The reliance of tumors [53] on NO-mediated mechanisms of progression and metastasis prompted an evaluation of l-NNA, a competitive inhibitor of NOS with selectivity for the neuronal and endothelial isoforms of the enzyme, in a phase 1 study of patients with NSCLC. Serial assessment with dynamic contrast-enhanced computed tomography demonstrated decreased vascular blood volume by 40%, an effect that was

sustained 24 hours posttreatment [54]. It is not known whether this decrease in blood volume was associated with tumor shrinkage. Extrapolation from these data suggests that tumors can only thrive within a hyponitroxic “comfort zone” of signaling cell strength; attenuation below and elevation above this level result in cell death or senescence [55]. Inhibition of NO synthesis has catastrophic effects on the tumor vasculature, selleck inhibitor which can be attributed to the involvement of NO in tumor angiogenesis and the maintenance of vasodilator tone of tumor blood vessels. The sustained disruption of the tumor vasculature was preceded by a mild transient increase in systemic blood pressure; this discrepancy was attributed

to a differential dependence on NO in healthy and cancerous tissues [56]. Unlike the cardiovascular Enzalutamide manufacturer system, which is subjected to tightly regulated homeostatic controls [56], the patency of vessels within tumors is largely regulated by increased expression of NO. Therefore, the consequence of NO inhibition was a conversion of net vasodilation to vasoconstriction, with a collapse of tumor blood flow. RRx-001 [57] is an aerospace industry–derived small-molecule redox regulator with NO-donating properties that has recently completed a phase I clinical trial in patients with a variety of solid tumors. In addition to generating ROS, RRx-001 has a novel mechanism of action that involves selective and specific modification of hemoglobin in a subpopulation of RBCs, resulting in a catalytic,

hypoxia-driven overproduction of NO [58]. This, in turn, leads to excess NOx, free Dapagliflozin radicals (RNS), diffusible metabolites, chemokines, and cytokines, all of which are preferentially toxic and selectively target the tumor microenvironment in a manner that mimics, with NOx instead of oxygen, the “respiratory burst” associated with intracellular killing of bacteria by phagocytes. The basis for therapeutic selectivity is controlled release of these endothelial cytotoxins under conditions of hypoxia and free radical overload—stress conditions that are unique to the aberrant tumor microvasculature. RRx-001 acts as an NO donor that irreversibly binds to and allosterically modifies its target, the β Cys93 residue on deoxygenated hemoglobin [59].