Bevacizumab enhances the therapeutic efficacy of Irinotecan against human head and neck squamous cell carcinoma xenografts

Abstract

Combining antiangiogenic agents with traditional cytotoxic chemotherapy offers the potential to target both vascular and cellular components of a growing tumor mass. Here, we examined the antitumor activity of the vascular endothelial growth factor antibody, Bevacizumab (Avastin®) in combination with the topoisomerase I inhibitor, Irinotecan (CPT-11) against human head and neck squamous cell carcinoma (HNSCC) xenografts. Bevacizumab was administered daily (at 5 mg/kg or 20 mg/kg) to nude mice bearing FaDu HNSCC xenografts for 28 days with the first dose beginning seven days prior to Irinotecan (100 mg/kg, weekly × 4). Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and immunohistochemical (IHC) methods were employed to study the antiangiogenic effects of Bevacizumab in vivo. Kinetics of tumor response to treatment was studied by monitoring tumor volume over a 60-day period. DCE-MRI detected a significant reduction in vascular permeability following treatment with Bevacizumab (5 mg/kg) while high dose Bevacizumab (20 mg/kg) induced significant microvascular damage and tumor necrosis, confirmed by immunohistochemistry (IHC). Irinotecan alone resulted in complete tumor regression (cures) in ~40% of animals while Bevacizumab alone did not result in any cures. Treatment with Bevacizumab (5 mg/kg/day × 28 days) in combination with Irinotecan (100 mg/kg, weekly × 4) was highly effective in inhibiting FaDu tumor growth and resulted in complete tumor regression in 80% of animals. These results demonstrate that long term administration of Bevacizumab effectively modulates chemotherapeutic efficacy against HNSCC xenografts. Further investigation into the therapeutic potential of this combination strategy against HNSCC is warranted.

Using intravital microscopy to observe bevacizumab-mediated anti-angiogenesis in human head and neck squamous cell carcinoma xenografts

“…In the pursuit of more efficient combinations, the importance of order and scheduling of drugs, and also the potential of xenografted HNSCC, are underestimated. The relevance of the model is shown by preclinical studies combining bevacizumab and cytotoxic drugs [18]. An emerging concept is to target multiple kinase pathways [19].…”

Noninvasive monitoring of early antiangiogenic therapy response in human nasopharyngeal carcinoma xenograft model using MRI with RGD-conjugated ultrasmall superparamagnetic iron oxide nanoparticles

“…Focus on angiogenesis factors, antiangiogenic agents alone or in conjunction with chemoradiotherapy, has proved to be an effective treatment in advanced NPC. 3,4 However, not all patients would…”

The Role of Antiangiogenic Agents in the Treatment of Head and Neck Cancer

“…VEGF expression has been shown to be enhanced by radiation, and in vitro studies suggest the enhanced cytotoxicity of the combination of RT and antibody-mediated VEGF neutralization is due to the effect on endothelial cells rather than to direct tumor cell cytotoxicity. These results suggest that VEGF is a protective factor of endothelial cells exposed to the stress imposed by ionizing radiation, and that VEGF blockade could overcome this protective effect [14]. …”

“…The question of timing is appealing as we consider, for example, the disappointing results of the bevacizumab and CPT11 combination, both in vitro and in vivo [14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31]. The reports suggest that CT dose and intratumor drug delivery are both fundamental to ensure tumor regression.…”