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

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-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. © 2000 Cancer Research Campaign