Microsatellite instability due to hMLH1 deficiency is associated with increased cytotoxicity to irinotecan in human colorectal cancer cell lines - PubMed (original) (raw)

Comparative Study

. 2008 Nov 18;99(10):1607-12.

doi: 10.1038/sj.bjc.6604691. Epub 2008 Oct 21.

Affiliations

Comparative Study

Microsatellite instability due to hMLH1 deficiency is associated with increased cytotoxicity to irinotecan in human colorectal cancer cell lines

E Vilar et al. Br J Cancer. 2008.

Abstract

Around 15% of colorectal cancers (CRCs) show microsatellite instability (MSI) due to dysfunction of the mismatch repair system (MMR). As a consequence of this, MSI tumours tend to accumulate errors in mononucleotide repeats as those in genes implicated in repairing double-strand breaks (DSBs). Previous studies have shown that irinotecan (CPT-11), a chemotherapy agent inducing DSB, is more active in MSI than in microsatellite stable (MSS) CRC. The purpose of this study was to compare the sensitivity to CPT-11 in a series of CRC cell lines with either proficient or deficient MMR and to assess the mutational status of two DSB repair genes, MRE11 and RAD50, in these cell lines. hMLH1-deficient cell lines due to either epigenetic silencing or mutation showed very similar IC(50) and were four- to nine-fold more sensitive to CPT-11 than the MSS line. Cell lines harbouring mutations in both MRE11 and RAD50 were most sensitive to CPT-11. We conclude that MSI cell lines display higher sensitivity to CPT-11 than MSS cells. Mutation of MRE11 and RAD50 could account for this difference in response to CPT-11. Future clinical trials tailoring chemotherapy regimens based on microsatellite status are warranted.

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Figures

Figure 1

Figure 1

Expression of hMSH6 (160 kDa), hMSH2 (100 kDa), hMLH1 (83 kDa), and _β_-actin (42 kDa) were analysed by western blotting in whole-cell protein extracts.

Figure 2

Figure 2

Cytotoxicity of CPT-11 to human colorectal cancer cell lines.

Figure 3

Figure 3

Cytotoxicity to CPT-11 of CRC cell lines. Histograms represent the IC50 and error bars represent 95% CI. IC50, concentrations resulting in 50% of growth inhibition; 95% CI, 95% confidence intervals.

Figure 4

Figure 4

Exposure to CPT-11 for 48 h results in G2/M arrest. CRC cell lines were treated with 5 μ

M, 10

μ

M

CPT-11, and supplemented medium (control). Cell cycle analyses were performed by FACS.

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References

    1. Aaltonen LA, Salovaara R, Kristo P, Canzian F, Hemminki A, Peltomaki P, Chadwick RB, Kaariainen H, Eskelinen M, Jarvinen H, Mecklin JP, de la Chapelle A (1998) Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. N Engl J Med 338: 1481–1487 - PubMed
    1. Benatti P, Gafa R, Barana D, Marino M, Scarselli A, Pedroni M, Maestri I, Guerzoni L, Roncucci L, Menigatti M, Roncari B, Maffei S, Rossi G, Ponti G, Santini A, Losi L, Di Gregorio C, Oliani C, Ponz de Leon M, Lanza G (2005) Microsatellite instability and colorectal cancer prognosis. Clin Cancer Res 11: 8332–8340 - PubMed
    1. Bertagnolli MM, Compton CC, Niedzwiecki D, Warren RS, Jewell S, Bailey GP, Mayer RJ, Goldberg R, Saltz L, Redston M (2006) Microsatellite instability predicts improved response to adjuvant therapy with irinotecan, 5-fluorouracil and leucovorin in stage III colon cancer. J Clin Oncol (Meeting Abstracts) 24: 10003–1000 - PMC - PubMed
    1. Carethers JM, Chauhan DP, Fink D, Nebel S, Bresalier RS, Howell SB, Boland CR (1999) Mismatch repair proficiency and in vitro response to 5-fluorouracil. Gastroenterology 117: 123–131 - PMC - PubMed
    1. de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A (2000) Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18: 2938–2947 - PubMed

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