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, 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.
Ogasawara
H
H
Pharmacology Division, National Cancer Center Research Institute, Tokyo.
Nishio
K
K
Kanzawa
F
F
Lee
Y S
YS
Funayama
Y
Y
Ohira
T
T
Kuraishi
Y
Y
Isogai
Y
Y
Saijo
N
N
D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism* / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism; D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000378:metabolism; D002945:Cisplatin / Q000627:therapeutic use; D004247:DNA / Q000378:metabolism; D004351:Drug Resistance; D018432:Drug Resistance, Multiple; D000080890:Duocarmycins; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008861:Microsomes / Q000201:enzymology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011760:Pyrrolidinones / Q000378:metabolism / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; C092034:DU 86; D000080890:Duocarmycins; D011760:Pyrrolidinones; C086920:KW 2189; D000077146:Irinotecan; D004247:DNA; D002265:Carboxylic Ester Hydrolases; D002945:Cisplatin; D002166:Camptothecin