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. 2010 Jul 27;103(3):340-6.
doi: 10.1038/sj.bjc.6605780. Epub 2010 Jul 6.

5-Fluorouracil response in a large panel of colorectal cancer cell lines is associated with mismatch repair deficiency

K Bracht  1 , A M Nicholls, Y Liu, W F Bodmer
Affiliations

5-Fluorouracil response in a large panel of colorectal cancer cell lines is associated with mismatch repair deficiency

K Bracht et al. Br J Cancer. .

Abstract

Background: Colorectal cancer is (CRC) one of the commonest cancers and its therapy is still based on few drugs. Currently, no biological criteria are used to choose the most effective of the established drugs for treatment.

Methods: A panel of 77 CRC cell lines was tested for sensitivity to 5-fluorouracil (5FU) using the SRB assay. The responses were grouped into three categories and correlated with genetic changes in the cell lines.

Results: The strongest and most clearcut correlation was between 5-fluorouracil response and replication error status (mismatch repair deficiency). All the other significant correlations (loss of heterozygosity for DCC and mutations in TGFbIIR) are secondary to the association with replication error status.

Interpretation and conclusion: Our findings validate previous analyses based mainly on clinical data, and indicate that replication error status could be a useful guide to 5-fluorouracil-based CRC therapy. Essentially, all previously described correlations with 5FU response are secondary to the association with replication error status.

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Figures

Figure 1
Figure 1
5-Fluorouracil GI50 values and correlation with RER status and TGFbIIR mutations. Sensitivity to 5FU is plotted by rank order. Cell lines are divided into three response groups (terciles). GI50 values=diamonds, RER status=circles (+) and squares (−), and mutations in TGFbIIR=triangles (mut) and diamonds (wt); cell lines from pairs of duplicates that are excluded from the analysis (see Materials and Methods) are represented by smaller and lighter symbols. Significance was tested as described in Table 1.
Figure 2
Figure 2
Representative dose-response curves. 5-Fluorouracil dose-response curves are shown using the SRB assay and incubation for three doubling times. Curves are examples from one experimental repeat and illustrate the response of the cell lines HDC73 (sensitive), SW403 (intermediate response), and COLO678 (resistant).
Figure 3
Figure 3
Drug responses in Matrigel. Total number of colonies per field of vision with a × 10 objective. s.d. are calculated from n=3 independent experiments.
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