaxel; D010880:Piperidines; D011725:Pyridines; D000077204:Temozolomide; D000093542:Gemcitabine; C015558:O(6)-methyl-2'-deoxyguanosine; C115354:lonafarnib; D003986:Dibenzocycloheptenes