Open AccessIntracellular Carboxyl Esterase Activity Is a Determinant of Cellular Sensitivity to the Antineoplastic Agent KW‐2189 in Cell Lines Resistant to Cisplatin and CPT‐11
Author(s) -
Ogasawara Hayato,
Nishio Kazuto,
Kanzawa Fumihiko,
Lee YongSik,
Funayama Yasunori,
Ohira Tatsuo,
Kuraishi Yasunobu,
Isogai Yukihide,
Saijo Nagahiro
Publication year - 1995
Publication title -
japanese journal of cancer research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 0910-5050
DOI - 10.1111/j.1349-7006.1995.tb02997.x
Subject(s) - intracellular , cell culture , cisplatin , esterase , biochemistry , chemistry , cell , microbiology and biotechnology , biology , enzyme , chemotherapy , genetics
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.