Prostate cancer will be diagnosed in over 300,000 American men in 1996 and over 40,000 men will die from the disease this year, making it the second leading cause of cancer death in men. Male hormone-dependent prostate cancer which has spread outside the prostate is initially well-controlled by anti-androgen therapies, but tumor cells almost lose hormonal dependency after one to three years of treatment as cells progress to hormone-independent and metastatic stages. Unfortunately, relatively slow-growing prostate tumor cells are resistant to standard chemotherapeutic agents, making hormone- independent metastatic prostate cancer an almost uniformly fatal disease. Understanding the mechanism(s) by which hormonally- sensitive tumor cells lose dependency or otherwise acquire the ability to defeat hormone deprivation-based therapies is therefore an important objective in this study. Another objective is to investigate the use of green tea catechins and related compounds as new chemotherapeutic agents which will be effective against hormone- independent disease.
The specific aims of this study are the following: 1) To understand at the molecular level the mechanism(s) driving the transition of clonal androgen-dependent LNCaP 104-S prostate tumors cells to androgen-independent LNCaP 104-R2 cells during long-term androgen deprivation. 2) To understand at the molecular level the mechanisms involved in androgen repression of proliferation in LNCaP 104-R1 and 104-R2 cells. In addition, we wish to understand at the molecular level how LNCaP 104-R2 cells re-acquire proliferative sensitivity after re-exposure to androgen. 3) To determine whether a mutant form of the tumor suppressor p53 affects the rate at which LNCaP 104-S cells progress to androgen independence. Can expression of dominant-negative p53, through the generation of genetic instability or through some other mechanism, accelerate the rate at which androgen-independent cells appear during androgen deprivation? 4) To explore the use of green tea catechins and related compounds as anti-tumor agents against prostate cancer using the LNCaP 104-S and 104-R model of androgen-dependent and -independent prostate tumors grown in athymic mice.
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