CPT-11 in human colon-cancer cell lines and xenografts: Characterization of cellular sensitivity determinants
✍ Scribed by Willy J.M. Jansen; Bas Zwart; Saskia T.M. Hulscher; Giuseppe Giaccone; Herbert M. Pinedo; Epic Boven
- Publisher
- John Wiley and Sons
- Year
- 1997
- Tongue
- French
- Weight
- 104 KB
- Volume
- 70
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
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-I 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-I activity and the cellular sensitivity to carboxylesteraseactivated CPT-11 (r 5 0.75, p F 0.1) as well as to SN-38 (r 5 0.89, p F 0.05). The higher topoisomerase-I 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-I activity was the best determinant for CPT-11/SN-38 sensitivity in this panel of unselected human colon-cancer cell lines.