Table 2. .

Proposed mechanisms through whichVEGF pathway inhibitors and radiotherapy interact to enhance tumour response.

Depending on dosing and timings, VEGF inhibition can “normalise” tumour blood vessels creating a better perfused and oxygenated, radiosensitive microenvironment. Radiotherapy when administered during this period is more effective.

VEGF is a pro-survival factor and can protect endothelial cells from radiation damage. Therefore, blocking VEGF signaling enhances radiation damage to endothelial cells. This can occur in the absence of vessel “normalisation” especially if the dosing of the anti-VEGF therapy is excessive and/or continuous, in which case vessels may regress and become poorly perfused, contributing to tumour cell death.

Fractionated radiotherapy can improve tumour blood flow (normalising effect) via various mechanisms such as reduction in oxygen consumption and tissue pressure due to tumour cell kill, radiation-induced production of vasoactive agents such as VEGF and nitric oxide, pruning of the most radiation-sensitive vessels. These changes are associated with waves of oxygenation that generate reactive oxygen species that in turn stabilise HIF1∝ in tumour cells and increase VEGF production. VEGF then drives more angiogenesis and tumour growth and confers resistance to radiotherapy. Therefore, anti-VEGF therapy can be effective in enhancing response to radiotherapy even when administered after radiotherapy.

High doses of radiotherapy can cause profound damage to tumour blood vessels and cause endothelial cell apoptosis through ASMase-mediated generation of ceramide. Profound apoptosis can contribute to indirect tumour cell kill. VEGF reduces ceramide production following a single high dose of radiation and therefore protects tumour vessels from radiation damage while VEGF inhibition promotes ceramide-mediated apoptosis and enhances the effect of radiotherapy.

VEGF inhibition reduces the acute mobilisation of circulating endothelial cells and endothelial progenitor cells, which could otherwise repopulate the tumour and contribute to radiotherapy resistance.

VEGF inhibition may in some instances radiosensitise tumour cells and reduce their survival and ability to repair DNA damage.

VEGF inhibition and radiotherapy may interact to modify the immune response to cancer cells.