Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Tumor Biology
Published in: Tumor Biology 12/2015

01-12-2015 | Research Article

Association between mismatch repair gene and irinotecan-based chemotherapy in metastatic colon cancer

Authors: Junli Ma, Yan Zhang, Hong Shen, Linda Kapesa, Wenqiang Liu, Mengsi Zeng, Shan Zeng

Published in: Tumor Biology | Issue 12/2015

Login to get access

Abstract

Mismatch repair (MMR) gene is closely related to the pathogenesis of colon cancer. This study aimed to evaluate the association between MMR status and efficacy of irinotecan-based chemotherapy. As a target of 5-FU, thymidylate synthase (TS) expression level might be influenced by irinotecan. Understanding whether this influence of TS is related with MMR status is helpful to the further exploration of the mechanism of irinotecan sensitivity in metastatic colon cancer with different MMR status. One hundred eighty-four patients with metastatic colon cancer receiving irinotecan-based chemotherapy for the first-line treatment were included. Correlations between MMR and clinicopathological characteristics and prognosis were determined. Two pairs of colon cancer cell lines (HCT-116-hMLH1Vector (deficient MMR, dMMR) versus HCT-116-hMLH1+ (proficient MMR, pMMR); SW480-shRNA-hMLH1 (dMMR) versus SW480-shRNA-Control (pMMR)) were established by regulating MMR status. Sensitivity of these cell lines to irinotecan was determined by MTT assay. Regulation of TS by irinotecan was evaluated by western blotting and quantitative real-time PCR assay. dMMR accounted for 18.5 % and was related with proximal colon cancer (p = 0.005), poorly differentiated tumors (p = 0.018) and favorable efficacy with a higher disease control rate (DCR), a longer progression-free survival (PFS) and a trend of longer overall survival (OS). dMMR colon cancer cells were more sensitive to irinotecan. TS expression level was reduced more in dMMR cells after irinotecan treatment (p < 0.05). Our study favors an increased sensitivity of irinotecan in colon cancer with dMMR status. MMR status may be a predictive biomarker of response to irinotecan-based chemotherapy in metastatic colon cancer.
Appendix
Available only for authorised users
Literature
1.
Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CA Cancer J Clin. 2014;64:104–17.CrossRefPubMed
2.
Gibson J, Lacy J, Matloff E, Robert M. Microsatellite instability testing in colorectal carcinoma: a practical guide. Clin Gastroenterol Hepatol. 2014;12:171–6.CrossRefPubMed
3.
Buecher B, Cacheux W, Rouleau E, Dieumegard B, Mitry E, et al. Role of microsatellite instability in the management of colorectal cancers. Dig Liver Dis. 2013;45:441–9.CrossRefPubMed
4.
5.
Pino MS, Chung DC. Microsatellite instability in the management of colorectal cancer. Expert Rev Gastroenterol Hepatol. 2011;5:385–99.CrossRefPubMed
6.
Lin CC, Lai YL, Lin TC, Chen WS, Jiang JK, et al. Clinicopathologic features and prognostic analysis of MSI-high colon cancer. Int J Color Dis. 2012;27:277–86.CrossRef
7.
Meyers M, Wagner MW, Hwang HS, Kinsella TJ, Boothman DA. Role of the hMLH1 DNA mismatch repair protein in fluoropyrimidine-mediated cell death and cell cycle responses. Cancer Res. 2001;61:5193–201.PubMed
8.
Duldulao MP, Lee W, Le M, Chen Z, Li W, et al. Gene expression variations in microsatellite stable and unstable colon cancer cells. J Surg Res. 2012;174:1–6.CrossRefPubMed
9.
Devaud N, Gallinger S. Chemotherapy of MMR-deficient colorectal cancer. Familial Cancer. 2013;12:301–6.CrossRefPubMed
10.
Sinicrope FA, Foster NR, Thibodeau SN, Marsoni S, Monges G, et al. DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-fluorouracil-based adjuvant therapy. J Natl Cancer Inst. 2011;103:863–75.CrossRefPubMedPubMedCentral
11.
Juo YY, Johnston FM, Zhang DY, Juo HH, Wang H, et al. Prognostic value of CpG island methylator phenotype among colorectal cancer patients: a systematic review and meta-analysis. Ann Oncol. 2014;25:2314–27.
12.
Sato K, Kitajima Y, Kohya N, Koga Y, Ohtaka K, et al. CPT-11 (SN-38) chemotherapy may be selectively applicable to biliary tract cancer with low hMLH1 expression. Anticancer Res. 2007;27:865–72.PubMed
13.
Bendardaf R, Lamlum H, Ristamaki R, Korkeila E, Syrjanen K, et al. Mismatch repair status is a predictive factor of tumour response to 5-fluorouracil and irinotecan chemotherapy in patients with advanced colorectal cancer. Tumour Biol. 2007;28:212–20.CrossRefPubMed
14.
Vilar E, Scaltriti M, Balmana J, Saura C, Guzman M, et al. Microsatellite instability due to hMLH1 deficiency is associated with increased cytotoxicity to irinotecan in human colorectal cancer cell lines. Br J Cancer. 2008;99:1607–12.CrossRefPubMedPubMedCentral
15.
Bertagnolli MM, Niedzwiecki D, Compton CC, Hahn HP, Hall M, et al. Microsatellite instability predicts improved response to adjuvant therapy with irinotecan, fluorouracil, and leucovorin in stage III colon cancer: Cancer and Leukemia Group B Protocol 89803. J Clin Oncol. 2009;27:1814–21.CrossRefPubMedPubMedCentral
16.
Bhonde MR, Hanski ML, Stehr J, Jebautzke B, Peiro-Jordan R, et al. Mismatch repair system decreases cell survival by stabilizing the tetraploid G1 arrest in response to SN-38. Int J Cancer. 2010;126:2813–25.PubMedPubMedCentral
17.
Torigoe S, Ogata Y, Matono K, Shirouzu K. Molecular mechanisms of sequence-dependent antitumor effects of SN-38 and 5-fluorouracil combination therapy against colon cancer cells. Anticancer Res. 2009;29:2083–9.PubMed
18.
Fukushima M, Sakamoto K, Ohshimo H, Nakagawa F, Taguchi T. Irinotecan overcomes the resistance to 5-fluorouracil in human colon cancer xenografts by down-regulation of intratumoral thymidylate synthase. Oncol Rep. 2010;24:835–42.PubMed
19.
Zeng S, Tao Y, Huang J, Zhang S, Shen L, et al. WD40 repeat-containing 62 overexpression as a novel indicator of poor prognosis for human gastric cancer. Eur J Cancer. 2013;49:3752–62.CrossRefPubMed
20.
Shen LF, Chen J, Zeng S, Zhou RR, Zhu H, et al. The superparamagnetic nanoparticles carrying the E1A gene enhance the radiosensitivity of human cervical carcinoma in nude mice. Mol Cancer Ther. 2010;9:2123–30.CrossRefPubMed
21.
Yoon YS, Yu CS, Kim TW, Kim JH, Jang SJ, et al. Mismatch repair status in sporadic colorectal cancer: immunohistochemistry and microsatellite instability analyses. J Gastroenterol Hepatol. 2011;26:1733–9.CrossRefPubMed
22.
23.
Fallik D, Borrini F, Boige V, Viguier J, Jacob S, et al. Microsatellite instability is a predictive factor of the tumor response to irinotecan in patients with advanced colorectal cancer. Cancer Res. 2003;63:5738–44.PubMed
24.
Kim JC, Roh SA, Cho DH, Kim TW, Yoon SN, et al. Chemoresponsiveness associated with canonical molecular changes in colorectal adenocarcinomas. Anticancer Res. 2009;29:3115–23.PubMed
25.
Braun MS, Richman SD, Quirke P, Daly C, Adlard JW, et al. Predictive biomarkers of chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS trial. J Clin Oncol. 2008;26:2690–8.CrossRefPubMed
26.
Koopman M, Kortman GA, Mekenkamp L, Ligtenberg MJ, Hoogerbrugge N, et al. Deficient mismatch repair system in patients with sporadic advanced colorectal cancer. Br J Cancer. 2009;100:266–73.CrossRefPubMedPubMedCentral
27.
Kim JE, Hong YS, Ryu MH, Lee JL, Chang HM, et al. Association between deficient mismatch repair system and efficacy to irinotecan-containing chemotherapy in metastatic colon cancer. Cancer Sci. 2011;102:1706–11.CrossRefPubMed
28.
Kim TW, Innocenti F. Insights, challenges, and future directions in irinogenetics. Ther Drug Monit. 2007;29:265–70.CrossRefPubMed
29.
Kim JH, Shin SH, Kwon HJ, Cho NY, Kang GH. Prognostic implications of CpG island hypermethylator phenotype in colorectal cancers. Virchows Arch. 2009;455:485–94.CrossRefPubMed
30.
Lochhead P, Kuchiba A, Imamura Y, Liao X, Yamauchi M, et al. Microsatellite instability and BRAF mutation testing in colorectal cancer prognostication. J Natl Cancer Inst. 2013;105:1151–6.CrossRefPubMedPubMedCentral
31.
Samadder NJ, Vierkant RA, Tillmans LS, Wang AH, Weisenberger DJ, et al. Associations between colorectal cancer molecular markers and pathways with clinicopathologic features in older women. Gastroenterology. 2013;145:348–56.CrossRefPubMedPubMedCentral
32.
33.
Fedier A, Schwarz VA, Walt H, Carpini RD, Haller U, et al. Resistance to topoisomerase poisons due to loss of DNA mismatch repair. Int J Cancer. 2001;93:571–6.CrossRefPubMed
34.
Jacob S, Aguado M, Fallik D, Praz F. The role of the DNA mismatch repair system in the cytotoxicity of the topoisomerase inhibitors camptothecin and etoposide to human colorectal cancer cells. Cancer Res. 2001;61:6555–62.PubMed
35.
Magrini R, Bhonde MR, Hanski ML, Notter M, Scherubl H, et al. Cellular effects of CPT-11 on colon carcinoma cells: dependence on p53 and hMLH1 status. Int J Cancer. 2002;101:23–31.CrossRefPubMed
36.
Elliott B, Jasin M. Repair of double-strand breaks by homologous recombination in mismatch repair-defective mammalian cells. Mol Cell Biol. 2001;21:2671–82.CrossRefPubMedPubMedCentral
37.
Tahara M, Inoue T, Sato F, Miyakura Y, Horie H, et al. The use of Olaparib (AZD2281) potentiates SN-38 cytotoxicity in colon cancer cells by indirect inhibition of Rad51-mediated repair of DNA double-strand breaks. Mol Cancer Ther. 2014;13:1170–80.CrossRefPubMed
38.
Inoue Y, Tanaka K, Hiro J, Yoshiyama S, Toiyama Y, et al. in vitro synergistic antitumor activity of a combination of 5-fluorouracil and irinotecan in human colon cancer. Int J Oncol. 2006;28:479–86.PubMed
39.
Guichard S, Cussac D, Hennebelle I, Bugat R, Canal P. Sequence-dependent activity of the irinotecan-5FU combination in human colon-cancer model HT-29 in vitro and in vivo. Int J Cancer. 1997;73:729–34.CrossRefPubMed
40.
Inoue Y, Miki C, Watanabe H, Hiro J, Toiyama Y, et al. Schedule-dependent cytotoxicity of 5-fluorouracil and irinotecan in a colon cancer cell line. J Gastroenterol. 2006;41:1149–57.CrossRefPubMed
41.
Cao S, Rustum YM. Synergistic antitumor activity of irinotecan in combination with 5-fluorouracil in rats bearing advanced colorectal cancer: role of drug sequence and dose. Cancer Res. 2000;60:3717–21.PubMed
42.
Azrak RG, Cao S, Slocum HK, Toth K, Durrani FA, et al. Therapeutic synergy between irinotecan and 5-fluorouracil against human tumor xenografts. Clin Cancer Res. 2004;10:1121–9.CrossRefPubMed
43.
Ide H, Kikuchi E, Hasegawa M, Hattori S, Yasumizu Y, et al. Therapeutic enhancement of S-1 with CPT-11 through down-regulation of thymidylate synthase in bladder cancer. Cancer Med. 2013;2:488–95.CrossRefPubMedPubMedCentral
44.
Takiuchi H, Kawabe S, Gotoh M, Katsu K. Thymidylate synthase gene expression in primary tumors predicts activity of s-1-based chemotherapy for advanced gastric cancer. Gastrointest Cancer Res. 2007;1:171–6.PubMedPubMedCentral
45.
Jensen SA, Vainer B, Kruhoffer M, Sorensen JB. Microsatellite instability in colorectal cancer and association with thymidylate synthase and dihydropyrimidine dehydrogenase expression. BMC Cancer. 2009;9:25.CrossRefPubMedPubMedCentral
46.
Kristensen MH, Weidinger M, Bzorek M, Pedersen PL, Mejer J. Correlation between thymidylate synthase gene variants, RNA and protein levels in primary colorectal adenocarcinomas. J Int Med Res. 2010;38:484–97.CrossRefPubMed
47.
Ohrling K, Karlberg M, Edler D, Hallstrom M, Ragnhammar P. A combined analysis of mismatch repair status and thymidylate synthase expression in stage II and III colon cancer. Clin Colorectal Cancer. 2013;12:128–35.CrossRefPubMed
Metadata
Title
Association between mismatch repair gene and irinotecan-based chemotherapy in metastatic colon cancer
Authors
Junli Ma
Yan Zhang
Hong Shen
Linda Kapesa
Wenqiang Liu
Mengsi Zeng
Shan Zeng
Publication date
01-12-2015
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 12/2015
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-3723-5

Other articles of this Issue 12/2015

Tumor Biology 12/2015 Go to the issue

Research Article

High expression of CD39/ENTPD1 in malignant epithelial cells of human rectal adenocarcinoma

Research Article

TGIF1 promoted the growth and migration of cancer cells in nonsmall cell lung cancer

Research Article

Association between polymorphisms of BAG-1 and XPD and chemotherapy sensitivity in advanced non-small-cell lung cancer patients treated with vinorelbine combined cisplatin regimen

Original Article

Autoantibodies to chromogranin A are potential diagnostic biomarkers for non-small cell lung cancer

Research Article

The possible role of EZH2 and DNMT1 polymorphisms in sporadic triple-negative breast carcinoma in southern Chinese females

Research Article

Stage-dependent changes of preoperative neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in colorectal cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits