Antioxidant Interactions with Prostate Cancer Treatments

描述（由申请人提供）：抗氧化剂维生素E （VE）和大豆异黄酮（ISF）有潜力作为前列腺癌（PCa）的重要化学预防剂，无论是单独使用还是与常用治疗剂联合使用。近年来，外部放射治疗和间质近距离放射治疗（植入放射性微球）的进步使这种微创治疗在前列腺癌患者中流行起来。然而，剂量相关的放射毒性通常限制了可用于治疗的有效剂量。我们对人类PCa细胞系的研究发现，在雄激素响应型和雄激素非依赖型细胞系中，以细胞周期阻滞为特征的加性生长抑制作用。我们最近的研究发现，低浓度的ISF和VE治疗降低了辐照（IR）暴露后PCa细胞的克隆性存活，这是辐射致敏效应的证据。本初步研究将进一步探讨VE和ISF补充剂对临床抗肿瘤放疗细胞毒性的影响。假设是，用低浓度的ISF和VE治疗人类前列腺癌细胞增加了对辐照治疗的敏感性，抑制了ir后存活细胞的生长，并可以减少促炎细胞因子的诱导。特异性目的1将确定膳食ISFs和VE单独或联合是否增强小鼠PC-3异种移植肿瘤体内IR的细胞毒性。肿瘤对IR的反应将被表征为细胞周期和凋亡途径的表达，以及炎症细胞因子的产生和生理相关的抗氧化剂的血液水平。特异性目的2将确定膳食ISF和/或VE是否发挥特定的辐照后作用，以抑制复发性前列腺异种移植肿瘤的进展。这是一种有针对性的新辅助方法，直接评估ISF和VE营养补充剂在ir后对减缓肿瘤生长进展的长期益处的潜在作用。特异性目标3将使用细胞培养模型来建立与抗氧化剂诱导的放射敏感性和抗性相关的遗传和蛋白质组学谱。实验将确定过度表达Bcl- 2（一种抗凋亡基因）的PC-3细胞是否对ISF和/或VE抗氧化剂的生长抑制和放射增敏作用敏感。如果基因/蛋白质组学特征表明它可能是放射敏感性肿瘤，抗氧化剂和放疗成为更理想的治疗选择。这些信息将有助于鉴定可能对肿瘤微环境和肿瘤侵袭性表型至关重要的蛋白质。总之，拟议的研究将提供机制证据，以证明这些营养因子是否会增强或潜在地干扰前列腺癌患者同时暴露于已建立的细胞毒性治疗剂。鉴于近距离放射疗法的普及和膳食补充剂消费量的增加，有希望的结果将证明迅速过渡到临床试验是合理的。

DESCRIPTION (provided by applicant): The antioxidants vitamin E (VE) and soy isoflavones (ISF) have potential as important chemoprevention agents for prostate cancer (PCa) as single agents and in combination with commonly used therapeutic agents. Recent improvements in external beam radiotherapy and interstitial brachytherapy (implantation of radioactive pellets) have made this minimally invasive treatment popular among prostate cancer patients. However, dosage-related radio-toxicity usually limits the effective doses that can be used for therapy. Our studies with human PCa cell lines have found additive growth inhibitory effects characterized by cell cycle arrest in androgen-responsive as well as androgen-independent cell lines. Our recent studies have found that treatment with low, physiologically relevant concentrations of ISF and VE decreases the clonogenic survival of PCa cells following irradiation (IR) exposure, evidence of a radiosensitizing effect. This proposed pilot study will further investigate the effects of VE and ISF supplements on the cytotoxicity of clinical anti-neoplastic radiotherapy treatments. The hypothesis is that the treatment of human prostate cancer cells with low concentrations of ISF and VE increases sensitivity to irradiation treatments inhibits growth of cells that survive post-IR, and can reduce the induction of pro-inflammatory cytokines. Specific Aim 1 will be to determine if dietary ISFs and VE, alone or in combination, enhance the cytotoxicity of IR in vivo in PC-3 xenograft tumors in mice. The response of tumors to IR will be characterized for expression of cell cycle and apoptotic pathways, as well as the production of inflammatory cytokines and physiologically relevant blood levels of antioxidants. Specific Aim 2 will determine whether dietary ISF and/or VE exert a specific post-irradiation effect to inhibit progression of recurrent prostate xenograft tumors. This is a targeted neoadjuvant approach to directly assess the potential usefulness of ISF and VE nutritional supplements for long-term benefit post-IR to slow progression of tumor growth. Specific Aim 3 will use a cell culture model to establish genetic and proteomic profiles that are associated with antioxidant-induced radiosensitivity and resistance. Experiments will determine if PC-3 cells overexpressing Bcl- 2, an anti-apoptotic gene, are sensitive to the growth-inhibitory and radiosensitizing effects of ISF and/or VE antioxidants. If a genetic/proteomic signature suggests that it is likely to be radiosensitive tumor, antioxidants and radiation become a more desirable treatment option. This information will serve to identify proteins that may be critical to the tumor microenvironment and tumor invasive phenotype. In summary, the proposed research will provide mechanistic evidence as to whether these nutritional factors enhance, or potentially interfere with concurrent exposure to established cytotoxic therapeutic agents in PCa. Promising results would justify rapid transition to clinical trials, given the popularity of brachytherapy and the increasing consumption of dietary supplements.