CPT-11 in human colon-cancer cell lines and xenografts: characterization of cellular sensitivity determinants

Int J Cancer. 1997 Jan 27;70(3):335-40. doi: 10.1002/(sici)1097-0215(19970127)70:3<335::aid-ijc15>3.0.co;2-e.


CPT-11, a new semisynthetic derivative of camptothecin, is active in a number of tumor types in the clinic, including colon cancer. CPT-11 is a drug that is converted into the active metabolite SN-38 by a carboxylesterase. Experiments were performed to obtain more insight in the cellular characteristics in 5 unselected human colon-cancer cell lines that account for the differential sensitivity to CPT-11 and SN-38. In vitro, the sensitivity to CPT-11 and SN-38 was highest in LS174T and COLO 320 cells, intermediate in SW1398 cells and lowest in COLO 205 and WiDr cells. SN-38 was 130 to 570 times more active than CPT-11. CPT-11 induced complete remissions in 6 out of 12 COLO 320 tumors grown as subcutaneous xenografts, but was not effective in WiDr tumors. The cellular carboxylesterase activity did not relate to the sensitivity to CPT-11. The enzyme activity was higher in normal mouse tissues, i.e., serum and liver, than in COLO 320 or WiDr xenografts, indicating that tumor carboxylesterase is of minor importance for CPT-11 efficacy. The topoisomerase-1 mRNA expression in tumor cells was not predictive of the antiproliferative effects of CPT-11 or SN-38. We observed a positive relationship between the DNA topoisomerase-1 activity and the cellular sensitivity to carboxylesterase-activated CPT-11 (r = 0.75, p < 0.1) as well as to SN-38 (r = 0.89, p < 0.05). The higher topoisomerase-1 activity in COLO 320 cells and tumors when compared with that in WiDr cells and tumors reflected the differences in sensitivity to the drug(s). In conclusion, the DNA topoisomerase-1 activity was the best determinant for CPT-11/SN-38 sensitivity in this panel of unselected human colon-cancer cell lines.

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Camptothecin / analogs & derivatives*
  • Camptothecin / pharmacology
  • Carboxylesterase
  • Carboxylic Ester Hydrolases / metabolism*
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / enzymology*
  • DNA Topoisomerases, Type I / metabolism*
  • Drug Screening Assays, Antitumor
  • Female
  • Humans
  • Irinotecan
  • Mice
  • Mice, Nude
  • Transplantation, Heterologous
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / enzymology


  • Antineoplastic Agents, Phytogenic
  • Irinotecan
  • Carboxylic Ester Hydrolases
  • Carboxylesterase
  • DNA Topoisomerases, Type I
  • Camptothecin