Nitric oxide (NO) is a small endogenous biological mediator that has many physiological and pathophysiological actions. It is synthesized from L-arginine by a family of NO synthases (NOS). NOS have been classified into two categories, constitutive (eNOS and nNOS) and inducible (iNOS). Increased NO production appears to be associated with many disorders including cancer. NO formed from the iNOS in various cells, including macrophages, has been implicated in the pathogenesis of various forms of circulatory shock and inflammation. INOS protein has been detected in both premalignanat and malignanat clinical biopsies from the human stomach, colon, lung, esophagus, and prostate; and increased iNOS activity was observed in human esophagus, colorectal, breast, lung, head and neck, and central nervous system tumors. Various NOS inhibitors have been developed but are ineffective or non specific NOS inhibitors. Very little is known regarding the involvement of iNOS in melanoma lung metastasis. Inhibition of iNOS with s,s’-1,4-phenylene-bis(1,2-ethanediyl)bis-isothiourea (PBIT), an iNOS specific inhibitor effectively inhibit colon and esophagus cancer in animal models. However, the dietary dose used in animal models were high and could not be used for clinical studies. Selenium is also a potent chemotherapeutic and chemopreventive agent. Selenium analogs of L-arginine were reported to be a potent inhibitors of iNOS; however, the compounds were unstable in aqueous solution. We have developed a new selenium derivative of PBIT. In vitro studies using vertical growth phase (VGP), WM115, and metastatic melanoma (MM), UACC903 and 1205 Lu, cell lines showed only Se-PBIT but not PBIT significantly reduces the cell viability at very low concentrations as demonstrated by their IC50 values (7.0 - 12.0 μM) compared to PBIT (>100 μM). In vivo metastasis studies using GFP expressing metastatic melanoma cells (UACC903 M) showed a significant reduction (~2.5 fold) in the lung metastatic area in the animals receiving Se-PBIT compared to the animals injected with DMSO vehicle. Collectively these studies show the effectiveness of Se-PBIT on lung metastasis inhibition. Results of our findings will be presented. We now report the inhibitory effect of selenium derivative of PBIT against Melanoma lung metastasis.The chemopreventive efficacy and mechanism of action of newly developed agent will be discussed against the Melanoma Lung Metastasis.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA