Transient alleviation of tumor hypoxia during first days of antiangiogenic therapy as a result of therapy-induced alterations in nutrient supply and tumor metabolism - Analysis by mathematical modeling

Abstract

A number of experiments on mouse tumor models, as well as certain clinical data, have demonstrated, that antiangiogenic therapy can lead to transient improvement in tumor oxygenation, that allows to increase efficiency of following radiotherapy. In the majority of works, this phenomenon has been explained by enhanced tumor perfusion due to normalization of capillaries' structure, that results in elevated oxygen inflow in tumor. However, changes in tumor perfusion often haven't been directly measured in relevant works, moreover, antiangiogenic therapy has been proven to have ambiguous effect on tumor perfusion both in mouse tumor models and in clinics. Herein, we suggest that elevation of blood perfusion may be not the only reason for transient alleviation of tumor hypoxia, and that it may manifest itself even under unchanged tumor blood flow. We propose that it may be as well caused by the decrease in tumor oxygen consumption rate (OCR) due to the reduction of tumor proliferation level, caused by nutrient shortage in result of antiangiogenic treatment. We provide detailed explanation of this hypothesis and visualize it using a specially developed mathematical model, which takes into account basic features of tumor growth and antiangiogenic therapy. We investigate the influence of the model parameters on oxygen dynamics; demonstrate, that transient alleviation of tumor hypoxia occurs in a fairly wide range of physiologically justified values of parameters; and point out the major factors, that determine oxygen dynamics during antiangiogenic therapy.

Keywords: Bevacizumab; Normalization window; Tumor oxygenation; Warburg effect.