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Sensitivity to CPT-11 of xenografted human colorectal cancers as a function of microsatellite instability and p53
R A Bras-Gonçalves1, C Rosty, P Laurent-Puig
1Institut Curie, UMR 147 CNRS-Institut Curie, Paris, France.
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.
Insights
Microsatellite instability (MSI) and p53 alterations influence colorectal cancer response to CPT-11. MSI-positive tumors show greater sensitivity, while mutated p53 is linked to poorer outcomes with this topoisomerase 1 inhibitor.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Colorectal cancer (CRC) treatment response varies significantly.
- CPT-11 (irinotecan) is a topoisomerase 1 inhibitor used in CRC therapy.
- Predictive biomarkers for CPT-11 efficacy are crucial.
Purpose of the Study:
- To investigate biological factors, specifically p53 status and microsatellite instability (MSI) phenotype, influencing CRC response to CPT-11.
- To correlate these parameters with xenografted tumor responses in mice.
Main Methods:
- Utilized a panel of nine human CRC xenografts in nude mice.
- Assessed tumor response to varying doses and schedules of CPT-11.
- Analyzed p53 status (wild-type or mutated) and MSI phenotype (MSI+ or MSI-).
- Quantified mRNA expression of top1, fasR, TP53, and mdr1 via RT-PCR.
Main Results:
- MSI+ CRC xenografts demonstrated greater sensitivity to CPT-11 compared to MSI- tumors.
- Wild-type p53 status was associated with improved CPT-11 response in MSI- tumors.
- Mutated p53 status correlated with a poorer response to CPT-11.
- No correlation was found between top1, fasR, TP53, mdr1 mRNA levels and CPT-11 response.
Conclusions:
- MSI phenotype and p53 alterations are key biological parameters affecting CPT-11 sensitivity in colorectal cancers.
- MSI+ status appears to confer moderate sensitivity, while mutated p53 is linked to resistance.
- These findings suggest potential for biomarker-guided CPT-11 therapy in CRC.