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.

Abstract

KW-2189, a novel antitumor antibiotic belonging to the duocarmycins, possesses marked DNA-binding activity upon activation by carboxyl esterase to its active form, DU-86. Three duocarmycins, KW-2189, DU-86 and duocarmycin SA, were active against the cisplatin (CDDP)-resistant human 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 which is also resistant to CPT-11 because of decreased intracellular activation of CPT-11, was about 12.8-fold more resistant to KW-2189. HAC2/0.1 was not resistant to other duocarmycins as compared to its parental 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 influence the sensitivity of HAC2 cells to KW-2189. However, the sensitivity of HAC2/0.1 cells to KW-2189 was enhanced to the level of HAC2. These results suggest that HAC2/0.1 is less potent than HAC2 in activating KW-2189. The carboxyl esterase activity of whole-cell and microsomal extracts 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 that decreased intracellular carboxyl esterase activity in HAC2/0.1 cells caused decreased intracellular conversion of KW-2189 to its active form, 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 carboxyl esterase activity.

• Authors: H Ogasawara, K Nishio, F Kanzawa, Y S Lee, Y Funayama, T Ohira, Y Kuraishi, Y Isogai, N Saijo
• Journal: Japanese journal of cancer research : Gann (Jpn J Cancer Res) Vol. 86 Issue 1 Pg. 124-9 (Jan 1995) ISSN: 0910-5050 [Print] Japan
• PMID: 7737904 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Antineoplastic Agents, Phytogenic
• DU 86
• Duocarmycins
• Pyrrolidinones
• KW 2189
• Irinotecan
• DNA
• Carboxylic Ester Hydrolases
• Cisplatin
• Camptothecin

Topics

• Antibiotics, Antineoplastic (therapeutic use)
• Antineoplastic Agents, Phytogenic (therapeutic use)
• Camptothecin (analogs & derivatives, therapeutic use)
• Carboxylic Ester Hydrolases (metabolism, pharmacology)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism)
• Carcinoma, Small Cell (drug therapy, metabolism)
• Cisplatin (therapeutic use)
• DNA (metabolism)
• Drug Resistance
• Drug Resistance, Multiple
• Duocarmycins
• Female
• Humans
• Irinotecan
• Lung Neoplasms (drug therapy, metabolism)
• Microsomes (enzymology)
• Ovarian Neoplasms (drug therapy, metabolism)
• Pyrrolidinones (metabolism, therapeutic use)
• Tumor Cells, Cultured