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Summary Recently, we reported the anti-angiogenic action along with anti-tumour activity of TNP-470 (AGM-1470). In this study, the effect of TNP-470 on the growth of human umbilical vein endothelial (HUVE) cells was examined. TNP-470 inhibited the growth of HUVE cells in a biphasic manner. The inhibition was cytostatic in the first phase (complete inhibition at 300 pg ml' to 3 fig ml-' with an IC50 of 15 pg ml-') and cytotoxic in the second phase ( > 30 ,ug ml-'). The cytostatic inhibition of HUVE cell growth by TNP-470 was durable after washing out TNP-470 in culture. Incorporation of thymidine but not uridine and leucine by HUVE cells was inhibited in the first phase, while that of all three compounds was inhibited in the second phase. Human and rat endothelial cells among various types of cells were the most sensitive to the cytostatic inhibition, while differences in the cytotoxic inhibition were minimal. These results suggest that TNP-470 exerts its specific anti-angiogenic action by inhibiting cytostatically growth of endothelial cells in a relatively specific manner.

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Prostate cancer is the most common form of cancer in males in the United States, and the second leading cause of cancer death. Initially, most cases of prostate cancer respond well to hormone therapy; however, resistance often develops rapidly, leading to castration-resistant prostate cancer (CRPC). Several mechanisms for castration resistance have been proposed, of which the most significant seems to be the "intracrine" production of androgens from adrenal androgen or intratumorally via the de novo route. This mechanism stimulates disease progression through reactivation of androgen receptor signaling in patients who have previously undergone castration therapy. 17,20-lyase is essential for androgen synthesis in both the adrenal glands and CRPC tissue, and some 17,20-lyase inhibitors and secondgeneration anti-androgens that were developed to treat CRPC are currently under clinical investigation, with encouraging preliminary data reported so far. However, resistance to some of these therapies has already been noted. The study of circulating tumor cells will likely be important not only to identify patients likely to receive benefit from this therapeutic approach, but also to further understand the molecular mechanisms of resistance. Clin Cancer Res; 16(17); 4319-24. ©2010 AACR.