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

• Published in: Cancer science 1995-01, Vol.86 (1), p.124-129
• Main Authors: Ogasawara, Hayato, Nishio, Kazuto, Kanzawa, Fumihiko, Lee, Yong‐Sik, Funayama, Yasunori, Ohira, Tatsuo, Kuraishi, Yasunobu, Isogai, Yukihide, Saijo, Nagahiro
• Format: Article
• Language: English
• Subjects: Antibiotics, Antineoplastic - therapeutic use; Antineoplastic agents; Antineoplastic Agents, Phytogenic - therapeutic use; Biological and medical sciences; Camptothecin - analogs & derivatives; Camptothecin - therapeutic use; Carboxyl esterase; Carboxylic Ester Hydrolases - metabolism; Carboxylic Ester Hydrolases - pharmacology; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Small Cell - drug therapy; Carcinoma, Small Cell - metabolism; Cell culture; Cisplatin; Cisplatin - therapeutic use; CPT‐11; Deoxyribonucleic acid; DNA; DNA - metabolism; Drug Resistance; Drug Resistance, Multiple; Duocarmycin; Esterase; Female; General aspects; Humans; Intracellular; Irinotecan; KW‐2189; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Medical sciences; Microsomes - enzymology; Non-small cell lung carcinoma; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Pharmacology. Drug treatments; Pyrrolidinones - metabolism; Pyrrolidinones - therapeutic use; Tumor cell lines; Tumor Cells, Cultured
• ISSN: 0910-5050; 1347-9032; 1349-7006; 1876-4673
• DOI: 10.1111/j.1349-7006.1995.tb02997.x

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.