权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Ascorbic acid as a pharmacologic agent in disease treatment

抗坏血酸作为疾病治疗中的药物

基本信息

批准号：
10919433
负责人：
MARK A LEVINE
金额：
$ 59.31万
依托单位：
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10919433
关键词：
Acids Advanced Malignant Neoplasm Animal Model Animals Antibiotics Antiviral Agents Ascorbic Acid Bacteria Biological Availability Blood Blood Vessels Bypass COVID-19 Case Series Cell Death Cells Cessation of life Clinic Clinical Clinical Trials Consumption Coupled DNA DNA Damage Data Diffusion Disease Dose Drug Kinetics Enzymes Evaluation Excretory function Extramural Activities Generations Glutathione Homeostasis Human Hydrogen Peroxide Immune checkpoint inhibitor In Vitro Infectious Agent Intravenous Investigation Iron Kidney Laboratories Light Malignant Neoplasms Measurement Mediating Membrane Metals Mitochondria Modality Molecular Mechanisms of Action Oral Oral Ingestion Outcome Pathologic Patients Pattern Peroxidases Persons Pharmacologic Ascorbate Phase Phase I/II Trial Phase II Clinical Trials Physicians Physiological Placebo Control Plasma Play Poly(ADP-ribose) Polymerases Prodrugs Proteins Publishing Reactive Oxygen Species Recommended Dietary Allowance Reporting Research Personnel Role Safety Sepsis Testing Therapeutic Time Tissues Toxic effect absorption ascorbate cancer cell cancer therapy chemical synthesis chemotherapy cofactor demethylation design double-blind placebo controlled trial experimental study extracellular in vivo intravenous administration novel oxidation pharmacokinetic model pharmacologic pre-clinical prevent repaired treatment group tumor growth

项目摘要

Pharmacologic Ascorbate Explanation When ingested orally, ascorbic acid is tightly controlled by four physiologic mechanisms: absorption, tissue transport, renal reabsorption/excretion, and utilization. Intravenous administration of ascorbic acid bypasses tight control until the kidney restores homeostasis, as determined from pharmacokinetics and bioavailability experiments conducted by this laboratory. These data have surprising and novel implications for cancer treatment. Approximately 50 years ago, Ewan Cameron proposed that ascorbic acid might have a beneficial effect in treating patients with cancer. Joined by the two-time Nobel Laureate Linus Pauling, they published two case series that suggested potential benefit of a large daily dose of ascorbic acid, 10 grams (10,000 mg), in some patients with terminal cancer. For comparison purposes, note that the recommended dietary allowance for ascorbic acid at that time was 60 mg daily, or 0.6% of the treating dose. The Cameron-Pauling reports were criticized because they were retrospective, without placebo control, in part subjective, and lacked independent pathologic confirmation. Investigators at the Mayo Clinic conducted two double-blind, placebo-controlled trials using 10 grams ascorbate daily to treat patients with advanced cancer, and found no effect. Based on these data, physicians were strongly advised to not use ascorbic acid in cancer treatment. In light of our extensive pharmacokinetics and bioavailability data, we reviewed the experiments of Cameron and colleagues, and the Mayo Clinic investigators. We were the first to recognize that the Cameron-associated patients received IV and oral ascorbic acid, but the Mayo Clinic-associated patients received only oral ascorbic acid. Thus, comparisons between the treatment groups were invalid, and the issue of ascorbic acid in cancer treatment needed re-evaluation. Based on our bioavailability data, pharmacokinetics modeling, and measurements in people who received intravenous doses, intravenous ascorbic acid can produce pharmacologic plasma concentrations. These concentrations are up to 1000-fold higher than maximally tolerated oral doses. In vitro, pharmacologic ascorbic acid concentrations that are easily achieved in humans kill cancer cells but not normal cells. Killing is mediated by extracellular ascorbic acid, its oxidation to ascorbate radical, and protein-dependent formation of hydrogen peroxide. To detect hydrogen peroxide without ascorbate interference, experiments required specialized chemical synthesis of peroxyxanthones, not commercially available. Based on the obtained data, we proposed and validated in vivo the hypothesis that pharmacologic ascorbic acid is a pro-drug for preferential formation of hydrogen peroxide in the extravascular space, but not in blood. From these findings, we developed and continue to test a global hypothesis explaining why cancer cells, but not normal cells, are sensitive to ascorbate mediated death via extracellular hydrogen peroxide formation. The essential prerequisite is formation of extracellular hydrogen peroxide in the presence of pharmacologic ascorbic acid. Extracellular hydrogen peroxide is then able to enter cells, likely by diffusion. Hydrogen peroxide in the presence of ascorbate and catalytic metals leads to formation of multiple reactive oxygen species (ROS). Reactive oxygen species thus formed may selectively kill cancer cells by one of many mechanisms: activation of poly ADP-ribose polymerase (PARP) and/or depletion of intracellular ATP; generation of DNA damage that cannot be repaired quickly enough to prevent cell death; depletion of intracellular reducing equivalents via their consumption by glutathione-dependent peroxidases; direct mitochondrial toxicity; direct membrane toxicity; interaction with intracellular iron stores. Additional mechanisms are predicted and likely, all based on generation of extracellular and intracellular reactive oxygen species from extracellular hydrogen peroxide. Experiments exploring these concepts continue. Findings from many other laboratories have confirmed our original observations. Additionally, some findings suggest that ascorbate may have mechanisms of action on some cancers that may not be directly related to extracellular hydrogen peroxide formation. For example, ascorbate as a co-factor increases activity of the ten-eleven translocation enzymes, causing DNA demethylation and an increase in hydroxy-methylation. How ascorbate mediates these actions, whether at physiologic or pharmacologic concentrations, and whether extracellular or intracellular hydrogen peroxide generation modifies such actions, has clinical implications for ascorbate use. Other current efforts are focused on: continued investigation of pharmacologic ascorbic acid as an agent to inhibit tumor growth in animal models with select treatment modalities; in vivo measurement of hydrogen peroxide in humans; initiation and continuation of phase II clinical trials; use of pharmacologic ascorbic acid in other diseases such as sepsis and COVID-19; and continued characterization of clinical usage patterns and safety. Phase I and Phase II clinical trials are promising, as are safety data to date.

药理抗坏血酸解释口服时，抗坏血酸受四种生理机制的严格控制：吸收、组织转运、肾重吸收/排泄和利用。根据本实验室进行的药代动力学和生物利用度实验，静脉注射抗坏血酸可绕过严格控制，直至肾脏恢复稳态。这些数据对癌症治疗具有令人惊讶的和新颖的意义。大约50年前，Ewan卡梅隆提出抗坏血酸可能对治疗癌症患者有有益的作用。两届诺贝尔奖获得者莱纳斯·鲍林（Linus Pauling）加入了他们的行列，他们发表了两个病例系列，表明每日大剂量抗坏血酸（10克（10，000毫克））对某些晚期癌症患者的潜在益处。为了比较的目的，请注意，当时抗坏血酸的推荐膳食允许量为每天60 mg，或治疗剂量的0.6%。卡梅伦-鲍林的报告受到批评，因为它们是回顾性的，没有安慰剂对照，部分主观，缺乏独立的病理学证实。马约诊所的研究人员进行了两项双盲、安慰剂对照试验，每天使用10克抗坏血酸盐治疗晚期癌症患者，结果没有发现效果。基于这些数据，医生被强烈建议不要在癌症治疗中使用抗坏血酸。根据我们广泛的药代动力学和生物利用度数据，我们回顾了卡梅隆和同事以及马约诊所研究人员的实验。我们是第一个认识到卡梅隆相关患者接受静脉注射和口服抗坏血酸，但马约诊所相关患者只接受口服抗坏血酸。因此，治疗组之间的比较是无效的，抗坏血酸在癌症治疗中的问题需要重新评估。基于我们的生物利用度数据、药代动力学模型和静脉注射抗坏血酸的测量结果，静脉注射抗坏血酸可以产生药理学血浆浓度。这些浓度比最大耐受口服剂量高1000倍。在体外，人体中容易达到的药理学抗坏血酸浓度可以杀死癌细胞，但不能杀死正常细胞。细胞外抗坏血酸、抗坏血酸自由基的氧化和过氧化氢的蛋白质依赖性形成介导杀伤。为了在不受抗坏血酸干扰的情况下检测过氧化氢，实验需要专门化学合成的过氧氧杂蒽酮，而这在市场上是买不到的。基于所获得的数据，我们提出并验证了体内的假设，即药理学抗坏血酸是一种前药，优先形成过氧化氢的血管外空间，但不是在血液中。从这些发现中，我们开发并继续测试一个全球性的假设，解释为什么癌细胞，而不是正常细胞，通过细胞外过氧化氢形成抗坏血酸介导的死亡是敏感的。必要的先决条件是在药理学抗坏血酸存在下形成细胞外过氧化氢。细胞外过氧化氢然后能够进入细胞，可能通过扩散。过氧化氢在抗坏血酸和催化金属的存在下导致形成多种活性氧物质（ROS）。由此形成的活性氧物质可以通过许多机制之一选择性地杀死癌细胞：聚ADP-核糖聚合酶（PARP）的活化和/或细胞内ATP的消耗;不能足够快地修复以防止细胞死亡的DNA损伤的产生;通过谷胱甘肽依赖性过氧化物酶消耗细胞内还原当量而消耗细胞内还原当量;直接线粒体毒性;直接膜毒性;与细胞内铁储存的相互作用。其他机制的预测和可能，所有的基础上产生的细胞外和细胞内的活性氧从细胞外过氧化氢。探索这些概念的实验仍在继续。许多其他实验室的发现证实了我们最初的观察结果。此外，一些研究结果表明，抗坏血酸可能对某些癌症有作用机制，这些癌症可能与细胞外过氧化氢的形成没有直接关系。例如，抗坏血酸作为辅因子增加了10 - 11易位酶的活性，导致DNA去甲基化和羟甲基化的增加。抗坏血酸如何介导这些作用，无论是在生理或药理学浓度，以及细胞外或细胞内过氧化氢的产生是否改变这些行动，抗坏血酸的使用具有临床意义。目前的其他努力集中在：继续研究药理学抗坏血酸作为药物，以抑制动物模型中的肿瘤生长，并选择治疗方式;人体过氧化氢的体内测量;启动和继续II期临床试验;在其他疾病中使用药理学抗坏血酸，如败血症和COVID-19;以及继续表征临床使用模式和安全性。I期和II期临床试验是有希望的，迄今为止的安全性数据也是如此。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pharmacologic Ascorbate in Myeloma Treatment: Doses Matter.

DOI：
10.1016/j.ebiom.2017.03.014
发表时间：
2017-04
期刊：
EBioMedicine
影响因子：
11.1
作者：
Violet PC;Levine M
通讯作者：
Levine M

Ascorbic acid kills Epstein-Barr virus positive Burkitt lymphoma cells and Epstein-Barr virus transformed B-cells in vitro, but not in vivo.

抗坏血酸在体外可杀死 Epstein-Barr 病毒阳性的 Burkitt 淋巴瘤细胞和 Epstein-Barr 病毒转化的 B 细胞，但在体内则无效。

DOI：
10.3109/10428194.2012.739686
发表时间：
2013
期刊：
Leukemia & lymphoma
影响因子：
2.6
作者：
Shatzer,AmberN;Espey,MichaelGraham;Chavez,Mayra;Tu,Hongbin;Levine,Mark;Cohen,JeffreyI
通讯作者：
Cohen,JeffreyI

Treatment of pancreatic cancer with intravenous vitamin C: a case report.

DOI：
10.1097/cad.0000000000000603
发表时间：
2018-04
期刊：
Anti-cancer drugs
影响因子：
2.3
作者：
Drisko JA;Serrano OK;Spruce LR;Chen Q;Levine M
通讯作者：
Levine M

Antitumor effect of pharmacologic ascorbate in the B16 murine melanoma model.

药理抗坏血酸在 B16 小鼠黑色素瘤模型中的抗肿瘤作用。

DOI：
10.1016/j.freeradbiomed.2015.06.032
发表时间：
2015
期刊：
Free radical biology & medicine
影响因子：
7.4
作者：
Serrano,OscarK;Parrow,NermiL;Violet,Pierre-Christian;Yang,Jacqueline;Zornjak,Jennifer;Basseville,Agnes;Levine,Mark
通讯作者：
Levine,Mark

Data Triumph at C.