PRECLINICAL EVALUATION OF INTERMEDIATE ENDPOINTS

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An experimental model of proliferative retinopathy produced in response to ischemia-induced retinal neovascularization in mice (Smith et al, 1994) lends itself as an ideal system in which to quantitate angiogenesis. The system is well characterized and highly reproducible generating a quantifiable neovascular response in 100% of animals (Pierce et al, 1995). It has been shown that VEGF expression is upregulated during retinal neovascularization and that its inhibition by VEGF antagonists leads to suppression of ischemia-induced neovascularization (Aiello et al, 1995). Besides VEGF, this model system can also be used to measure the levels of expression of several genes such as VEGF, VEGFR, Tie 2, E-Selectin, Collagen IV, and AC133 etc, which are known to be upregulated during angiogenesis and play an essential role during various phases of angiogenesis in multiple cancers. A quantitative RT-PCR model is being standardized and tested to measure the angiogenic response . The goal of the study is to develop a molecular technique(s) to quantitate angiogenesis, which is highly sensitive and less labor-intensive than the existing biological assays or staining procedures and can be used to monitor angiogenic changes in early neoplastic lesions. This project is a) developing a quantitative angiogenesis assay in the mouse model of proliferative retinopathy and b) validating its sensitivity and usefulness in human tumor model system(s) as well as in clinical specimens.