This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.ABSTRACTDirect introduction of therapeutic genes into malignant cells in vivo may provide an effective treatment of solid tumors such as adenocarcinoma of the prostate. The p53 tumor suppressor protein is involved in various stress-related cellular processes including cell cylce regulation, apoptosis, senescence, DNA repair, cell differentiation and angiogenesis. Therefore, mutations in the p53 gene can lead to various aberrant cellular activities that contribute to tumorigenesis and numerous human cancers, including colon, lung, breast and prostate cancer have been shown to harbor p53 mutations.Because of the established association between loss of p53 functionand prostate cancer metastasis, we have pursued the identification, characterization and functional analysis of p53-target genes in prostate cancer. We identified the mouse RTVP-1 (mRTVP-1) (related to testes-specific, vespid and pathogenesis proteins) mRNA as being up-regulated by p53 in mouse prostate cancer cells. We further showed that human RTVP-1 is also a direct p53 target gene and is progressively down-regulated in human prostate cancer. Overall our studies are consistent with a tumor suppressor role for RTVP-1 in prostate cancer and potentially other malignancies. Importantly, we have also shown that RTVP-1 (mouse or human) has pro-apoptotic, anti-angiogenic and immunostimulatory activities and that adenoviral-vector-mediated mRTVP-1 expression can suppress growth and metastasis of prostate cancer in vivo.This trial will begin by testing the toxicity of a low dose of vector in 3-6 patients, observing them for 28 days and, if no significant toxicity is observed, increasing the test dose by a 1/2 log scale in another 3-6 patients and observing them for 28 days. Initially, 3-6 patients will be entered into the study and injected with a dose of 1x10/10 vp, per patient for Cohort #1. We plan direct intraprostatic injections. This dose will be diluted in a total of 2mls and split into two separate injections of 1 ml each into the right and left prostatic lobes. If a decision is made to increase the test dose, another 3-6 patients will be treated with 5.0x10/10vp. If no significant toxicity is observed another 3-6 patients will receive the next higher dose until dose limiting toxicity of 5.0x10/12vp are reached.
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