Pharmacological Ascorbate as a Radiosensitizer in Pancreatic Cancer

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，并且发病率呈上升趋势。静脉注射抗坏血酸（即抗坏血酸、维生素C），而不是口服抗坏血酸，会产生高血浆浓度，其浓度在对肿瘤细胞具有细胞毒性的范围内。我们目前资助的为期2年的U01基金CA166800“抗坏血酸诱导的胰腺癌放射增敏”研究表明，在人体可达到的剂量下，抗坏血酸通过h2o2介导的机制，与电离辐射协同作用，降低所有胰腺癌细胞系的生存能力和增殖能力。我们最近完成的I期研究表明，抗坏血酸联合吉西他滨是安全且耐受性良好的，可能会给IV期胰腺癌患者带来总体的临床益处。本建议的重点是在胰腺癌治疗中使用补充方法（高剂量抗坏血酸）提高标准抗癌治疗（电离辐射）的治疗比例。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，因为抗坏血酸增加了自身氧化，导致H2O2的产生增加，那么抗坏血酸有望成为患者化疗放疗的有效和耐受性良好的辅助药物。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，可以选择性地增加抗坏血酸诱导的放射增敏和氧化应激。最后，抗坏血酸诱导的放射增敏有望使肿瘤细胞对临床相关的抑制H2O2去除的药理学药物敏感。目前的提议将验证通过金属离子催化抗坏血酸的自氧化产生H2O2介导抗坏血酸诱导的人类胰腺癌细胞毒性和化学放射致敏的假设。我们将通过以下三个具体目标来验证我们的假设：1)在一项I期试验中确定在吉西他滨放射治疗期间给予抗坏血酸药物治疗不可切除胰腺癌的安全性；2)确定抗坏血酸诱导的放射增敏是否可以通过氧化还原活性金属催化剂选择性地增强；3)确定抗坏血酸诱导的放射致敏是否可以通过临床相关的葡萄糖和过氧化氢代谢药物抑制剂来增强。I期试验将量化不良事件，并确定患者氧化应激系统参数的变化。临床前研究将使用生物化学/分子

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.