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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