INTRACELLULAR CARBOXYL ESTERASE-ACTIVITY IS A DETERMINANT OF CELLULAR-SENSITIVITY TO THE ANTINEOPLASTIC AGENT KW-2189 IN CELL-LINES RESISTANT TO CISPLATIN AND CPT-11

KW-2189, a novel antitumor antibiotic belonging to the duocarmycins, p ossesses marked DNA-binding activity upon activation by carboxyl ester ase to its active form, DU-86. Three duocarmycins, KW-2189, DU-86 and duocarmycin SA, were active against the cisplatin (CDDP)-resistant hum an non-small cell lung cancer cell lines PC-9/CDDP and PC-14/CDDP, and the multidrug-resistant human small cell lung cancer cell line H69/VP . However, HAC2/0.1, a CDDP-resistant human ovarian cancer cell line w hich is also resistant to CPT-11 because of decreased intracellular ac tivation of CPT-11, was about 12.8-fold more resistant to KW-2189. HAC 2/0.1 was not resistant to other duocarmycins as compared to its paren tal cell line, HAC2. There was no difference between HAC2 and HAC2/0.1 with regard to the intracellular accumulation of KW-2189. Addition of 130 mU/ml of carboxyl esterase to the culture medium did not influenc e the sensitivity of HAC2 cells to KW-2189, However, the sensitivity o f HAC2/0.1 cells to KW-2189 was enhanced to the level of HAC2, These r esults suggest that HAC2/0.1 is less potent than HAC2 in activating KW -2189, The carboxyl esterase activity of whole-cell and microsomal ext racts from HAC2/0.1 was approximately 60% of that from HAC2. The cell- free experiment revealed that KW-2189 bound to DNA more efficiently in the presence of HAC2 than HAC2/0.1 cell extract. It was concluded tha t decreased intracellular carboxyl esterase activity in HAC2/0.1 cells caused decreased intracellular conversion of KW-2189 to its active fo rm, thus producing resistance to KW-2189. The decreased conversion of CPT-11 to SN-38 in HAC2/0.1 cells might be explained by decreased carb oxyl esterase activity.