Targeting angiogenic processes by combination low-dose paclitaxel and radiation therapy

Tumor growth and angiogenesis are interdependent. Paclitaxel and radiation therapy are commonly used in the clinic, in a number of disease sites, requiring high dosages of both drug and radiation for cure. Paclitaxel (Taxol) is a diterpenoid with antitumor activity against a variety of human neoplasms and can amplify the cytotoxic effect of ionizing radiation in vitro, presumably by inducing arrest at metaphase, known to be a very radiosensitive phase of the cell cycle. Little is known about how angiogenesis is affected by paclitaxel when the combination of paclitaxel and radiation are used. We have evaluated the combination of paclitaxel and radiation at various concentrations, on cytokine-induced angiogenesis in vitro with the goal of determining whether reduction of radiation and paclitaxel doses is possible without sacrificing efficacy. We have found that paclitaxel inhibited endothelial cell proliferation, migration, and tube formation (differentiation) at one-tenth the concentration needed to achieve a similar effect on tumor cell lines. In combination with radiation, inhibition of endothelial cell function was additive and increased twofold. The combination of low-dose paclitaxel and radiation suggests a complementary strategy with potential clinical ramifications to target angiogenesis-dependent malignancies.