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Angiostatic Therapy: A New Treatment Modality for Prostate Cancer

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Annual rept. 1 Jan-31 Dec 1999

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The overall goal is to investigate if blockade of vascular endothelial growth factor in combination with conventional cytotoxic agents could be a new innovative treatment regimen for hormone-refractory prostate cancer. We proposed to use our in vivo model to examine the capacity of a soluble VEGF receptor fusion protein flt-lgG to inhibit angiogenesis and growth of tumor tissue derived from patients and compare with established prostate cancer cell lines. We experienced very poor growth of prostate carcinoma implanted in our in vivo system, however, since the stroma plays a pivotal role in prostate cancer progression, we hypothesized that the model would be much improved if we were to develop a more orthotopic milieu. To achieve this goal, we implanted murine prostate tissue prior to implantation of tumor spheroids. Interestingly, adult prostate tissue becomes highly re-vascularized. However, the murine stroma did not much affect growth of human biopsies, but, growth of the murine prostate carcinoma cell line TRAMP C2, was significantly enhanced. We hypothesized, that the stromal factors are species specific. We therefore isolated peritumor fibroblasts from one of our biopsies and mixed these with the tumor cells, which resulted in significantly higher growth rates. We had proposed to label tumor cells with an in vivo dye CMTMR, but due to serious limitations with the in vivo dye, we introduced a histone-GFP fusion protein as a marker for our tumor cells. This labeling technique allows us to evaluate not only tumor size, but also mitotic and apoptotic indices of the implanted tumor spheroids. With these significant and necessary modifications we have a unique pseudo-orthotopic model, which allows us to evaluate, in prostate cancer, in detail the underlying mechanisms behind chemotherapy and angiostatic mediated tumor regression.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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