du-86 has been researched along with Lung-Neoplasms* in 1 studies
1 other study(ies) available for du-86 and Lung-Neoplasms
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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. Topics: Antibiotics, Antineoplastic; Antineoplastic Agents, Phytogenic; Camptothecin; Carboxylic Ester Hydrolases; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Cisplatin; DNA; Drug Resistance; Drug Resistance, Multiple; Duocarmycins; Female; Humans; Irinotecan; Lung Neoplasms; Microsomes; Ovarian Neoplasms; Pyrrolidinones; Tumor Cells, Cultured | 1995 |