The role of the DNA mismatch repair system in the cytotoxicity of the topoisomerase inhibitors camptothecin and etoposide to human colorectal cancer cells.
The DNA mismatch repair (MMR) system is involved in the correction of base/base mismatches and insertion/deletion loops arising during replication. In addition, some of the MMR components participate in recombination and double-strand break repair as well as cell cycle regulation and apoptosis. The inactivation of MMR genes, usually hMSH2 or hMLH1, is associated with human colorectal cancers and is responsible for the characteristic microsatellite instability (MSI)+ phenotype of these tumors. Because MMR is assumed to modulate cytotoxicity to various chemotherapeutic agents that act upon DNA, our objectives have been to define its possible involvement in the cytotoxicity of topoisomerase inhibitors. We have shown that colorectal cancer cell lines defective in DNA MMR exhibit an increased sensitivity to both camptothecin, a topoisomerase I inhibitor, and etoposide, a topoisomerase II inhibitor. Sensitivity to these drugs cannot be predicted by measuring endogenous levels of topoisomerase I and II. Our results also indicate that neither p53 status, nor cell cycle alterations correlate with the sensitivity of colorectal cancer cells to topoisomerase inhibitors. On the other hand, our data showing that resistance to these drugs can be achieved by the functional complementation of hMLH1 in an hMLH1-defective cell line have allowed us to establish that MMR is a critical determinant for chemosensitivity. Interestingly, our observations provide the rationale for the better responsiveness of MSI+ tumors to CPT-11, a camptothecin derivative, which we have observed in patients with metastatic colorectal cancers.
Jacob
S
S
Centre National de la Recherche Scientifique Unité Mixte de Recherche 1598, Institut Gustave Roussy, 94 800 Villejuif, France.
Aguado
M
M
Fallik
D
D
Praz
F
F
D048868:Adaptor Proteins, Signal Transducing; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D020137:Base Pair Mismatch; D002166:Camptothecin / Q000494:pharmacology*; D002352:Carrier Proteins; D002453:Cell Cycle / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D004260:DNA Repair / Q000502:physiology*; D004264:DNA Topoisomerases, Type I / Q000096:biosynthesis; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis; D004268:DNA-Binding Proteins; D018432:Drug Resistance, Multiple / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology*; D006801:Humans; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D012189:Retrospective Studies; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D000972:Antineoplastic Agents, Phytogenic; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D002166:Camptothecin