Phospho-valproic acid for pancreatic cancer prevention

磷酸丙戊酸预防胰腺癌

• 批准号: 8465133
• 负责人: Basil Rigas
• 金额: $ 29.7万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8465133
• 关键词: Animal Model; Animals; Anticonvulsants; Area; Cancer Control; Cancer Etiology; Cancer cell line; Chemoprevention; Chemopreventive Agent; Cimetidine; Clinical; Complex; Data; Development; Growth; Histone Deacetylation; Human; In Vitro; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Metabolism; New Agents; Pathway interactions; Pre-Clinical Model; Prevention; Property; Protocols documentation; STAT3 gene; Safety; Signal Transduction; Signaling Molecule; Testing; Toxic effect; Tumor Volume; Valproic Acid; Work; Xenograft Model; cancer prevention; genotoxicity; in vivo; inhibitor/antagonist; mortality; novel; overexpression; pancreatic cancer cells; pancreatic neoplasm; prevent; public health relevance

DESCRIPTION (provided by applicant): An impressive body of evidence supports the notion that chemoprevention has the potential to be a major component of control of cancer, including pancreatic cancer, one of the most lethal cancers. We propose to study phospho-valproic acid (P-V), a novel derivative of valproic acid, as an agent for the prevention of pancreatic cancer. P-V inhibits the growth of human cancer cell lines up to 245-fold more potently than VPA. In animal models, P-V is twice as effective against pancreatic cancer as VPA. For example, in xenograft models P-V reduced tumor volume by 68%, compared to control, whereas VPA reduced it by 34% (chemoprevention protocol). Remarkably, when given in combination with cimetidine, a clinically available antiulcer compound, P-V prevented 100% of pancreatic tumors in the same animal model. P-V appears to be safe, as shown by genotoxicity and animal toxicity studies. Its mechanism of action is complex, involving several signaling cascades, most prominently STAT3. Our hypothesis is that P-V 1 cimetidine is an effective and safe chemopreventive agent against pancreatic cancer, acting primarily through the STAT3 pathway. To test this hypothesis, we will pursue the following specific aims: Specific Aim # 1: Determine the chemopreventive efficacy of P-V 1 cimetidine in preclinical models of pancreatic cancer; Specific Aim # 2: Determine the mechanism of action of P-V 1 cimetidine in vitro and in vivo; Specific Aim # 3: Determine the metabolism of P-V 1 cimetidine in cultured pancreatic cancer cells and animals and its safety in animals. At the completion of these studies, we expect to have determined key pharmacological parameters of a promising novel agent and its combination with cimetidine. Given the importance of pancreatic cancer and the lack of effective agents against it, we believe that the proposed work holds the promise of a significant advance in this area.

描述（由申请人提供）：令人印象深刻的证据支持这样的观念：化学预防有可能成为控制癌症的主要组成部分，包括胰腺癌，这是最致命的癌症之一。我们建议研究一种新型的丙丙酸衍生物磷酸化磷酸 - 谷酸，作为预防胰腺癌的药物。 P-V比VPA抑制人类癌细胞的生长高达245倍。在动物模型中，P-V对胰腺癌的有效性是VPA的两倍。例如，在异种移植模型中，与对照相比，P-V模型将肿瘤的体积降低了68％，而VPA降低了34％（化学预防方案）。值得注意的是，当与Cimetidine（一种临床上可用的抗硫磺化合物）结合使用时，P-V可以防止同一动物模型中100％的胰腺肿瘤。 P-V似乎是安全的，如遗传毒性和动物毒性研究所示。它的作用机理很复杂，涉及几个信号级联，最突出的STAT3。我们的假设是，P-V 1甲苯二胺是一种针对胰腺癌的有效且安全的化学预防剂，主要通过STAT3途径作用。为了检验这一假设，我们将追求以下特定目的：具体目的＃1：确定p-V 1 cimetidine在胰腺癌的临床前模型中的化学预防疗效；特定目的＃2：确定P-V 1 Cimetidine在体外和体内的作用机理；具体目的＃3：确定培养的胰腺癌细胞和动物中P-V 1甲胺定的代谢及其在动物中的安全性。这些研究完成时，我们希望已经确定有前途的新型药物的关键药理参数及其与Cimetidine的组合。鉴于胰腺癌的重要性以及缺乏有效的药物，我们认为拟议的工作有望在这一领域取得重大进展。