Differential modulation of chemosensitivity to alkylating agents and platinum compounds by DNA repair modulators in human lung cancer cell lines

Modulation of DNA repair represents one strategy to overcome cellular drug resistance to alkylating agents and platinum compounds. The effects of different known DNA repair modulators such as O-6-benzylguanine (6 mu g/ml), fludarabine (25 ng/ml), aphidicolin (8.5 ng/ml), pentoxifylline (1.4 mu g/ml) and methoxamine (12.4 mu g/ml) on the cytotoxicity of mafosfamide, chlorambucil, 1,3-bis- (2-chloroethyl)-1-nitrosourea (BCNU), cisplatin and carboplatin were tested in human lung cancer cell lines. Methods: Chemosensitivity of the human adenocarcinoma cell line MOR/P and the cisplatin-resistant subline MOR/CPR as well as the large-cell lung cancer cell line L23/P and its cisplatin-resistant counterpart L23/CPR were evaluated by the MTT colorimetric assay. Results: O-6-benzylguanine, an inhibitor of O-6-alkylguanine-DNA alkyltransferase, significantly sensitised MOR/P and MOR/CPR cells to the cytotoxic effect of BCNU. Fludarabine, methoxamine and aphidicolin did not change the chemosensitivity of the parental and cisplatin-resistant cell lines to any cytotoxic drug tested. Interestingly, O-6-benzylguanine enhanced the chemoresistance of parental and cisplatin-resistant cell lines to platinum compounds. Also, pentoxifylline increased resistance of the MOR cell lines to mafosfamide. Conclusions: Modulation of DNA repair elicits not only chemosensitisation but may also enhance cellular resistance to DNA-affine drugs.