title: The vitamin E analog, alpha-tocopheryloxyacetic acid enhances the anti-tumor activity of trastuzumab against HER2/neu-expressing breast cancer.
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.
  
  
  CONCLUSIONS
  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.
authors: Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, Portland, OR 97213, USA. tobias.hahn@providence.org
authors: Tobias
authors: T
authors: Hahn
authors: Deborah J
authors: DJ
authors: Bradley-Dunlop
authors: Laurence H
authors: LH
authors: Hurley
authors: Daniel
authors: D
authors: Von-Hoff
authors: Stephen
authors: S
authors: Gately
authors: Disis L
authors: DL
authors: Mary
authors: Hailing
authors: H
authors: Lu
authors: Manuel L
authors: ML
authors: Penichet
authors: David G
authors: DG
authors: Besselsen
authors: Brook B
authors: BB
authors: Cole
authors: Tanisha
authors: T
authors: Meeuwsen
authors: Edwin
authors: E
authors: Walker
authors: Emmanuel T
authors: ET
authors: Akporiaye
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000975:Antioxidants / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D008954:Models, Biological; D010446:Peptide Fragments / Q000378:metabolism; D024505:Tocopherols / Q000494:pharmacology*; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000975:Antioxidants; D010446:Peptide Fragments; C488288:2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy acetic acid; D000068878:Trastuzumab; D024505:Tocopherols