CPT-11 converting carboxylesterase and topoisomerase activities in tumour and normal colon and liver tissues.

Abstract

CPT-11 is a prodrug activated by carboxylesterases to the active metabolite SN-38 which is a potent inhibitor of topoisomerase I. CPT-11 is of clinical interest in the treatment of colorectal cancer. We evaluated the activities of CPT-11 converting carboxylesterase (CPT-CE) and topoisomerase I (topo I) in 53 colorectal tumours, in eight liver metastases and in normal tissue adjacent to the tumours. Both CPT-CE and topo I activities were widely variable in the malignant and the normal tissue of patients with colorectal carcinomas. CPT-CE was only two to threefold lower in primary tumours compared to normal liver, suggesting that a local conversion to SN-38 might occur in tumour cells. CPT-CE was similar in liver and in normal colon tissues. Levels of topo I in tumour ranged from 580 to 84 900 U mg protein(-1) and was above 40 000 U mg protein(-1) in 11 of 53 patients. Similarly, a very high ratio (> 5) between tumour and normal tissues were observed in 12 of 53 patients. An inverse correlation was observed between the topo I activity and the clinical stage of disease. Clinical studies are in progress in our institution to explore a possible relationship between CPT-CE and topo I activities in tumour cells and the response to CPT-11-based chemotherapy in patients with colorectal cancer.

• Authors: S Guichard, C Terret, I Hennebelle, I Lochon, P Chevreau, E Frétigny, J Selves, E Chatelut, R Bugat, P Canal
• Journal: British journal of cancer (Br J Cancer) Vol. 80 Issue 3-4 Pg. 364-70 (May 1999) ISSN: 0007-0920 [Print] England
• PMID: 10408839 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents, Phytogenic
• Enzyme Inhibitors
• Topoisomerase I Inhibitors
• Irinotecan
• CPT-11 converting enzyme
• Carboxylic Ester Hydrolases
• DNA Topoisomerases, Type I
• Camptothecin

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents, Phytogenic (pharmacokinetics, pharmacology)
• Camptothecin (analogs & derivatives, pharmacokinetics, pharmacology)
• Carboxylic Ester Hydrolases (metabolism)
• Colon (drug effects, enzymology)
• Colonic Neoplasms (enzymology, pathology)
• DNA Topoisomerases, Type I (metabolism)
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (pharmacokinetics, pharmacology)
• Female
• Humans
• Irinotecan
• Liver (drug effects, enzymology)
• Liver Neoplasms (enzymology, pathology)
• Male
• Middle Aged
• Rectal Neoplasms (enzymology, pathology)
• Topoisomerase I Inhibitors