Sensitivity to CPT-11 of xenografted human colorectal cancers as a function of microsatellite instability and p53 status

Bras-Goncalves, R. A., Rosty, C., Laurent-Puig, P., Soulie, P., Dutrillaux, B. and Poupon, M. F. (2000) Sensitivity to CPT-11 of xenografted human colorectal cancers as a function of microsatellite instability and p53 status. British Journal of Cancer, 82 4: 913-923. doi:10.1054/bjoc.1999.1019


Author Bras-Goncalves, R. A.
Rosty, C.
Laurent-Puig, P.
Soulie, P.
Dutrillaux, B.
Poupon, M. F.
Title Sensitivity to CPT-11 of xenografted human colorectal cancers as a function of microsatellite instability and p53 status
Journal name British Journal of Cancer   Check publisher's open access policy
ISSN 0007-0920
1532-1827
Publication date 2000-02
Sub-type Article (original research)
DOI 10.1054/bjoc.1999.1019
Open Access Status DOI
Volume 82
Issue 4
Start page 913
End page 923
Total pages 11
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Formatted abstract
Biological parameters influencing the response of human colorectal cancers (CRCs) to CPT-11, a topoisomerase 1 (top1) inhibitor, were investigated using a panel of nine CRCs xenografted into nude mice. CRC xenografts differed in their p53 status (wt or mut) and in their microsatellite instability phenotype (MSI+ when altered). Five CRC xenografts were established from clinical samples. All five had a functional p53, two were MSI+ and three were MSI-. Tumour-bearing nude mice were treated intraperitonealy (i.p.) with CPT-11. At 10 mg kg-1 of CPT-11, four injections at 4-day intervals, four of the five xenografts responded to CPT-II (growth delay of up to 10 days); the non-responder tumour was MSI-. At 40 mg kg-1 of CPT-11, six injections at 4-day intervals, the five CRCs displayed variable but marked responses with complete regressions. In order to assess the role of p53 status in CPT-11 response, four CRC lines were used. HT29 cell line was MSI-/Ala273-mutp53, its subclone HT29A3 being transfected by wtp53. LoVo cell line was MSI+/wtp53, its subclone X17LoVo dominantly expressed Ala273-mutp53 after transfection. LoVo tumours (MSI+/mutp53) were more sensitive than X17LoVo (MSI+/mutp53. HT 29 tumours (MSI-/mutp53), were refractory to CPT-11 while HT29A3 tumours (MSI-/wtp53) were sensitive, showing that wtp53 improves the drug-response in these MSI- tumours. Levels of mRNA expression of top1, fasR, TP53 and mdr1 were semi-quantified by reverse transcription polymerase chain reaction. None of these parameters correlated with CPT-11 response. Taken together, these observations indicate that MSI and p53 alterations could be associated with different CPT-11 sensitivities; MSI phenotype moderately influences the CPT-11 sensitivity, MSI+ being more sensitive than MSI- CRC freshly obtained from patients, mutp53 status being associated with a poor response to CPT-11.
Keyword Cpt-11
Msi
p53
Top1
Human colorectal cancer
Nude mice
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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Created: Wed, 09 Mar 2011, 14:19:46 EST