The vitamin E analog, alpha-tocopheryloxyacetic acid enhances the anti-tumor activity of trastuzumab against HER2/neu-expressing breast cancer

Tobias Hahn, Deborah J. Bradley-Dunlop, Laurence Hurley, Daniel Von-Hoff, Stephen Gately, Disis L. Mary, Hailing Lu, Manuel L. Penichet, David G. Besselsen, Brook B. Cole, Tanisha Meeuwsen, Edwin Walker, Emmanuel T. Akporiaye

Research output: Contribution to journalArticle

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Abstract

Background: HER2/neu is an oncogene that facilitates neoplastic transformation due to its ability to transduce growth signals in a ligand-independent manner, is over-expressed in 20-30% of human breast cancers correlating with aggressive disease and has been successfully targeted with trastuzumab (Herceptin®). Because trastuzumab alone achieves only a 15-30% response rate, it is now commonly combined with conventional chemotherapeutic drugs. While the combination of trastuzumab plus chemotherapy has greatly improved response rates and increased survival, these conventional chemotherapy drugs are frequently associated with gastrointestinal and cardiac toxicity, bone marrow and immune suppression. These drawbacks necessitate the development of new, less toxic drugs that can be combined with trastuzumab. Recently, we reported that orally administered alpha-tocopheryloxyacetic acid (α-TEA), a novel ether derivative of alpha-tocopherol, dramatically suppressed primary tumor growth and reduced the incidence of lung metastases both in a transplanted and a spontaneous mouse model of breast cancer without discernable toxicity.Methods: In this study we examined the effect of α-TEA plus HER2/neu-specific antibody treatment on HER2/neu-expressing breast cancer cells in vitro and in a HER2/neu positive human xenograft tumor model in vivo.Results: We show in vitro that α-TEA plus anti-HER2/neu antibody has an increased cytotoxic effect against murine mammary tumor cells and human breast cancer cells and that the anti-tumor effect of α-TEA is independent of HER2/neu status. More importantly, in a human breast cancer xenograft model, the combination of α-TEA plus trastuzumab resulted in faster tumor regression and more tumor-free animals than trastuzumab alone.Conclusion: Due to the cancer cell selectivity of α-TEA, and because α-TEA kills both HER2/neu positive and HER2/neu negative breast cancer cells, it has the potential to be effective and less toxic than existing chemotherapeutic drugs when used in combination with HER2/neu antibody.

Original languageEnglish (US)
Article number471
JournalBMC Cancer
Volume11
DOIs
StatePublished - Nov 2 2011

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Vitamin E
Breast Neoplasms
Neoplasms
Poisons
Heterografts
Pharmaceutical Preparations
Antibodies
Drug Therapy
alpha-Tocopherol
Growth
2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy acetic acid
Trastuzumab
Oncogenes
Ether
Bone Marrow
Neoplasm Metastasis
Ligands
Lung
Incidence

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Genetics

Cite this

The vitamin E analog, alpha-tocopheryloxyacetic acid enhances the anti-tumor activity of trastuzumab against HER2/neu-expressing breast cancer. / Hahn, Tobias; Bradley-Dunlop, Deborah J.; Hurley, Laurence; Von-Hoff, Daniel; Gately, Stephen; Mary, Disis L.; Lu, Hailing; Penichet, Manuel L.; Besselsen, David G.; Cole, Brook B.; Meeuwsen, Tanisha; Walker, Edwin; Akporiaye, Emmanuel T.

In: BMC Cancer, Vol. 11, 471, 02.11.2011.

Research output: Contribution to journalArticle

Hahn, T, Bradley-Dunlop, DJ, Hurley, L, Von-Hoff, D, Gately, S, Mary, DL, Lu, H, Penichet, ML, Besselsen, DG, Cole, BB, Meeuwsen, T, Walker, E & Akporiaye, ET 2011, 'The vitamin E analog, alpha-tocopheryloxyacetic acid enhances the anti-tumor activity of trastuzumab against HER2/neu-expressing breast cancer', BMC Cancer, vol. 11, 471. https://doi.org/10.1186/1471-2407-11-471
Hahn, Tobias ; Bradley-Dunlop, Deborah J. ; Hurley, Laurence ; Von-Hoff, Daniel ; Gately, Stephen ; Mary, Disis L. ; Lu, Hailing ; Penichet, Manuel L. ; Besselsen, David G. ; Cole, Brook B. ; Meeuwsen, Tanisha ; Walker, Edwin ; Akporiaye, Emmanuel T. / The vitamin E analog, alpha-tocopheryloxyacetic acid enhances the anti-tumor activity of trastuzumab against HER2/neu-expressing breast cancer. In: BMC Cancer. 2011 ; Vol. 11.
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abstract = "Background: HER2/neu is an oncogene that facilitates neoplastic transformation due to its ability to transduce growth signals in a ligand-independent manner, is over-expressed in 20-30{\%} of human breast cancers correlating with aggressive disease and has been successfully targeted with trastuzumab (Herceptin{\circledR}). Because trastuzumab alone achieves only a 15-30{\%} response rate, it is now commonly combined with conventional chemotherapeutic drugs. While the combination of trastuzumab plus chemotherapy has greatly improved response rates and increased survival, these conventional chemotherapy drugs are frequently associated with gastrointestinal and cardiac toxicity, bone marrow and immune suppression. These drawbacks necessitate the development of new, less toxic drugs that can be combined with trastuzumab. Recently, we reported that orally administered alpha-tocopheryloxyacetic acid (α-TEA), a novel ether derivative of alpha-tocopherol, dramatically suppressed primary tumor growth and reduced the incidence of lung metastases both in a transplanted and a spontaneous mouse model of breast cancer without discernable toxicity.Methods: In this study we examined the effect of α-TEA plus HER2/neu-specific antibody treatment on HER2/neu-expressing breast cancer cells in vitro and in a HER2/neu positive human xenograft tumor model in vivo.Results: We show in vitro that α-TEA plus anti-HER2/neu antibody has an increased cytotoxic effect against murine mammary tumor cells and human breast cancer cells and that the anti-tumor effect of α-TEA is independent of HER2/neu status. More importantly, in a human breast cancer xenograft model, the combination of α-TEA plus trastuzumab resulted in faster tumor regression and more tumor-free animals than trastuzumab alone.Conclusion: Due to the cancer cell selectivity of α-TEA, and because α-TEA kills both HER2/neu positive and HER2/neu negative breast cancer cells, it has the potential to be effective and less toxic than existing chemotherapeutic drugs when used in combination with HER2/neu antibody.",
author = "Tobias Hahn and Bradley-Dunlop, {Deborah J.} and Laurence Hurley and Daniel Von-Hoff and Stephen Gately and Mary, {Disis L.} and Hailing Lu and Penichet, {Manuel L.} and Besselsen, {David G.} and Cole, {Brook B.} and Tanisha Meeuwsen and Edwin Walker and Akporiaye, {Emmanuel T.}",
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T1 - The vitamin E analog, alpha-tocopheryloxyacetic acid enhances the anti-tumor activity of trastuzumab against HER2/neu-expressing breast cancer

AU - Hahn, Tobias

AU - Bradley-Dunlop, Deborah J.

AU - Hurley, Laurence

AU - Von-Hoff, Daniel

AU - Gately, Stephen

AU - Mary, Disis L.

AU - Lu, Hailing

AU - Penichet, Manuel L.

AU - Besselsen, David G.

AU - Cole, Brook B.

AU - Meeuwsen, Tanisha

AU - Walker, Edwin

AU - Akporiaye, Emmanuel T.

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N2 - Background: HER2/neu is an oncogene that facilitates neoplastic transformation due to its ability to transduce growth signals in a ligand-independent manner, is over-expressed in 20-30% of human breast cancers correlating with aggressive disease and has been successfully targeted with trastuzumab (Herceptin®). Because trastuzumab alone achieves only a 15-30% response rate, it is now commonly combined with conventional chemotherapeutic drugs. While the combination of trastuzumab plus chemotherapy has greatly improved response rates and increased survival, these conventional chemotherapy drugs are frequently associated with gastrointestinal and cardiac toxicity, bone marrow and immune suppression. These drawbacks necessitate the development of new, less toxic drugs that can be combined with trastuzumab. Recently, we reported that orally administered alpha-tocopheryloxyacetic acid (α-TEA), a novel ether derivative of alpha-tocopherol, dramatically suppressed primary tumor growth and reduced the incidence of lung metastases both in a transplanted and a spontaneous mouse model of breast cancer without discernable toxicity.Methods: In this study we examined the effect of α-TEA plus HER2/neu-specific antibody treatment on HER2/neu-expressing breast cancer cells in vitro and in a HER2/neu positive human xenograft tumor model in vivo.Results: We show in vitro that α-TEA plus anti-HER2/neu antibody has an increased cytotoxic effect against murine mammary tumor cells and human breast cancer cells and that the anti-tumor effect of α-TEA is independent of HER2/neu status. More importantly, in a human breast cancer xenograft model, the combination of α-TEA plus trastuzumab resulted in faster tumor regression and more tumor-free animals than trastuzumab alone.Conclusion: Due to the cancer cell selectivity of α-TEA, and because α-TEA kills both HER2/neu positive and HER2/neu negative breast cancer cells, it has the potential to be effective and less toxic than existing chemotherapeutic drugs when used in combination with HER2/neu antibody.

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