A Hypothesis Concerning the Biphasic Dose-response of Tumors to Angiostatin and Endostatin

Abstract

This manuscript proposes a hypothesis to explain the U-shaped dose-response observed for angiostatin and other high-molecular-weight drugs in various anti-cancer bio-assays. The dose-response curves for angiostatin and endostatin (measured as suppression of tumor growth) go through an optimum (i.e., minimum tumor growth) and then becomes less effective at higher doses. The literature suggests that at lower doses the primary action of these high-molecular-weight drugs is to counteract the angiogenic effects of vascular endothelial growth factor (VEGF). To do this, the drugs must pass out of the blood vessel and enter the extra-cellular matrix (ECM) where VEGF induces the growth and fusion of tip cells. Ironically, VEGF actually facilitates access of the drugs to the ECM by making the vascular endothelium leaky. At higher doses, the high-molecular-weight drugs seem to reverse VEGF-induced permeability of the endothelium. Thus, at high dose rates, it is hypothesized that the drugs are not able to enter the ECM and block the angiogenic effects of VEGF there. As a result, high doses of the drugs do not suppress vascularization of the tumor or tumor growth. Moreover, if the permeability of the vessels is suppressed, the VEGF released by the stroma is concentrated in the ECM where it amplifies the angiogenic activity around the tumor.

Keywords: ECM; VEGF; angiogenesis; angiostatin; biphasic; cancer; dose; endostatin; macrophage; response; tip cell; tumor.

Figure 1.

Two S-shaped Curves Produce a U-shaped Curve. Based on inspection of typical S-shaped curves, we estimate that the ED₅₀ for the anti-angiogenic effect is about half-way down the slope and the ED₅₀ for the anti-permeability effect is about at the bottom of the U.