Bevacizumab-Induced Transient Remodeling of the Vasculature in Neuroblastoma Xenografts Results in Improved Delivery and Efficacy of Systemically Administered Chemotherapy

Abstract

Purpose: Dysfunctional tumor vessels can be a significant barrier to effective cancer therapy.However, increasing evidence suggests that vascular endothelial growth factor (VEGF) inhibition can effect transient ''normalization''of the tumor vasculature, thereby improving tumor perfusion and, consequently, delivery of systemic chemotherapy. We sought to examine temporal changes in tumor vascular function in response to the anti-VEGF antibody, bevacizumab. Experimental Design: Established orthotopic neuroblastoma xenografts treated with bevacizumab were evaluated at serial time points for treatment-associated changes in intratumoral vascular physiology, penetration of systemically administered chemotherapy, and efficacy of combination therapy. Results: After a single bevacizumab dose, a progressive decrease in tumor microvessel density to <30% of control was observed within 7 days. Assessment of the tumor microenvironment revealed a rapid, sustained decrease in both tumor vessel permeability and tumor interstitial fluid pressure, whereas intratumoral perfusion, as assessed by contrast-enhanced ultrasonography, was improved, although this latter change abated by 1week. Intratumoral drug delivery mirrored these changes; penetration of chemotherapy was improved by as much as 81% when given 1to 3 days after bevacizumab, compared with when both drugs were given concomitantly, or 7 days apart. Finally, administering topotecan to tumor-bearing mice 3 days after bevacizumab resulted in greater tumor growth inhibition (36% of control size) than with monotherapy (88% bevacizumab, 54% topotecan) or concomitant administration of the two drugs (44%). Conclusions: Bevacizumab-mediated VEGF blockade effects alterations in tumor vessel physiology that allow improved delivery and efficacy of chemotherapy, although careful consideration of drug scheduling is required to optimize antitumor activity.

Phase 2 study of S‐1 and carboplatin plus bevacizumab followed by maintenance S‐1 and bevacizumab for chemotherapy‐naive patients with advanced nonsquamous non–small cell lung cancer

“…15 It is believed that bevacizumab is targets the tumor vasculature, reducing interstitial pressure and increasing vessel permeability, thereby resulting in enhanced tumor sensitivity to cytotoxic chemotherapy. 16,17 Although there are limitations to comparisons of results among different studies, the ORR (54.2%) obtained in the current trial is indicative of increased antitumor activity of S-1 and carboplatin with the addition of bevacizumab. Our trial also indicates a favorable toxicity profile for the study treatment.…”

Angiogenesis and lymphangiogenesis are downregulated in primary breast cancer

“…As primary breast tumours seem to grow without an upregulated expression of VEGF-A, blockade of VEGF-A signalling cannot be expected to strongly impair further tumour growth. As anti-VEGF therapies can also induce 'normalisation' of tumour vessels and thus improve delivery of chemotherapeutics, this alternative mode of action could account for the observed clinical benefit in combination with standard chemotherapy (Jain, 2005;Dickson et al, 2007).…”

Pericyte coverage decreases invasion of tumour cells into blood vessels in prostate cancer xenografts

“…20,21 There is substantial evidence that tumour vessels are normalized after anti-VEGF treatment, resulting in fewer, but more efficient vessels with proper pericyte coverage, increasing drug delivery to the tissue. [22][23][24] Anti-angiogenic strategies targeting both the VEGF and the platelet-derived growth factor (PDGF)-B signalling systems affecting both endothelial proliferation and vessel stabilization have shown to be more efficient on tumour growth than only targeting the VEGF signalling. 25 This strategy disrupts the pericyte coverage and thereby increases the effect of the VEGF blockade, as pericytes induce vessel stability and induce nondependency for VEGF signalling.…”