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-II, a topoisomerase 1 (top1) inhibitor, were investigated usi ng a panel of nine CRCs xenografted into nude mice. CRC xenografts differed in their p53 status (wt or mut) and in their microsatellite instability ph enotype (MSI+ when altered), Five CRC xenografts were established from clin ical samples. All five had a functional p53, two were MSI+ and three were M SI-. 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); th e 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 w ith 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-mutp5 3, its subclone HT29A3 being transfected by wtp53. LoVo cell line was MSI+/ wtp53, its subclone X17LoVo dominantly expressed Ala273-mutp53 after transf ection. LoVo tumours (MSI+/mutp53) were more sensitive than X17LoVo (MSI+/m utp53). HT 29 tumours (MSI-/mutp53), were refractory to CPT-11 while HT29A3 rumours (MSI-/wtp53) were sensitive, showing that wtp53 improves the drug response in these MSI- rumours. Levels of mRNA expression of top1, fasR, TP 53 and mdr1 were semi-quantified by reverse transcription polymerase chain reaction. None of these parameters correlated with CPT-11 response. Taken t ogether, these observations indicate that MSI and p53 alterations could be associated with different CPT-11 sensitivities; MSI+ phenotype moderately i nfluences the CPT-II sensitivity, MSI+ being more sensitive than MSI- CRC f reshly obtained from patients, mutp53 status being associated with a poor r esponse to CPT-11. (C) 2000 Cancer Research Campaign.