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Synergistic antitumor effects of HER2/neu antisense oligodeoxynucleotides and conventional chemotherapeutic agents
H Roh1, C B Hirose, C B Boswell
1Department of Surgery, Washington University School of Medicine, St Louis, MO 63110, USA.
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.
Insights
Antisense therapy targeting the HER2/neu oncogene can enhance chemotherapy effectiveness against HER2/neu overexpressing tumors. This combination therapy shows synergistic antitumor effects in vitro and in vivo.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- HER2/neu oncogene overexpression is common in human tumors.
- HER2/neu overexpressing tumors may exhibit intrinsic resistance to chemotherapy.
- Investigating strategies to overcome chemoresistance in HER2/neu positive cancers is crucial.
Purpose of the Study:
- To evaluate if antisense-mediated downregulation of HER2/neu expression can enhance chemotherapy efficacy.
- To assess the combined effects of HER2/neu antisense oligodeoxynucleotides (ODNs) and chemotherapeutic agents.
- To determine the impact on tumor cell proliferation and apoptosis.
Main Methods:
- In vitro studies assessed the effects of HER2/neu antisense ODNs combined with various chemotherapeutic agents on tumor cell growth and apoptosis.
- In vivo experiments utilized human tumor xenografts in nude mice to evaluate the combination of HER2/neu antisense ODNs and doxorubicin hydrochloride.
- Tumor growth inhibition and synergistic activation of apoptosis were key outcome measures.
Main Results:
- Combination therapy involving HER2/neu antisense ODNs and chemotherapeutic agents demonstrated additive or synergistic inhibition of tumor cell proliferation.
- Synergistic activation of apoptosis was observed with the combination therapy.
- In vivo studies showed synergistic antitumor effects when HER2/neu antisense ODNs were combined with doxorubicin hydrochloride.
Conclusions:
- Downregulating HER2/neu expression can sensitize HER2/neu overexpressing human cancers to chemotherapy.
- Antisense ODNs targeting HER2/neu represent a potential therapeutic strategy for enhancing cancer treatment outcomes.
- This approach may improve the efficacy of conventional chemotherapy in specific cancer types.