Sequence-dependent enhancement of cytotoxicity produced by ecteinascidin 743 (ET-743) with doxorubicin or paclitaxel in soft tissue sarcoma cells

Clin Cancer Res. 2001 Oct;7(10):3251-7.

Abstract

Ecteinascidin 743 (ET-743) is a potent antitumor agent from the Caribbean tunicate Ecteinascidin turbinata and is presently in clinical trials for human cancers. To better understand how ET-743 might be used clinically, the present study used SRB assays to examine the cytotoxicity resulting from combining ET-743 with three other antineoplastic agents: doxorubicin (DXR), trimetrexate, and paclitaxel in different administration schedules in two soft tissue sarcoma cell lines, HT-1080 and HS-18, in vitro. Concurrent exposure of ET-743 with DXR resulted in synergistic interactions in both cell lines. Addition of ET-743 for 24 h before DXR was the most effective cytotoxic regimen against both cell lines. Morphological study by fluorescence microscopy revealed that combination treatment of both cells with ET-743 and DXR induced apoptosis. Exposure to paclitaxel before ET-743 was also an effective regimen. These results encourage studies of the combination of ET-743 and DXR in the treatment of soft tissue sarcoma, because each of these agents have activity in this disease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Division / drug effects*
  • Dioxoles / pharmacology*
  • Doxorubicin / pharmacokinetics
  • Doxorubicin / pharmacology*
  • Drug Synergism
  • Flow Cytometry
  • Humans
  • Inhibitory Concentration 50
  • Isoquinolines / pharmacology*
  • Microscopy, Fluorescence
  • Paclitaxel / pharmacology*
  • Sarcoma / drug therapy
  • Sarcoma / pathology
  • Tetrahydroisoquinolines
  • Trabectedin
  • Trimetrexate / pharmacology
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism

Substances

  • Antineoplastic Agents
  • Dioxoles
  • Isoquinolines
  • Tetrahydroisoquinolines
  • Doxorubicin
  • Trabectedin
  • Paclitaxel
  • Trimetrexate