Unique pattern of ET-743 activity in different cellular systems with defined deficiencies in DNA-repair pathways

Int J Cancer. 2001 May 15;92(4):583-8. doi: 10.1002/ijc.1221.

Abstract

The cytotoxic activity of ecteinascidin 743 (ET-743), a natural product derived from the marine tunicate Ecteinascidia turbinata that exhibits potent anti-tumor activity in pre-clinical systems and promising activity in phase I and II clinical trials, was investigated in a number of cell systems with well-defined deficiencies in DNA-repair mechanisms. ET-743 binds to N2 of guanine in the minor groove, but its activity does not appear to be related to DNA-topoisomerase I poisoning as the drug is equally active in wild-type yeast and in yeast with a deletion in the DNA-topoisomerase I gene. Defects in the mismatch repair pathway, usually associated with increased resistance to methylating agents and cisplatin, did not affect the cytotoxic activity of ET-743. However, ET-743 did show decreased activity (from 2- to 8-fold) in nucleotide excision repair (NER)-deficient cell lines compared to NER-proficient cell lines, from either hamsters or humans. Restoration of NER function sensitized cells to ET-743 treatment. The DNA double-strand-break repair pathway was also investigated using human glioblastoma cell lines MO59K and MO59J, respectively, proficient and deficient in DNA-dependent protein kinase (DNA-PK). ET-743 was more effective in cells lacking DNA-PK; moreover, pre-treatment of HCT-116 colon carcinoma cells with wortmannin, a potent inhibitor of DNA-PK, sensitized cells to ET-743. An increase in ET-743 sensitivity was also observed in ataxia telangiectasia-mutated cells. Our data strongly suggest that ET-743 has a unique mechanism of interaction with DNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstadienes / pharmacology
  • Animals
  • Antineoplastic Agents, Alkylating / pharmacology*
  • Blotting, Western
  • CHO Cells
  • Camptothecin / pharmacology
  • Cell Survival
  • Cricetinae
  • DNA / metabolism
  • DNA Repair*
  • DNA Topoisomerases, Type I / metabolism
  • DNA-Activated Protein Kinase
  • DNA-Binding Proteins*
  • Dioxoles / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Isoquinolines / pharmacology*
  • Nuclear Proteins
  • Protein-Serine-Threonine Kinases / metabolism
  • Tetrahydroisoquinolines
  • Trabectedin
  • Tumor Cells, Cultured
  • Wortmannin

Substances

  • Androstadienes
  • Antineoplastic Agents, Alkylating
  • DNA-Binding Proteins
  • Dioxoles
  • Enzyme Inhibitors
  • Isoquinolines
  • Nuclear Proteins
  • Tetrahydroisoquinolines
  • DNA
  • DNA-Activated Protein Kinase
  • PRKDC protein, human
  • Protein-Serine-Threonine Kinases
  • DNA Topoisomerases, Type I
  • Trabectedin
  • Camptothecin
  • Wortmannin