Provascular strategy: Targeting functional adaptations of mature blood vessels in tumors to selectively influence the tumor vascular reactivity and improve cancer treatment

Blood flow and flow-related microenvironmental parameters (tissue pO2, pH, distribution, bioenergetic status, and nutrient supply) are important factors known to modulate the sensitivity of cancer cells to ionizing radiations and circulating anticancer agents. Whereas tumor pO2 and consequently tumor radiosensitivity are highly influenced by local perfusion ensuring oxygen supply, blood also serves as a vehicle for the delivery of anticancer agents to tumor cells. In expanding tumors, blood flow is generally low due to the aberrant vascular architecture and to the altered microenvironment, leading to chronic hypoxia. Perfusion can also fluctuate and even stop and resume, accounting for intermittent/fluctuant hypoxia. Different approaches have been developed aimed at transiently increasing blood flow and oxygen bioavailability in tumors at the time of treatment. This review focuses on provascular approaches that exploit functional adaptations of mature vessels to the tumor microenvironment to sensitize tumors to radio- and chemotherapy. Our contribution to the field has revealed that the stimulation of endogenous nitric oxide production and the systemic delivery of endothelin-1 inhibitors both achieve selective and transient tumor vasodilation. Others have studied the provascular potential of angiotensin II, bradykinin, calcium antagonists, hydralazine, hyperthermia, and nicotinamide. These approaches are discussed with a clinical perspective.