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

Background: The HER2/neu oncogene is overexpressed in a substantial fractio n of human tumors. HER2/neu overexpressing tumors may be intrinsically resi stant to chemotherapy. The present study examined the ability of antisense- mediated downregulation of HER2/neu expression to enhance the antitumor, ef fects of conventional chemotherapeutic agents against human tumor cells tha t overexpress HER2/neu, Methods: The effects of HER2/neu antisense oligodeoxynucleotides (ODNs) on the growth inhibitory and proapoptotic activity of several distinct chemoth erapeutic agents were examined in vitro. In vivo effects of HER2/neu antise nse ODNs in combination with doxorubicin hydrochloride were assessed by exa mining the growth of human tumor xenografts implanted into nude mice. Results: The proliferation of tumor cell lines that overexpress HER2/neu wa s inhibited by antisense ODN's in combination with conventional chemotherap eutic agents in nn additive or synergistic fashion. Such combination therap y also demonstrated synergistic activation of apoptosis. HER2/neu antisense ODNs in combination with doxorubicin hydrochloride demonstrated synergisti c antitumor effects in vivo as well. Conclusions: Downregulation of HER2/neu. expression can enhance the sensiti vity of human cancer cells, which overexpress HER2/neu to the cytotoxic eff ects of chemotherapy. Antisense ODNs targeting the HER2/neu gene may play a role in cancer therapy.