Nitric oxide (NO) is cytotoxic to cancer cells by inducing protein tyrosine nitrosation protein thiol nitrosylation, protein ADP ribosylation, inhibiting mitochondrial respiration, and inhibiting ribonucleotide reductase. Exposure of leukemia and solid tumor cells to NO induces apoptosis. On the other and, NO is an important mediator involved in the physiologic regulation of systemic vasomotor tone. NO acts as a potent vasodilator by activating the soluble guanylate cyclase (sGC) and cGMP production in vascular smooth muscle cells. The cytotoxic effects of NO are sGC/cGMP independent. Interleukin 2 (IL-2) treatment of mice or humans strongly induces (NO) synthesis. In mice, NO contributes significantly to the anti-tumor effects of IL-2. The dose limiting toxicity of IL-2 treatment is cardiovascular manifested by hypotension and the vascular leak syndrome (VLS). Inhibition of NO production in mice treated with IL-2 prevents the VLS but diminishes its anti-neoplastic effects. The investigator's hypothesis is that the cardiovascular toxicity of IL-2 is mediated by the sGC/cGMP signal transduction axis as a consequence of NO production. The importance of this concept is that inhibition of the sGC signaling pathway could allow the selective inhibition of the cardiovascular toxicities of IL-2-induced NO synthesis without interfering with NO dependent cytotoxic mechanisms. This hypothesis will be tested in the proposed experiments using the selective sGC inhibitor H-[1,2,4]oxadiazole[4,3,-a]quinoxaline-lone (ODQ).
The aims are as follow l -Determine the pharmacokinetics, optimal dosage route, schedule of administration, formulation and the toxicity profile of the sGC inhibitor ODQ in a murine model. 2 - Study the effect of ODQ on the IL-2 induced cardiovascular toxicity and VLS. 3 - Study the effect of the combination of IL-2 and ODQ on tumor growth in vivo using murine models. By dissociating the tumor cytotoxicity of NO (and therefore IL-2) from its vascular effects, they will demonstrate that it is feasible to use NO inducers or NO donors in vivo for the treatment of malignant neoplasms without prohibitive cardiovascular toxicity. Furthermore, this approach will allow dose escalations studies of IL-2 and could also be applicable to other immunologic therapeutic strategies for cancer.
