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，并且发病率正在增加。静脉内抗坏血酸盐（即，抗坏血酸、维生素C），而不是口服抗坏血酸盐，产生高血浆浓度，其在对肿瘤细胞具有细胞毒性的范围内。来自我们目前资助的2年U 01基金CA 166800“抗坏血酸诱导的胰腺癌放射增敏作用”的研究表明，在人体可达到的剂量下，抗坏血酸与电离辐射协同作用，通过H2 O2介导的机制降低所有胰腺癌细胞系的活力和增殖。我们最近完成的I期研究表明，药理学抗坏血酸盐联合吉西他滨是安全的，耐受性良好，并可能导致IV期胰腺癌患者的总体临床获益。该建议集中于在胰腺癌的治疗中使用补充方法（高剂量抗坏血酸盐）来提高标准抗癌疗法（电离辐射）的治疗率。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，由于抗坏血酸自氧化增加，导致H2 O2的产生增加，那么抗坏血酸将被预期是有效的和耐受良好的佐剂化疗辐射的患者。此外，用氧化还原活性金属催化剂增加抗坏血酸盐的自动氧化速率以产生更多的H2 O2应选择性地增加抗坏血酸盐诱导的放射增敏和氧化应激。最后，预期抗坏血酸诱导的放射增敏可使肿瘤细胞对抑制H2 O2去除的临床相关药理学试剂敏感。目前的建议将测试的假设，通过金属离子催化的抗坏血酸的自动氧化的H2 O2的生产介导抗坏血酸诱导的细胞毒性和化学-放射增敏在人胰腺癌。我们将用以下三个具体目标来检验我们的假设。1)在I期试验中确定在吉西他滨-放射治疗同时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增强; 3）确定抗坏血酸诱导的放射增敏是否可以通过临床相关的葡萄糖和氢过氧化物代谢的药理学抑制剂增强。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的变化。临床前研究将使用生物化学/分子生物学 生物技术来确定抗坏血酸诱导的放射增敏和氧化应激，并采用非侵入性的体内细胞增殖指数。如果我们能够严格证明，药理学抗坏血酸介导的放射增敏诱导优先氧化应激和随后的细胞毒性在人胰腺癌细胞，那么这个拟议的研究计划的结果将提供一个合理的设计一个新的综合方式癌症治疗胰腺癌的基础。

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.