CPT-11 converting carboxylesterase and topoisomerase activities in tumour and normal colon and liver tissues.
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.
Guichard
S
S
Groupe de Pharmacologie Clinique et Expérimentale, Institut Claudius Regaud, Toulouse, France.
Terret
C
C
Hennebelle
I
I
Lochon
I
I
Chevreau
P
P
Frétigny
E
E
Selves
J
J
Chatelut
E
E
Bugat
R
R
Canal
P
P
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism*; D003106:Colon / Q000187:drug effects / Q000201:enzymology*; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000473:pathology; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008113:Liver Neoplasms / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012004:Rectal Neoplasms / Q000201:enzymology* / Q000473:pathology; D059004:Topoisomerase I Inhibitors
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; C072888:CPT-11 converting enzyme; D002265:Carboxylic Ester Hydrolases; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin