Synergistic antitumor effects of HER2/neu antisense oligodeoxynucleotides and conventional chemotherapeutic agents.
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.
Roh
H
H
Department of Surgery, Washington University School of Medicine, St Louis, MO 63110, USA.
Hirose
C B
CB
Boswell
C B
CB
Pippin
J A
JA
Drebin
J A
JA
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013629:Tamoxifen / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004317:Doxorubicin; D016376:Oligonucleotides, Antisense; D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen