Pharmacological Ascorbate as a Radiosensitizer in Pancreatic Cancer

抗坏血酸作为胰腺癌放射增敏剂的药理作用

基本信息

批准号：
9241357
负责人：
Joseph J Cullen
金额：
$ 34.88万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9241357
关键词：
Adjuvant Adverse event Alpha Cell Ascorbic Acid Biochemical Biochemistry Cancer Etiology Cell Line Cell Proliferation Cessation of life Clinical Diagnosis Disease Dose Drug Targeting Excision Foundations Funding Glucose Grant Human Hydrogen Peroxide In Vitro Incidence Intravenous Ionizing radiation Ions Lead Left Malignant Neoplasms Malignant neoplasm of pancreas Manganese Mediating Medicine Metabolic Metabolism Metals Molecular Biology Techniques Newsletter Normal Cell Oxidation-Reduction Oxidative Stress Pancreas Pancreatic Adenocarcinoma Patients Pharmacology Plasma Prodrugs Production Radiation Tolerance Radiation therapy Radiation-Sensitizing Agents Radiosensitization Reporting Research Safety Testing Therapeutic United States Work ascorbate autooxidation cancer cell cancer therapy catalyst chemoradiation clinically relevant combined cancer modality therapy cytotoxic cytotoxicity design gemcitabine improved in vivo indexing inhibitor/antagonist neoplastic cell novel novel strategies oxidation pancreatic cancer cells personalized care phase 1 study phase I trial preclinical study programs public health relevance radio-sensitizes radiosensitive response

项目摘要

DESCRIPTION (provided by applicant): Adenocarcinoma of the pancreas is the fourth leading cause of cancer death in the United States and is increasing in incidence. Intravenous ascorbate (i.e., ascorbic acid, vitamin C), but not oral ascorbate, produces high plasma concentrations, which are in the range that are cytotoxic to tumor cells. Studies from our currently funded 2 year U01 grant CA166800 "Ascorbate-induced radiosensitization in pancreatic cancer" have demonstrated that ascorbate, in doses achievable in humans, synergizes with ionizing radiation in decreasing viability and proliferation in all pancreatic cancr cell lines examined, via a H2O2-mediated mechanism. Our recently completed phase I study demonstrated that pharmacological ascorbate combined with gemcitabine is safe and well-tolerated and may lead to overall clinical benefit in patients with stage IV pancreatic cancer. Thi proposal focuses on improvement of the therapeutic ratio of a standard anti-cancer therapy (ionizing radiation) using a complementary approach (high dose ascorbate), in the treatment of pancreatic cancer. If pancreatic cancer cells (relative to normal cells) are more susceptible to ascorbate-induced cytotoxicity due to increased ascorbate auto-oxidation leading to increased H2O2 production, then ascorbate would be expected to be efficacious and well-tolerated adjuvant to chemo-radiation in patients. Furthermore, increasing the rate of auto- oxidation of ascorbate with redox active metal catalysts to generate more H2O2 should selectively increase ascorbate-induced radiosensitization and oxidative stress. Finally, ascorbate-induced radiosensitization would be expected to sensitize tumor cells to clinically relevant pharmacological agents that inhibit the removal of H2O2. The current proposal will test the hypothesis that production of H2O2 via the metal ion catalyzed auto- oxidation of ascorbate mediates ascorbate-induced cytotoxicity and chemo-radiosensitization in human pancreatic cancer. We will test our hypothesis with the following three Specific Aims. 1) Determine in a phase I trial the safety of administering pharmacological ascorbate during concurrent gemcitabine-radiation therapy for the treatment of non-resectable pancreatic cancer; 2) Determine if ascorbate-induced radiosensitization can be selectively enhanced by redox active metal catalysts; 3) Determine if the ascorbate-induced radiosensitization can be enhanced by clinically relevant pharmacological inhibitors of glucose and hydroperoxide metabolism. The phase I trial will quantify adverse events and determine changes in systemic parameters indicative of oxidative stress in patients. The preclinical studies will use biochemistry/molecular biology techniques to determine ascorbate-induced radiosensitization and oxidative stress and employ a non- invasive in vivo index of cell proliferation. If we can rigorously demonstrate that the radiosensitization mediated by pharmacological ascorbate induces preferential oxidative stress and subsequent cytotoxicity in human pancreatic cancer cells, then the results of this proposed research program will provide a foundation for the rational design of a novel combined modality cancer therapy for pancreatic cancer.

描述（由申请人提供）：胰腺腺癌是美国癌症死亡的第四个主要原因，并且发病率正在增加。静脉抗坏血酸（即抗坏血酸，维生素C），但不是口服抗坏血酸，会产生高血浆浓度，该血浆浓度在肿瘤细胞的细胞毒性范围内。我们目前资助的2年U01赠款CA166800的研究“抗坏血酸诱导的胰腺癌的放射敏化”已经表明，在人类中可实现的剂量，在所有pancreatic pancr细胞系中都可以通过降低所有pancreatic pancr细胞系在人类的剂量中，通过电离辐射来协同辐射。我们最近完成的I期研究表明，与吉西他滨结合的药理学抗坏血酸是安全且耐受性良好的，并且可能导致IV期胰腺癌患者的总体临床益处。 Thi提案的重点是改善使用互补方法（高剂量抗坏血酸）在胰腺癌治疗中使用互补方法（高剂量抗坏血酸）的治疗比率。如果胰腺癌细胞（相对于正常细胞）更容易受到抗坏血酸诱导的细胞毒性，这会导致抗坏血酸自身氧化导致H2O2产生增加，则预计抗坏血酸将有效且耐受性良好，对患者的化学疗法进行疗养。此外，用氧化还原活性金属催化剂增加抗坏血酸的自氧化速率以产生更多的H2O2，应有选择地增加抗坏血酸诱导的放射敏化和氧化应激。最后，预期抗坏血酸诱导的放射敏化将使肿瘤细胞对抑制H2O2去除的临床相关药理剂敏感。当前的提案将检验以下假设：通过金属离子催化抗坏血酸的自氧化的H2O2介导抗坏血酸诱导的人类胰腺癌中的细胞毒性和化学 - 放射敏化。我们将通过以下三个特定目标来检验我们的假设。 1）在I期试验中确定在吉西他滨放射治疗中对药理学抗坏血酸的治疗方法的安全性来治疗不可切除的胰腺癌； 2）确定是否可以通过氧化还原活性金属催化剂选择抗坏血酸诱导的放射性化； 3）确定抗坏血酸诱导的放射敏化是否可以通过葡萄糖和氢过氧代谢的临床相关药理学抑制剂来增强。 I期试验将量化不良事件，并确定指示患者氧化应激的全身参数变化。临床前研究将使用生物化学/分子确定抗坏血酸诱导的放射敏化和氧化应激的生物学技术，并采用非浸润性在细胞增殖的体内指数。如果我们严格地证明，药理学抗坏血酸介导的放射敏化会引起人类胰腺癌细胞中的优先氧化应激和随后的细胞毒性，那么该提出的研究计划的结果将为胰腺癌的新型合并型癌症治疗的合理设计提供基础。