High doses of vitamin C to improve cancer treatment passes human safety trial

Clinical trials found that it is safe to regularly infuse brain and lung cancer patients with 800 - 1000 times the daily recommended amount of vitamin C as a potential strategy to improve outcomes of standard cancer treatments. In a work presented in Cancer Cell, University of Iowa researchers also show pathways by which altered iron metabolism in cancer cells, and not normal cells, lead to increased sensitivity to cancer cell death caused by high dose vitamin C.

"This paper reveals a metabolic frailty in cancer cells that is based on their own production of oxidizing agents that allows us to utilize existing redox active compounds, like vitamin C, to sensitize cancer cells to radiation and chemotherapy," says co-author Garry Buettner, who was one of the first to propose that cancer cells might have a vulnerability to redox active compounds over 40 years ago. Buettner, along with study senior authors Bryan Allen and Douglas Spitz, are faculty members at the University of Iowa's Department of Radiation Oncology, Free Radical and Radiation Biology Program, in the Holden Comprehensive Cancer Center.

The 11 evaluable patients enrolled in the brain cancer safety trial received three infusions of vitamin C a week for 2 months followed by two infusions per week for 7 months while receiving standard care radiation and chemotherapy. The goal of each infusion was to raise the concentration of vitamin C in a patient's blood to 20,000 μM, as compared to a blood level of about 70 μM found in most adults. The high dose is necessary because vitamin C has a half-life of about two hours in the circulation of humans. The treatment was generally well tolerated; with modest side effects including frequent trips to the bathroom and dry mouth. Rarely, some patients developed high blood pressure that subsided quickly following infusion.

Why is this approach safe? Vitamin C, even at high levels, isn't toxic to normal cells. The research group at Iowa found, however, that tumor tissue's abnormally high levels of redox active iron molecules (a by-product of abnormal mitochondrial metabolism) react with vitamin C to form hydrogen peroxide and free radicals derived from hydrogen peroxide. These free radicals are believed to cause DNA damage selectively in cancer cells (versus normal cells) leading to enhanced cancer cell death as well as sensitization to radiation and chemotherapy in cancer cells.

"This is a significant example of how knowing details of potential mechanisms and the basic science of redox active compounds in cancer versus normal cells can be leveraged clinically in cancer therapy," says co-senior author Douglas Spitz, who focused on the biochemical studies. "Here, we verified convincingly that increased redox active metal ions in cancer cells were responsible for this differential sensitivity of cancer versus normal cells to very high doses of vitamin C."

The safety study sets the stage for phase II clinical trials looking at whether high dose vitamin C is effective at extending overall lifespan and quality of life for patients undergoing radiation and chemotherapy. The researchers are currently enrolling patients with stage 4 lung cancer and will soon begin enrolling people with glioblastoma multiforme (brain cancer) in these phase II trials. They are hopeful that brain cancer responses to radiation and chemotherapy can be enhanced in these phase II trials. This guarded optimism is based on the phase I trial data showing an increase in overall survival of 4-6 months in 11 glioblastoma multiforme patients (18-22 months) versus the 14-16 months survival typically seen with the standard treatment.

"The majority of cancer patients we work with are excited to participate in clinical trials that could benefit future patient outcomes down the line," says co-senior author Bryan Allen, who led the clinical side of the study. "Results look promising but we're not going to know if this approach really improves therapy response until we complete these phase II trials."

The cost per patient above standard insurance billing for the phase II vitamin C glioblastoma multiforme protocol is approximately $8000 spread over 9 months of test infusions. This cost can be less than a single dose of some immunotherapy and/or chemotherapy drugs.

This work is supported by the American Society for Radiation Oncology, the Carver Research Program of Excellence in Redox Biology, the US National Institutes of Health, Ms. Marie Foster/matched by IBM, the University of Iowa Holden Comprehensive Cancer Center, and the University of Iowa Medical Scientist Training Program. Co-author Dennis Riley is the Chief Scientific Officer of Galera Therapeutics, Inc., which supplied some materials for use in the basic science studies.

Joshua D. Schoenfeld, Zita A. Sibenaller, Kranti A. Mapuskar, Brett A. Wagner, Kimberly L. Cramer-Morales, Muhammad Furqan, Sonia Sandhu, Thomas L. Carlisle, Mark C. Smith, Taher Abu Hejleh, Daniel J. Berg, Jun Zhang, John Keech, Kalpaj R. Parekh, Sudershan Bhatia, Varun Monga, Kellie L. Bodeker, Logan Ahmann, Sandy Vollstedt, Heather Brown, Erin P. Shanahan Kauffman, Mary E. Schall, Ray J. Hohl, Gerald H. Clamon, Jeremy D. Greenlee, Matthew A. Howard, Michael K. Shultz, Brian J. Smith, Dennis P. Riley, Frederick E. Domann, Joseph J. Cullen, Garry R. Buettner, John M. Buatti, Douglas R. Spitz, Bryan G. Allen.
O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate.
Cancer Cell, 2017, ISSN 1535-6108, doi: 10.1016/j.ccell.2017.02.018.

Most Popular Now

SK bioscience and GSK start Phase 3 trial of adjuv…

SK bioscience (SK) and GlaxoSmithKline plc (GSK) today announced the initiation of a Phase 3 clinical study of SK's COVID-19 vaccine candidate, GBP510, in combination wit...

Blood vessels produce growth factor that promotes …

Blood vessels supply tumors with nutrients and, on the other hand, enable cancer cells to spread throughout the body. The settlement of circulating tumor cells in a dista...

No serious health effects linked to mRNA COVID-19 …

Federal and Kaiser Permanente researchers combing the health records of 6.2 million patients found no serious health effects that could be linked to the 2 mRNA COVID-19 v...

First-in-human clinical trial for a vaccine to tre…

The first patients have been enrolled in a phase 1 randomized placebo-controlled clinical trial to study a therapeutic vaccine for opioid use disorder developed by resear...

New study examines 'Achilles heel' of cancer tumou…

Researchers at the University of British Columbia's faculty of medicine and BC Cancer Research Institute have uncovered a weakness in a key enzyme that solid tumour cance...

AI algorithm solves structural biology challenges

Determining the 3D shapes of biological molecules is one of the hardest problems in modern biology and medical discovery. Companies and research institutions often spend ...

A drug costing less than €2 a day helps in the tre…

Metoprolol, a drug widely used to treat cardiovascular disease, is beneficial when administered to COVID-19patients. This is the finding of a study by investigators at th...

Sandoz strengthens pipeline by entering into agree…

Sandoz, a Novartis division, today announced that it has entered into a commercialization agreement with Bio-Thera Solutions, Ltd. for biosimilar bevacizumab (BAT1706). B...

Pfizer and BioNTech submit a variation to EMA with…

Pfizer Inc. (NYSE: PFE) and BioNTech SE (Nasdaq: BNTX) announced that they submitted a variation to the European Medicines Agency (EMA) requesting to update the Condition...

Rheumatoid arthritis treated with implanted cells …

With a goal of developing rheumatoid arthritis therapies with minimal side effects, researchers at Washington University School of Medicine in St. Louis have genetically ...

One in three Americans had COVID-19 by the end of …

A new study published in the journal Nature estimates that 103 million Americans, or 31 percent of the U.S. population, had been infected with SARS-CoV-2 by the end of 20...

NIH scientists build a cellular blueprint of multi…

Chronic lesions with inflamed rims, or "smoldering" plaques, in the brains of people with multiple sclerosis (MS) have been linked to more aggressive and disabling forms ...