Cell Cycle Effects and Increased Adduct Formation by Temozolomide Enhance the Effect of Cytotoxic and Targeted Agents in Lung Cancer Cell Lines

Abstract

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 O⁶-alkylguanine-DNA-alkyltransferase (AGT) expression, gene methylation, cell cycle distribution and adduct formation. Synergism/additivity was found with O⁶-benzylguanine (O⁶-BG), gemcitabine, lonafarnib and paclitaxel, but not with platinum analogs and topoisomerase-inhibitors. O⁶-bG enhanced TMZ-induced accumulation in the G2/m-phase by increasing formation and retention of the O⁶- 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 O⁶-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.

Keywords:

• Temozolomide
• non-small cell lung cancer
• MGMT
• cytotoxic agents
• targeted agents