title: Time-dependent pretreatment with bevacuzimab increases tumor specific uptake of cetuximab in preclinical oral cavity cancer studies.
abstract: Inadequate delivery of therapeutics into tumors has been suggested as a reason for poor response. We hypothesize that bevacizumab, an antibody to vascular endothelial growth factor (VEGF), can improve cetuximab uptake in squamous cell carcinoma tumors. Athymic nude mice were implanted with OSC19 and SCC1 human cancer lines in a subcutaneous flank model. Mice were imaged daily for 14 days after intravenous tail vein injections of the following groups: IgG-IRDye800 (Control), cetuximab-IRDye800 (CTX800 Only), bevacizumab-IRDye800 (BVZ800 Only), cetuximab-IRDye800 + bevacuzimuab-IRDye800 (Simultaneous), and unlabeled bevacizumab followed by cetuximab-IRDye800 3 days later (Neoadjuvant). Within single-agent groups, the CTX800 Only tumor-specific uptake (TSU) was significantly higher than BVZ800 Only at Day 13 (TSU 8.6 vs 2.8, P < 0.001). The Simultaneous treatment with BVZ800 and CTX800 demonstrated no increase in antibody delivery. However, administration of unlabeled bevacizumab 3 days prior to CTX800 (Neoadjuvant group) resulted in significantly higher tumor specific delivery than administration of both antibodies at the same time (11.8 vs Simultaneous 5.0, P < 0.001). This difference can be attributed to a slower decline in tumor fluorescence intensity (-6.8% vs. Simultaneous -11.5% per day, respectively). Structural changes in pericyte coverage and functional vessel changes demonstrating decreased proliferation and tumor growth corroborate these fluorescence results. Although simultaneous administration of bevacizumab with cetuximab failed to increase antibody delivery to the tumor, pretreatment with bevacizumab improved TSU reflecting an increase in tumor-specific uptake of cetuximab as a result of vessel normalization.
authors.affiliation: a Division of Otolaryngology; Department of Surgery; University of Alabama at Birmingham ; Birmingham , AL USA.
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Chung
authors.forename: Jason
authors.initials: J
authors.lastname: Warram
authors.forename: Kristine E
authors.initials: KE
authors.lastname: Day
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Hartman
authors.forename: Eben L
authors.initials: EL
authors.lastname: Rosenthal
mesh_terms: D000818:Animals; D000068258:Bevacizumab / Q000008:administration & dosage / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000068258:Bevacizumab; D000068818:Cetuximab
keywords: EGFR; anti-angiogenesis therapy; bevacuzimab-IRDye800; EPR; cetuximab-IRDye800; BVZ800; endothelial growth factor receptor; VEGF; enhanced permeability and retention.; head and neck cancer; head and neck squamous cell carcinoma; TSU; human epidermal growth factor receptor 2; HNSCC; monoclonal antibody therapy; near-infrared fluorescence; optical imaging; therapeutic delivery; tumor specific uptake; CTX800; vascular endothelial growth factor; HER2; vessel normalization