Low‐dose angiostatic tyrosine kinase inhibitors improve photodynamic therapy for cancer: lack of vascular normalization

Andrea Weiss,Debora Bonvin,Arjan W Griffioen,Patrycja Nowak‐Sliwinska,Judy R Van Beijnum,Patrice Jichlinski,Paul J Dyson

doi:10.1111/jcmm.12199

Abstract

Photodynamic therapy (PDT) is an effective clinical treatment for a number of different cancers. PDT can induce hypoxia and inflammation, pro-angiogenic side effects, which may counteract its angio-occlusive mechanism. The combination of PDT with anti-angiogenic drugs offers a possibility for improved anti-tumour outcome. We used two tumour models to test the effects of the clinically approved angiostatic tyrosine kinase inhibitors sunitinib, sorafenib and axitinib in combination with PDT, and compared these results with the effects of bevacizumab, the anti-VEGF antibody, for the improvement of PDT. Best results were obtained from the combination of PDT and low-dose axitinib or sorafenib. Molecular analysis by PCR revealed that PDT in combination with axitinib suppressed VEGFR-2 expression in tumour vasculature. Treatment with bevacizumab, although effective as monotherapy, did not improve PDT outcome. In order to test for tumour vessel normalization effects, axitinib was also applied prior to PDT. The absence of improved PDT outcome in these experiments, as well as the lack of increased oxygenation in axitinib-treated tumours, suggests that vascular normalization did not occur. The current data imply that there is a future for certain anti-angiogenic agents to further improve the efficacy of photodynamic anti-cancer therapy.

Highlights

Photodynamic therapy (PDT) is a minimally invasive therapy in which visible or near infrared light irradiation is combined with light sensitive molecules to produce reactive oxygen species (ROS)
As there are many clinically approved effective angiogenesis inhibitors, it is proposed that these compounds can significantly prolong the beneficial angio-occlusive effect of PDT [4]
The results of the present study show that angiostatic small molecule TKI can synergistically improve the anti-tumour effect of PDT, in both an ovarian and a colorectal tumour model

Summary

Introduction

Photodynamic therapy (PDT) is a minimally invasive therapy in which visible or near infrared light irradiation is combined with light sensitive molecules (photosensitizers) to produce reactive oxygen species (ROS). These ROS can damage blood vessels in such a way that vascular occlusion occurs [1]. Angio-occlusive PDT can cause tissue responses, such as hypoxia and inflammation [1], both of which play a role in inducing angiogenesis [4]. This angiogenic tissue response following PDT can in principle counteract the angio-occlusive effect of PDT, leading to a reduced tumoricidal outcome.

Methods

Results

Conclusion