Expression of genes involved in nucleotide excision repair and sensitivity to cisplatin and melphalan in human cancer cell lines.
DNA repair has been proposed to be an important determinant of cancer cell sensitivity to alkylating agents and cisplatin (DDP). Nucleotide excision repair (NER), which represents one of the most important cellular DNA repair processes able to remove a broad spectrum of DNA lesions, is involved in the recognition and repair of the crosslinks caused by DDP and melphalan (L-PAM). In this study, the mRNA levels of the different genes involved in NER (ERCC1, XPA, XPB, XPC, XPD, XPF) were examined in a panel of eight different human cancer cell lines, together with the overall DNA repair capacity using a host cell reactivation assay of a damaged plasmid. A statistically significant correlation was observed between the relative expression of XPA/XPC (P < 0.05) and ERCC1/XPC (P < 0.05) mRNAs. No correlation was found between the DDP and L-PAM IC50S and the relative mRNA expression of the tested NER genes. When the overall cellular DNA repair capacity was studied, carcinomas seemed to have a higher repair activity than leukaemias; but this repair DNA activity correlated neither with the mRNA expression of the different NER genes nor with DDP and L-PAM IC50S. These data seem to suggest that even if the NER pathway is an important determinant for the cytotoxicity of alkylating agents, as demonstrated by the extremely high sensitivity to alkylating agents in cells lacking this repair system, other factors have to play a role in regulating the cellular sensitivity/resistance to these antitumour drugs.
Damia
G
G
Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Guidi
G
G
D'Incalci
M
M
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D015152:Blotting, Northern; D002945:Cisplatin / Q000008:administration & dosage; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics; D004260:DNA Repair; D005260:Female; D015870:Gene Expression; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics; D008558:Melphalan / Q000008:administration & dosage; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D002945:Cisplatin; D008558:Melphalan