Novel vitamin D analog for kidney cancer

描述(申请人提供)：肾癌约占所有成人恶性肿瘤的3%，每年造成30,000多例病例和12,000人死亡。不幸的是，目前缺乏对这种致命疾病的有效干预，迫切需要对这种致命疾病进行有效的治疗。大量的流行病学研究有力地证明了饮食中维生素D在预防各种癌症中的重要性。此外，维生素D及其类似物的生物活性代谢物1，25-二羟基维生素D3(1，25(OH)2D3)在癌症中的治疗潜力也得到了很好的证明。然而，这种激素固有的钙化毒性，特别是在治疗剂量下，阻碍了它作为抗癌药物的普遍使用，为开发具有强大的抗增殖活性并降低全身毒性的维生素D类似物打开了大门。最近我们开发了一种新的1，25(OH)2D3[11，25-二羟基维生素D3-3-溴乙酸酯，1，25(OH)2D3-3-Be]的衍生物，它共价连接到VDR的配体结合袋中。我们证明了1，25(OH)2D3-3-Be对几种人类癌细胞的生长有强烈的抑制作用，其中包括一组肾癌细胞。我们还证明，在小鼠异种移植模型中，1，25(OH)2D3-3-Be在0.1-0.5 5g/kg剂量水平下可以减少激素不敏感的前列腺癌，而没有明显的毒性。总而言之，这些结果证明了这种化合物对肾癌的潜在治疗作用。本R21建议的目的是评价1，25(OH)2D3-3-BE在肾癌中的潜在治疗价值，并评价这种新型VDR-1，25(OH)2D3的交联物的分子机制。这些目标将通过两个特定目标来实现：特定目标1：确定1，25(OH)2D3-3-Be在小鼠异种移植模型中对人肾癌的疗效；以及特定目标2：评价1，25(OH)2D3-3-Be抑制肾癌细胞生长和诱导细胞凋亡的分子机制。这一试点项目的成功完成将对开发治疗肾癌的1，25(OH)2D3-3-BE和类似的维生素D激素的VDR烷基化类似物至关重要。与公共卫生相关：维生素D的生物活性代谢物1，25-二羟基维生素D3(1，25(OH)2D3)固有的钙化毒性阻碍了其作为抗癌剂的广泛使用。最近我们开发了一种新的1，25(OH)2D3的衍生物，它能强烈抑制几种人肾癌细胞的生长，并诱导这些细胞的程序性死亡。该项目的目标是评估这种化合物在肾癌中的治疗潜力。

DESCRIPTION (provided by applicant): Kidney cancer comprises approximately 3% of all adult malignancies, and account for over 30,000 cases and 12,000 deaths per year. Unfortunately, efficient intervention of this deadly disease is currently lacking, and effective therapy for this deadly disease is urgently needed. Numerous epidemiological studies have strongly demonstrated the importance of dietary vitamin D in preventing various cancers. In addition, therapeutic potential of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the biologically active metabolite of vitamin D and its analogs in cancer is well-documented. However, inherent calcemic toxicity of this hormone, particularly at therapeutic doses, has prevented its general use as an anticancer agent, opening the door for the development of vitamin D analogs with potent antiproliferative activity with reduced systemic toxicity. Recently we developed a novel derivative of 1,25(OH)2D3 [11,25- dihydroxyvitamin D3-3-bromoacetate, 1,25(OH)2D3-3-BE] that covalently attaches 1,25(OH)2D3 inside the ligand-binding pocket of VDR. We demonstrated that 1,25(OH)2D3-3-BE strongly inhibits the growth of several human cancer cells, including a set of kidney cancer cells. We also demonstrated that 1,25(OH)2D3-3-BE reduces hormone-insensitive prostate tumor at 0.1-0.5 5g/kg dose level in a mouse xenograft model without significant toxicity. Collectively, these results demonstrate potential therapeutic utility of this compound in kidney cancer. The goal of this R21 proposal is to appraise the potential therapeutic value of 1,25(OH)2D3-3-BE in kidney cancer, and evaluate the molecular mechanism of this novel VDR-cross-linking derivative of 1,25(OH)2D3. These goals will be met by two specific aims: Specific Aim 1: Determine the efficacy of 1,25(OH)2D3-3-BE on human renal cell carcinoma in a mouse xenograft model; and Specific Aim 2: Evaluate the molecular mechanism of growth-inhibition and apoptosis by 1,25(OH)2D3-3-BE in kidney cancer cells. Successful completion of this pilot project will be crucial for the development of 1,25(OH)2D3-3-BE and similar VDR-alkylating analogs of vitamin D hormone for kidney cancer. PUBLIC HEALTH RELEVANCE: Inherent calcemic toxicity of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the biologically active metabolite of vitamin D has prevented its general use as an anticancer agent. Recently we developed a novel derivative of 1,25(OH)2D3 that strongly inhibits the growth of several human kidney cancer cells, and induces programmed cell death in these cells. The goal of this project is to evaluate the therapeutic potential of this compound in kidney cancer.