title: GU81, a VEGFR2 antagonist peptoid, enhances the anti-tumor activity of doxorubicin in the murine MMTV-PyMT transgenic model of breast cancer.
abstract: BACKGROUND
  Vascular endothelial growth factor (VEGF) is a primary stimulant of angiogenesis under physiological and pathological conditions. Anti-VEGF therapy is a clinically proven strategy for the treatment of a variety of cancers including colon, breast, lung, and renal cell carcinoma. Since VEGFR2 is the dominant angiogenic signaling receptor, it has become an important target in the development of novel anti-angiogenic therapies. We have reported previously the development of an antagonistic VEGFR2 peptoid (GU40C4) that has promising anti-angiogenic activity in vitro and in vivo.
  
  
  METHODS
  In the current study, we utilize a derivative of GU40C4, termed GU81 in therapy studies. GU81 was tested alone or in combination with doxorubicin for in vivo efficacy in the MMTV-PyMT transgenic model of breast cancer.
  
  
  RESULTS
  The derivative GU81 has increased in vitro efficacy compared to GU40C4. Single agent therapy (doxorubicin or GU81 alone) had no effect on tumor weight, histology, tumor fat content, or tumor growth index. However, GU81 is able to significantly to reduce total vascular area as a single agent. GU81 used in combination with doxorubicin significantly reduced tumor weight and growth index compared to all other treatment groups. Furthermore, treatment with combination therapy significantly arrested tumor progression at the premalignant stage, resulting in increased tumor fat content. Interestingly, treatment with GU81 alone increased tumor-VEGF levels and macrophage infiltration, an effect that was abrogated when used in combination with doxorubicin.
  
  
  CONCLUSIONS
  This study demonstrates the VEGFR2 antagonist peptoid, GU81, enhances the anti-tumor activity of doxorubicin in spontaneous murine MMTV-PyMT breast tumors.
authors.affiliation: Division of Surgical Oncology, Department of Surgery, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 76259, USA.
authors.forename: Kristi D
authors.initials: KD
authors.lastname: Lynn
authors.forename: D Gomika
authors.initials: DG
authors.lastname: Udugamasooriya
authors.forename: Christina L
authors.initials: CL
authors.lastname: Roland
authors.forename: Diego H
authors.initials: DH
authors.lastname: Castrillon
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kodadek
authors.forename: Rolf A
authors.initials: RA
authors.lastname: Brekken
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000494:pharmacology*; D034444:Peptoids / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C555531:GU 81 compound; D010455:Peptides; D034444:Peptoids; D042461:Vascular Endothelial Growth Factor A; D004317:Doxorubicin; D040301:Vascular Endothelial Growth Factor Receptor-2