Synergistic antitumor effects of HER2/neu antisense oligodeoxynucleotides and conventional chemotherapeutic agents

Surgery. 1999 Aug;126(2):413-21.

Abstract

Background: The HER2/neu oncogene is overexpressed in a substantial fraction of human tumors. HER2/neu overexpressing tumors may be intrinsically resistant to chemotherapy. The present study examined the ability of antisense-mediated downregulation of HER2/neu expression to enhance the antitumor effects of conventional chemotherapeutic agents against human tumor cells that overexpress HER2/neu.

Methods: The effects of HER2/neu antisense oligodeoxynucleotides (ODNs) on the growth inhibitory and proapoptotic activity of several distinct chemotherapeutic agents were examined in vitro. In vivo effects of HER2/neu antisense ODNs in combination with doxorubicin hydrochloride were assessed by examining the growth of human tumor xenografts implanted into nude mice.

Results: The proliferation of tumor cell lines that overexpress HER2/neu was inhibited by antisense ODNs in combination with conventional chemotherapeutic agents in an additive or synergistic fashion. Such combination therapy also demonstrated synergistic activation of apoptosis. HER2/neu antisense ODNs in combination with doxorubicin hydrochloride demonstrated synergistic antitumor effects in vivo as well.

Conclusions: Downregulation of HER2/neu expression can enhance the sensitivity of human cancer cells, which overexpress HER2/neu to the cytotoxic effects of chemotherapy. Antisense ODNs targeting the HER2/neu gene may play a role in cancer therapy.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Down-Regulation
  • Doxorubicin / pharmacology
  • Drug Synergism
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Oligonucleotides, Antisense / pharmacology*
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Tamoxifen / pharmacology
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Oligonucleotides, Antisense
  • Tamoxifen
  • Doxorubicin
  • Receptor, ErbB-2