摘要：

2010 Phosphatidylinositol 3 kinase (PI3-K) is a heterodimer of a regulatory subunit, p85, and a catalytic subunit, p110. A number of previous reports showed that PI3-K functions in diverse cellular phenomena such as cell proliferation, glucose catabolism, cell adhesion, and vesicle transport. It is also well known that survival signals from the receptor tyrosine kinases utilizes Akt via PI3-K to protect cells from apoptosis. The activity of PI3-K, a key component of multiple signal transduction pathways, was investigated in melanoma cell lines that have varying degrees of radiation resistance. Analysis of PI3-K biproducts (PI-3,4-P2 and PI-3,4,5-triphosphate) revealed a direct correlation between radiation resistance and levels of PI3-K activity. We found that the PI3-K inhibitor LY294002 increases radiation efficacy in various melanoma cell lines, most of them are radiation-resistant. Since PI3-K is a central component in survival signaling pathways, using PI3-K inhibitor without proper targeting toward tumor cells may be detrimental. Thus, in collaboration with Semafore Pharmaceuticals we evaluated a novel integrin-targeted PI3-K inhibitor, SF1126. Inhibition of cell surface integrin receptors, ανβ3 and ανβ5, induces endothelial apoptosis and inhibits angiogenesis. RGDS is an effective integrin ανβ3/ανβ5 function-blocking peptide containing the arginine-glycine-aspartic amino acid sequence. RGDS inhibits in vivo angiogenesis and tumor growth. SF1126 is LY294002 conjugated to RGDS. We tested the efficacy of SF1126 in combination radiation therapy in mouse xenografts that are generated by implanting human melanoma WM35 and WM3211 cell lines. Combination of the integrin-targeted PI3-K inhibitor with radiation therapy may offer a novel, effective strategy for cancer treatment.

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