ASCORBATE-INDUCED RADIOSENSITIZATION IN PANCREATIC CANCER

抗坏血酸引起的胰腺癌放射增敏

• 批准号: 8519979
• 负责人: Joseph J Cullen
• 金额: $ 18.52万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-03 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8519979
• 关键词: Adjuvant; Ascorbic Acid; Biochemical; Biochemistry; Cancer Etiology; Cancer cell line; Caring; Cell Proliferation; Cessation of life; Clinical Trials; Development; Diagnosis; Disease; Dose; Drug Delivery Systems; Drug Targeting; Foundations; Funding; Generations; Grant; Human; Hydrogen Peroxide; In Vitro; Incidence; Intravenous; Ionizing radiation; Ions; Label; Left; Life; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Medicine; Metals; Molecular Biology Techniques; National Center for Complementary and Alternative Medicine; Normal Cell; Oral; Oxidative Stress; Pancreatic Adenocarcinoma; Patients; Plasma; Positron-Emission Tomography; Predisposition; Prodrugs; Production; Radiation Tolerance; Radiation therapy; Radio; Radiosensitization; Reactive Oxygen Species; Relative (related person); Reporting; Research; Testing; Therapeutic; Thymidine; United States; Work; ascorbate; cancer care; cancer therapy; combined cancer modality therapy; cytotoxic; cytotoxicity; design; improved; in vivo; indexing; neoplastic cell; novel strategies; outcome forecast; oxidation; pancreatic cancer cells; pancreatic neoplasm; pre-clinical; preclinical study; programs; response; tumor

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; the prognosis remains dismal. We propose to investigate an entirely new approach, using pharmacological ascorbate as an adjuvant to radio-therapy, to treat pancreas cancer. 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. Preliminary studies from our group have demonstrated that ascorbate induces oxidative stress and cytotoxicity in pancreatic cancer cells; this cytotoxicity appears to be greater in tumor vs. normal cells. We have firmly established that pharmacological ascorbate is a pro-drug for delivery of hydrogen peroxide (H2O2) in vitro and in vivo via its autoxidation. Studies from our previously funded R21 grant CA137230 "Mechanisms of ascorbate-induced cytotoxicity in pancreatic cancer" have demonstrated that ascorbate, in doses achievable in humans, decreases viability and proliferation in all pancreatic cancer cell lines examined, via a H2O2-mediated mechanism. The current application extends this preclinical work to determine if this strategy can be used effectively as an adjuvant in radiotherapy for pancreatic cancer. If pancreatic cancer cells (relative to normal cells) are more susceptible to ascorbate-induced cytotoxicity due to increased metal ion catalyzed ascorbate autoxidation leading to increased production of H2O2, then using ascorbate as an adjuvant would be expected to sensitize pancreatic tumor cells to standard therapies such as ionizing radiation that increase levels of reactive oxygen species. We will use biochemistry/molecular biology techniques to determine relative susceptibility to ascorbate-induced radiosensitization and oxidative stress in vitro and in vivo; we will employ FLT-PET (fluoro-labeled thymidine positron emission tomography) as a non- invasive in vivo index of cell proliferation. This 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. The current proposal will test the hypothesis that metal ion catalyzed H2O2 generation from the auto-oxidation of ascorbate induces radiosensitization of human pancreatic cancer cells in vitro and in vivo. We will test our hypotheses with the following two Specific Aims: 1. Determine if ascorbate selectively induces radio-sensitization of human pancreatic cancer cells (vs. normal cells) in vitro via the flux of H2O2 generated from metal ion catalyzed auto-oxidation of ascorbate. 2. Determine if ascorbate selectively induces radio-sensitization of human pancreatic cancer cells in vivo. 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 application will provide a foundation for the rational design of a combined modality cancer therapy that is highly responsive to the RFA PA-09-167 from NCCAM entitled "Developmental Projects in Complementary Approaches to Cancer Care".

描述（由申请人提供）：胰腺腺癌是美国癌症死亡的第四大原因，并且发病率正在增加；预后仍然悲观。我们建议研究一种全新的方法，使用药理学抗坏血酸作为放射治疗的辅助剂来治疗胰腺癌。静脉注射抗坏血酸（即抗坏血酸、维生素 C）（而非口服抗坏血酸）会产生高血浆浓度，该浓度处于对肿瘤细胞具有细胞毒性的范围内。我们课题组的初步研究表明，抗坏血酸会诱导胰腺癌细胞产生氧化应激和细胞毒性；与正常细胞相比，这种细胞毒性在肿瘤细胞中似乎更大。我们已经确定，药理学抗坏血酸是一种前药，可通过其自动氧化作用在体外和体内输送过氧化氢 (H2O2)。我们之前资助的 R21 资助 CA137230“抗坏血酸诱导的胰腺癌细胞毒性机制”的研究表明，在人类可达到的剂量下，抗坏血酸通过 H2O2 介导的机制降低所有检查的胰腺癌细胞系的活力和增殖。目前的应用扩展了这一临床前工作，以确定该策略是否可以有效地用作胰腺癌放射治疗的辅助剂。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的影响，因为金属离子催化的抗坏血酸自氧化作用增加，导致H2O2产生增加，那么使用抗坏血酸作为佐剂有望使胰腺肿瘤细胞对标准疗法敏感，例如增加活性氧水平的电离辐射。我们将使用生物化学/分子生物学技术来确定体外和体内抗坏血酸诱导的放射增敏和氧化应激的相对敏感性；我们将采用FLT-PET（氟标记胸苷正电子发射断层扫描）作为细胞增殖的非侵入性体内指标。该提案的重点是使用补充方法（高剂量抗坏血酸）提高标准抗癌疗法（电离辐射）在胰腺癌治疗中的治疗率。目前的提案将测试以下假设：金属离子催化抗坏血酸自氧化产生 H2O2 会在体外和体内诱导人胰腺癌细胞的放射增敏。我们将通过以下两个具体目标来检验我们的假设： 1. 确定抗坏血酸是否通过金属离子催化抗坏血酸自动氧化产生的 H2O2 通量在体外选择性诱导人胰腺癌细胞（相对于正常细胞）的放射增敏。 2. 确定抗坏血酸是否选择性地诱导体内人胰腺癌细胞的放射增敏。如果我们能够严格证明药理抗坏血酸介导的放射增敏作用会在人胰腺癌细胞中诱导优先氧化应激和随后的细胞毒性，那么本申请的结果将为合理设计联合模式癌症疗法奠定基础，该疗法对 NCCAM 题为“癌症护理补充方法的开发项目”的 RFA PA-09-167 高度敏感。