Cellular parameters predictive of the clinical response of colorectal cancers to irinotecan. A preliminary study.
BACKGROUND
We have examined, in this study, the feasibility of determining cellular factors contributing to irinotecan activity in colorectal cancers. Irinotecan is a camptothecin derivative requiting carboxylesterase activation to SN-38, which interacts with its target enzyme, topoisomerase I.


METHODS
In 9 surgical or biopsy samples of colorectal tumours and corresponding normal tissue, kept in a tumour bank, we evaluated topoisomerase I expression and activity, respectively by Western blotting and DNA relaxation assay, carboxylesterase activity using two different substrates and p53 status by immunohistochenistry.


RESULTS
Topoisomerase I expression and activity were significantly correlated, as were the two types of determinations for carboxylesterase activity. Topoisomerase I was significantly more active in tumours than in corresponding normal tissue. The three samples presenting the highest topoisomerase I expression and activity originated from the patients who responded to irinotecan treatment. No such features were apparent for carboxylesterase activity and p53 staining.


CONCLUSIONS
Topoisomerase I expression appeared as the parameter most likely to predict response to irinotecan therapy in the clinical setting.
Pavillard
Valérie
V
Laboratoire de Pharmacologie des Agents Anticancéreux, Institut Bergonié et Université Victor Segalen Bordeaux 2, 229, cours de l'Argonne 33076 Bordeaux-cedex, France.
Charasson
Virginie
V
Laroche-Clary
Audrey
A
Soubeyran
Isabelle
I
Robert
Jacques
J
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D015153:Blotting, Western; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D043182:Carboxylesterase / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D059004:Topoisomerase I Inhibitors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D059004:Topoisomerase I Inhibitors; D016159:Tumor Suppressor Protein p53; D000077146:Irinotecan; D043182:Carboxylesterase; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin