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

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 muf) 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-11 (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-Imutp53), 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.

• Authors: R A Bras-Gonçalves, C Rosty, P Laurent-Puig, P Soulié, B Dutrillaux, M F Poupon
• Journal: British journal of cancer (Br J Cancer) Vol. 82 Issue 4 Pg. 913-23 (Feb 2000) ISSN: 0007-0920 [Print] England
• PMID: 10732766 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• DNA Primers
• Tumor Suppressor Protein p53
• Irinotecan
• Camptothecin

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Base Sequence
• Camptothecin (analogs & derivatives, pharmacology)
• Cell Division (drug effects)
• Colorectal Neoplasms (genetics, pathology)
• DNA Primers
• Female
• Humans
• Irinotecan
• Male
• Mice
• Mice, Nude
• Microsatellite Repeats (genetics)
• Mutation
• Phenotype
• Tumor Suppressor Protein p53 (genetics)