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CPT‐11 in human colon‐cancer cell lines and xenografts: Characterization of cellular sensitivity determinants
Author(s) -
Jansen Willy J.M.,
Zwart Bas,
Hulscher Saskia T.M.,
Giaccone Giuseppe,
Pinedo Herbert M.,
Boven Epic
Publication year - 1997
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19970127)70:3<335::aid-ijc15>3.0.co;2-e
Subject(s) - colorectal cancer , cancer research , cell culture , medicine , cancer , oncology , biology , pathology , genetics
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‐l 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. Int. J. Cancer , 70:335–340, 1997. © 1997 Wiley‐Liss, Inc.