title: Vascular priming enhances chemotherapeutic efficacy against head and neck cancer.
abstract: OBJECTIVE
  The need to improve chemotherapeutic efficacy against head and neck squamous cell carcinomas (HNSCC) is well recognized. In this study, we investigated the potential of targeting the established tumor vasculature in combination with chemotherapy in head and neck cancer.
  
  
  METHODS
  Experimental studies were carried out in multiple human HNSCC xenograft models to examine the activity of the vascular disrupting agent (VDA) 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in combination with chemotherapy. Multimodality imaging (magnetic resonance imaging, bioluminescence) in conjunction with drug delivery assessment (fluorescence microscopy), histopathology and microarray analysis was performed to characterize tumor response to therapy. Long-term treatment outcome was assessed using clinically-relevant end points of efficacy.
  
  
  RESULTS
  Pretreatment of tumors with VDA prior to administration of chemotherapy increased intratumoral drug delivery and treatment efficacy. Enhancement of therapeutic efficacy was dependent on the dose and duration of VDA treatment but was independent of the chemotherapeutic agent evaluated. Combination treatment resulted in increased tumor cell kill and improvement in progression-free survival and overall survival in both ectopic and orthotopic HNSCC models.
  
  
  CONCLUSIONS
  Our results show that preconditioning of the tumor microenvironment with an antivascular agent primes the tumor vasculature and results in enhancement of chemotherapeutic delivery and efficacy in vivo. Further investigation into the activity of antivascular agents in combination with chemotherapy against HNSCC is warranted.
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Folaron
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: James
authors.initials: J
authors.lastname: Kalmuk
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Jaimee
authors.initials: J
authors.lastname: Lockwood
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Costakis
authors.initials: C
authors.lastname: Frangou
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Jordan
authors.initials: J
authors.lastname: Vokes
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Turowski
authors.affiliation: Department of Pathology & Laboratory Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Mihai
authors.initials: M
authors.lastname: Merzianu
authors.affiliation: Department of Head & Neck/Plastic and Reconstructive Surgery, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Nestor R
authors.initials: NR
authors.lastname: Rigual
authors.affiliation: Department of Dentistry & Maxillofacial Prosthetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Maureen
authors.initials: M
authors.lastname: Sullivan-Nasca
authors.affiliation: Department of Head & Neck/Plastic and Reconstructive Surgery, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Moni A
authors.initials: MA
authors.lastname: Kuriakose
authors.affiliation: Department of Head & Neck/Plastic and Reconstructive Surgery, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Wesley L
authors.initials: WL
authors.lastname: Hicks
authors.affiliation: Department of Radiation Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Anurag K
authors.initials: AK
authors.lastname: Singh
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA; Department of Head & Neck/Plastic and Reconstructive Surgery, Roswell Park Cancer Institute, Buffalo, NY 14263, USA; Department of Dentistry & Maxillofacial Prosthetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. Electronic address: Mukund.Seshadri@roswellpark.org.
authors.forename: Mukund
authors.initials: M
authors.lastname: Seshadri
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D006258:Head and Neck Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008856:Microscopy, Fluorescence; D044004:Xanthones / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D044004:Xanthones; C066668:vadimezan
keywords: Angiogenesis; Head and neck squamous cell carcinoma; Vascular disrupting agents; Vascular targeting
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