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 tre atment of colorectal tumors. It is a prodrug, converted to an active metabo lite, SN-38, by carboxylesterases (CEs). CEs are ubiquitary enzymes that re act with numerous substrates. A specific CPT-11 converting enzyme was isola ted from rat serum, with different kinetic properties than other CEs. We de termined kinetic properties of specific CPT-11 CE activity (CPT-CE) In huma n normal liver and colon tumors. K-m were very similar (3.4 mu M in liver a nd 3.8 mu M in colon tumors), but V-max was higher in liver (2.7 pmol/min/m g 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 col on tumors. The large interpatient variability observed in liver CPT-CE acti vity could play a potential role in the pharmacokinetic variability observe d with irinotecan. [(C) 2000 Lippincott Williams & Wilkins].