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

Jpn J Cancer Res. 1995 Jan;86(1):124-9. doi: 10.1111/j.1349-7006.1995.tb02997.x.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibiotics, Antineoplastic / therapeutic use*
  • Antineoplastic Agents, Phytogenic / therapeutic use
  • Camptothecin / analogs & derivatives
  • Camptothecin / therapeutic use
  • 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
  • Cisplatin / therapeutic use
  • DNA / metabolism
  • Drug Resistance*
  • Drug Resistance, Multiple
  • Duocarmycins
  • Female
  • Humans
  • Irinotecan
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Microsomes / enzymology
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / metabolism
  • Pyrrolidinones / metabolism
  • Pyrrolidinones / therapeutic use
  • Tumor Cells, Cultured

Substances

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