The long-term objective of the proposal is to investigate the role of neurotransmitter dopamine (DA) in colon tumor neovascularization. Although substantial amount of endogenous DA is present in normal colon tissues, in contrast there is loss of DA in malignant colon tumor tissues. Furthermore, as we have recently demonstrated that DA inhibits vascular permeability factor/ vascular endothelial growth factor (VPF/VEGF) induced angiogenesis and because VPF/VEGF mediated angiogenesis promotes growth and metastasis of colon cancer, it is therefore possible that DA may also inhibit tumor neovascularization and thereby growth of colon cancer. The experiments proposed here are designed to investigate the role of DA on angiogenesis and vasculogenesis in preclinical colon cancer model. Finally, the role of endogenous colon DA on colon tumor angiogenesis and growth will be ascertained.
Aim I. To investigate the effect of DA on neovascularization and growth of metastatic colon cancer. Experimental Design: The anti-angiogenic and anti-tumor efficacy of DA either alone or in combination with conventional anticancer drugs in mice bearing highly metastatic orthotopic human colon cancer.
Aim II. To elucidate the molecular mechanisms of DA mediated regulation of tumor neovascularization. Experimental Design: The signaling pathways (PKA and MAPK) through which DA inhibits angiogenesis and vasculogenesis will be elucidated.
Aim III. To investigate the role of endogenous DA on the angiogenesis and growth of colon cancer. Experimental Design: the rate of tumor angiogenesis and growth will be determined in DA depleted mice and mice treated with specific DA D2 receptor antagonists. Finally, the mechanism (synuclein mediated) of depletion of colon tissue DA will be determined. The knowledge generated from this proposal may not only identify a novel regulator of malignant colon tumor neovascularization and growth, but can also suggest a newer and an effective therapy for the treatment of advanced colon cancer patients. Most importantly, DA (a small molecule and a relatively cheap drug) is already in clinical use with an established safety record; therefore any positive findings from this proposal can be rapidly translated to the clinics for undertaking a clinical trial to treat advanced colon cancer patients. ? ? ?
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