This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jacob, S. Articles by Praz, F. Search for Related Content PubMed PubMed Citation Articles by Jacob, S. Articles by Praz, F.

The Role of the DNA Mismatch Repair System in the Cytotoxicity of the Topoisomerase Inhibitors Camptothecin and Etoposide to Human Colorectal Cancer Cells¹

Centre National de la Recherche Scientifique Unité Mixte de Recherche 1598, Institut Gustave Roussy, "Molecular Interactions and Cancer" [S. J., M. A., D. F., F. P.] and Centre National de la Recherche Scientifique Unité Proprede Recherche 2169, "Genetic Instability and Cancer" [S. J., F. P.], 94 800 Villejuif, France

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.

This article has been cited by other articles:

				S. A. Flanagan, C. M. Krokosky, S. Mannava, M. A. Nikiforov, and D. S. Shewach MLH1 Deficiency Enhances Radiosensitization with 5-Fluorodeoxyuridine by Increasing DNA Mismatches Mol. Pharmacol., September 1, 2008; 74(3): 863 - 871. [Abstract] [Full Text] [PDF]

				R. Rodriguez, L. T. Hansen, G. Phear, J. Scorah, M. Spang-Thomsen, A. Cox, T. Helleday, and M. Meuth Thymidine Selectively Enhances Growth Suppressive Effects of Camptothecin/Irinotecan in MSI+ Cells and Tumors Containing a Mutation of MRE11 Clin. Cancer Res., September 1, 2008; 14(17): 5476 - 5483. [Abstract] [Full Text] [PDF]

				C Campregher, M G Luciani, and C Gasche Activated neutrophils induce an hMSH2-dependent G2/M checkpoint arrest and replication errors at a (CA)13-repeat in colon epithelial cells Gut, June 1, 2008; 57(6): 780 - 787. [Abstract] [Full Text] [PDF]

				X. Zeng and T. J. Kinsella Mammalian Target of Rapamycin and S6 Kinase 1 Positively Regulate 6-thioguanine-Induced Autophagy Cancer Res., April 1, 2008; 68(7): 2384 - 2390. [Abstract] [Full Text] [PDF]

				Q. Wen, J. Scorah, G. Phear, G. Rodgers, S. Rodgers, and M. Meuth A Mutant Allele of MRE11 Found in Mismatch Repair-deficient Tumor Cells Suppresses the Cellular Response to DNA Replication Fork Stress in a Dominant Negative Manner Mol. Biol. Cell, April 1, 2008; 19(4): 1693 - 1705. [Abstract] [Full Text] [PDF]

				E. Gurkan, J. E. Schupp, M. A. Aziz, T. J. Kinsella, and K. A. Loparo Probabilistic Modeling of DNA Mismatch Repair Effects on Cell Cycle Dynamics and Iododeoxyuridine-DNA Incorporation Cancer Res., November 15, 2007; 67(22): 10993 - 11000. [Abstract] [Full Text] [PDF]

				K. Yamane, J. E. Schupp, and T. J. Kinsella BRCA1 Activates a G2-M Cell Cycle Checkpoint following 6-Thioguanine-Induced DNA Mismatch Damage Cancer Res., July 1, 2007; 67(13): 6286 - 6292. [Abstract] [Full Text] [PDF]

				H F A Vasen, G Moslein, A Alonso, I Bernstein, L Bertario, I Blanco, J Burn, G Capella, C Engel, I Frayling, et al. Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer) J. Med. Genet., June 1, 2007; 44(6): 353 - 362. [Abstract] [Full Text] [PDF]

				X. Zeng, T. Yan, J. E. Schupp, Y. Seo, and T. J. Kinsella DNA Mismatch Repair Initiates 6-Thioguanine-Induced Autophagy through p53 Activation in Human Tumor Cells Clin. Cancer Res., February 15, 2007; 13(4): 1315 - 1321. [Abstract] [Full Text] [PDF]

				J. R. Hart, O. Glebov, R. J. Ernst, I. R. Kirsch, and J. K. Barton DNA mismatch-specific targeting and hypersensitivity of mismatch-repair-deficient cells to bulky rhodium(III) intercalators PNAS, October 17, 2006; 103(42): 15359 - 15363. [Abstract] [Full Text] [PDF]

				L. Tentori, C. Leonetti, M. Scarsella, A. Muzi, E. Mazzon, M. Vergati, O. Forini, R. Lapidus, W. Xu, A. S. Dorio, et al. Inhibition of poly(ADP-ribose) polymerase prevents irinotecan-induced intestinal damage and enhances irinotecan/temozolomide efficacy against colon carcinoma FASEB J, August 1, 2006; 20(10): 1709 - 1711. [Abstract] [Full Text] [PDF]

				M. A. Shah, N. Kemeny, A. Hummer, M. Drobnjak, M. Motwani, C. Cordon-Cardo, M. Gonen, and G. K. Schwartz Drg1 Expression in 131 Colorectal Liver Metastases: Correlation with Clinical Variables and Patient Outcomes Clin. Cancer Res., May 1, 2005; 11(9): 3296 - 3302. [Abstract] [Full Text] [PDF]

				K. Yamane and T. J. Kinsella Casein Kinase 2 Regulates Both Apoptosis and the Cell Cycle Following DNA Damage Induced by 6-Thioguanine Clin. Cancer Res., March 15, 2005; 11(6): 2355 - 2363. [Abstract] [Full Text] [PDF]

				J. Yu, W. D. Shannon, M. A. Watson, and H. L. McLeod Gene Expression Profiling of the Irinotecan Pathway in Colorectal Cancer Clin. Cancer Res., March 1, 2005; 11(5): 2053 - 2062. [Abstract] [Full Text] [PDF]

				S. Jacob, C. Miquel, A. Sarasin, and F.ço. Praz Effects of camptothecin on double-strand break repair by non-homologous end-joining in DNA mismatch repair-deficient human colorectal cancer cell lines Nucleic Acids Res., January 7, 2005; 33(1): 106 - 113. [Abstract] [Full Text] [PDF]

				Y. Yoshitake, T. Nakatsura, M. Monji, S. Senju, H. Matsuyoshi, H. Tsukamoto, S. Hosaka, H. Komori, D. Fukuma, Y. Ikuta, et al. Proliferation Potential-Related Protein, an Ideal Esophageal Cancer Antigen for Immunotherapy, Identified Using Complementary DNA Microarray Analysis Clin. Cancer Res., October 1, 2004; 10(19): 6437 - 6448. [Abstract] [Full Text] [PDF]

				E. Papouli, P. Cejka, and J. Jiricny Dependence of the Cytotoxicity of DNA-Damaging Agents on the Mismatch Repair Status of Human Cells Cancer Res., May 15, 2004; 64(10): 3391 - 3394. [Abstract] [Full Text] [PDF]

				J. Boyer, E. G. McLean, S. Aroori, P. Wilson, A. McCulla, P. D. Carey, D. B. Longley, and P. G. Johnston Characterization of p53 Wild-Type and Null Isogenic Colorectal Cancer Cell Lines Resistant to 5-Fluorouracil, Oxaliplatin, and Irinotecan Clin. Cancer Res., March 15, 2004; 10(6): 2158 - 2167. [Abstract] [Full Text] [PDF]

				B. W. Robinson, M. M. Im, M. Ljungman, F. Praz, and D. S. Shewach Enhanced Radiosensitization with Gemcitabine in Mismatch Repair-Deficient HCT116 Cells Cancer Res., October 15, 2003; 63(20): 6935 - 6941. [Abstract] [Full Text] [PDF]

				O. Humbert, I. Achour, D. Lautier, G. Laurent, and B. Salles hMSH2 expression is driven by AP1-dependent regulation through phorbol-ester exposure Nucleic Acids Res., October 1, 2003; 31(19): 5627 - 5634. [Abstract] [Full Text] [PDF]

				K. Kishi, Y. Doki, M. Yano, T. Yasuda, Y. Fujiwara, S. Takiguchi, S. Kim, I. Higuchi, and M. Monden Reduced MLH1 Expression after Chemotherapy Is an Indicator for Poor Prognosis in Esophageal Cancers Clin. Cancer Res., October 1, 2003; 9(12): 4368 - 4375. [Abstract] [Full Text] [PDF]

				D. Fallik, F. Borrini, V. Boige, J. Viguier, S. Jacob, C. Miquel, J.-C. Sabourin, M. Ducreux, and F. Praz Microsatellite Instability Is a Predictive Factor of the Tumor Response to Irinotecan in Patients with Advanced Colorectal Cancer Cancer Res., September 15, 2003; 63(18): 5738 - 5744. [Abstract] [Full Text] [PDF]

				G.M. Nash, M. Gimbel, J. Shia, A.T. Culliford, D.R. Nathanson, M. Ndubuisi, Y. Yamaguchi, Z.S. Zeng, F. Barany, and P.B. Paty Automated, Multiplex Assay for High-Frequency Microsatellite Instability in Colorectal Cancer J. Clin. Oncol., August 15, 2003; 21(16): 3105 - 3112. [Abstract] [Full Text] [PDF]

				S. Yanamadala and M. Ljungman Potential Role of MLH1 in the Induction of p53 and Apoptosis by Blocking Transcription on Damaged DNA Templates Mol. Cancer Res., August 1, 2003; 1(10): 747 - 754. [Abstract] [Full Text] [PDF]

				A. Mohindra, L. E. Hays, E. N. Phillips, B. D. Preston, T. Helleday, and M. Meuth Defects in homologous recombination repair in mismatch-repair-deficient tumour cell lines Hum. Mol. Genet., September 1, 2002; 11(18): 2189 - 2200. [Abstract] [Full Text] [PDF]

				C. E. Perrone, K. C. Takahashi, and G. M. Williams Inhibition of Human Topoisomerase II{alpha} by Fluoroquinolones and Ultraviolet A Irradiation Toxicol. Sci., September 1, 2002; 69(1): 16 - 22. [Abstract] [Full Text] [PDF]

				M. Motwani, F. M. Sirotnak, Y. She, T. Commes, and G. K. Schwartz Drg1, a Novel Target for Modulating Sensitivity to CPT-11 in Colon Cancer Cells Cancer Res., July 15, 2002; 62(14): 3950 - 3955. [Abstract] [Full Text] [PDF]