Mechanisms of Radiosensitization by the Neurotensin Receptor Antagonist SR48692 in Prostate Cancer Models
Annual rept. 1 Apr 2008-31 Mar 2009
VIRGINIA UNIV CHARLOTTESVILLE
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Radiation is one of the most used treatments for prostate cancer. However, it causes several negative sideeffects, including the damage to surrounding normal tissues. An agent which selectively sensitizes prostate tumor but not normal prostate could improve the therapeutic ratio of radiation. Neurotensin is a one of the factors secreted by neuroendocrine cells in prostate, which stimulates and promotes cancer cell growth and proliferation. In this project we are investigating if the inhibition of neurotensin receptor by SR48692 drug could sensitize cancer cells to radiation. SR48692 activity was measured in PC3, C42 and LNCaP prostate cancer cells, as well as in RWPE1 normal prostate epithelial cells, using clonogenic survival and growth inhibition assays. PC3Mluc orhtotopic xenografts in nude mice were treated with SR48962, radiation, or in combination, and tumor growth was determined by bioluminescence imaging. Our results show that inhibition of neurotensin receptor by SR48692 effectively sensitizes human prostate cancer cells to radiation, while the effects on normal prostate epithelial cells are minimal. Importantly, the combination therapy SR48692 and radiation suppressed xenograft tumor growth in nude mice significantly more that either treatment alone. Our study suggest that NTR1 receptor, or neurotensin signaling pathway, are viable targets for combined chemoradiotherapy of prostate cancer. This is the first year report for grant W81 XWH-08-1-0114 covering the initial phase of the project. During this phase we have concentrated on Specific Aim 1, investigating the radiosensitizing activity of SR48692 in both in-vivo and in-vitro model systems.