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

Br J Cancer. 2000 Feb;82(4):913-23. doi: 10.1054/bjoc.1999.1019.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


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