Differential modulation of chemosensitivity to alkylating agents and platinum compounds by DNA repair modulators in human lung cancer cell lines.
OBJECTIVE
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 O6-benzylguanine (6 microg/ml), fludarabine (25 ng/ml), aphidicolin (8.5 ng/ml), pentoxifylline (1.4 microg/ml) and methoxamine (12.4 microg/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
O6-benzylguanine, an inhibitor of O6-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, O6-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.
Heim
M M
MM
Department of Internal Medicine (Cancer Research), University of Essen Medical School, West German Cancer Centre Essen, Germany.
Eberhardt
W
W
Seeber
S
S
Müller
M R
MR
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D004260:DNA Repair / Q000187:drug effects*; D004347:Drug Interactions; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D017671:Platinum Compounds / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
D018906:Antineoplastic Agents, Alkylating; D017671:Platinum Compounds; C064976:O(6)-benzylguanine; D006147:Guanine; D014740:Vidarabine; C024352:fludarabine