Accelerated Tumor Cell Death by Anglogenic Modifiers

摘要

Because of the potential synergistic interaction between an anti- angiogenic aminosterol, squalamine, and other angiogenic modifiers such as vascular endothelial growth factor (VEGF) and cytokines that may be released during intermittent androgen withdrawal therapy, we tested extensively the interaction between squalamine and VEGF for an enhanced cytotoxicity to human prostate cancer cells in vitro and xenografts tumor models in vivo. While in vitro synergistic interaction was demonstrated specifically in human prostate cancer cell lines containing a functional androgen receptor, we encountered difficulty in demonstrating such synergism in vivo for the reason that severe toxicity was noted when VEGF was delivered as an Ad-CMV-TK vector. For this reason, we explored other possible synergistic interaction between squalamine and castration. Squalamine is highly synergistic to castration-induced endothelial destruction when applied at the time of castration. We noted VEGF receptor, fit-1 and integrin profile (e.g. alpha6beta4) can predict squalamine response. Prostate cancer cells lacking the expression of these markers may be less responsive to the synergistic interaction between squalamine and castration. We are currently assessing the possible interaction between squalamine and VEGF and squalamine and androgen status of the cell culture and in animals subjected to castration to evaluate if synergism may exist panicularly against the growth of endothelial cells.