Antioxidant Interactions with Prostate Cancer Treatments

说明(申请人提供)：抗氧化剂维生素E(VE)和大豆异黄酮类(ISF)作为前列腺癌(PCA)的单一药物和与常用治疗药物联合使用，具有作为重要的化学预防药物的潜力。最近在体外放射治疗和组织间近距离放射治疗(植入放射性粒子)方面的改进使这种微创治疗在前列腺癌患者中很受欢迎。然而，与剂量相关的放射毒性通常会限制可用于治疗的有效剂量。我们对人前列腺癌细胞系的研究发现，在雄激素反应性和雄激素非依赖性细胞系中，以细胞周期停滞为特征的加性生长抑制作用。我们最近的研究发现，低浓度的生理上相关的ISF和VE治疗降低了辐射(IR)后PCa细胞的克隆形成存活率，这是放射增敏效应的证据。这项拟议的初步研究将进一步调查VE和ISF补充剂对临床抗肿瘤放射治疗的细胞毒性的影响。假说是，用低浓度的ISF和VE治疗人前列腺癌细胞会增加对放射治疗的敏感性，抑制IR后存活的细胞的生长，并可以减少促炎细胞因子的诱导。具体目标1将确定饮食中的ISF和VE是否单独或联合使用，在小鼠PC-3异种移植瘤中增强IR的体内细胞毒性。肿瘤对IR的反应将表现为细胞周期和凋亡途径的表达，以及炎性细胞因子的产生和与生理相关的血液抗氧化剂水平。具体目标2将确定饮食中的ISF和/或VE是否在照射后发挥特定的作用，以抑制复发的前列腺移植瘤的进展。这是一种有针对性的新辅助方法，可以直接评估ISF和VE营养补充剂对IR后减缓肿瘤生长的长期益处的潜在有用性。特殊目标3将使用细胞培养模型来建立与抗氧化剂诱导的辐射敏感性和抵抗力相关的遗传和蛋白质组图谱。实验将确定过表达抗凋亡基因Bcl-2的PC-3细胞是否对ISF和/或VE抗氧化剂的生长抑制和辐射增敏作用敏感。如果基因/蛋白质组特征表明它很可能是辐射敏感的肿瘤，抗氧化剂和辐射就成为更可取的治疗选择。这些信息将有助于确定可能对肿瘤微环境和肿瘤侵袭表型至关重要的蛋白质。总之，这项拟议的研究将提供机制证据，证明这些营养因素是否会增强或潜在地干扰PCa患者同时暴露于已有的细胞毒治疗药物。鉴于近距离放射治疗的流行和膳食补充剂的消费增加，前景看好的结果将证明快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.