Angiostatic Therapy: A New Treatment Modality for Prostate Cancer
Final rept. 1 Jan 1999-30 Jun 2001
SIDNEY KIMMEL CANCER CENTER SAN DIEGO CA
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The overall goal of this project is to investigate if blockade of vascular endothelial growth factor combined with conventional cytotoxic agents could be a new innovative treatment regimen for hormone-refractory prostate cancer. This was to be achieved with human prostate cancer tissue and established cell lines in a xenograft chamber model. Using soluble-fit and chemotherapy regimens, combinatorial strategies for prostate cancer were to be examined. During the first 18-month period, the growth and angiogenesis of three human prostate tumor cell lines transduced with a Histone H2B GFP fusion protein DU 145, PC3, and LnCAP were evaluated using an intravital microscopic system in nude mice. Unlike other human carcinoma cell lines, the human prostate carcinoma cell lines regressed rapidly in the chamber model, with poor angiogenesis, massive apoptosis and little mitotic activity. Tumorigenic potential could only be rescued with prostate stroma and diversion of the innate immune system. The goals of our proposed SOW could not be achieved with this artificial model. A pseudo-orthotopic syngeneic system was therefore developed using the TRAMP-C2 H2BGFP model with anterior murine prostate tissue in the chamber model. These hybrid tumorspheroids became fully vascularized and grew progressively over a 4-week period, with low mitotic indices, low cell death and a highly invasive phenotype. Using this model we identified surgical castration, COX-2 inhibition and dendritic cell based immunotherapy as effective mono and combined therapies for prostate carcinoma.
- Anatomy and Physiology
- Medicine and Medical Research