Characterization of CPT-11 converting carboxylesterase activity in colon tumor and normal tissues:: comparison with p-nitra-phenylacetate converting carboxylesterase activity

Irinotecan (CPT-11) is a topoisomerase I inhibitor commonly used in the treatment of colorectal tumors. It is a prodrug, converted to an active metabolite, SN-38, by carboxylesterases (CEs). CEs are ubiquitary enzymes that react with numerous substrates. A specific CPT-11 converting enzyme was isolated from rat serum, with different kinetic properties than other CEs. We determined kinetic properties of specific CPT-11 CE activity (CPT-CE) In human normal liver and colon tumors. K-m were very similar (3.4 mu M in liver and 3.8 mu M in colon tumors), but V-max was higher in liver (2.7 pmol/min/mg protein) than in colon tumor (1.7 pmol/min/mg protein). CPT-CE and total CE (using p-nitro-phenylacetate as substrate) were weakly correlated in colon tumors. The large interpatient variability observed in liver CPT-CE activity could play a potential role in the pharmacokinetic variability observed with irinotecan. [(C) 2000 Lippincott Williams & Wilkins].