Abstract:
PURPOSE: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. CONCLUSION: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.
journal_name
Oral Oncoljournal_title
Oral oncologyauthors
Folaron M,Kalmuk J,Lockwood J,Frangou C,Vokes J,Turowski SG,Merzianu M,Rigual NR,Sullivan-Nasca M,Kuriakose MA,Hicks WL Jr,Singh AK,Seshadri Mdoi
10.1016/j.oraloncology.2013.06.011subject
Has Abstractpub_date
2013-09-01 00:00:00pages
893-902issue
9eissn
1368-8375issn
1879-0593pii
S1368-8375(13)00631-3journal_volume
49pub_type
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