When Garry Buettner, PhD, who has been studying the chemistry and biochemistry of vitamin C for at least four decades, was diagnosed with myelodysplastic syndromes (MDS), he applied his research to his own life — reviewing the data and designing a protocol for his treatment.
The biochemist’s work has helped establish that at millimolar concentrations, intravenous delivery of vitamin C (ascorbate) can act as a prooxidant — generating hydrogen peroxide in a rodent tumor’s microenvironment. In fact, Buettner and his colleagues from the Free Radical and Radiation Biology Program at the University of Iowa in Iowa City, Iowa, recently published a scientific paper demonstrating that high-dose ascorbate increased the effectiveness of the chemotherapy agent azacytidine (Vidaza) in preclinical cell studies and in mice.
Buettner received his first chemotherapy treatment for MDS in early September 2023, shortly after he was diagnosed with cancer. He began taking infusions of high-dose ascorbate in February 2024, which have continued to be a part of each of his cancer treatment cycles since.
He receives azacytidine as the standard of care in a repeating 28-day cycle (4 weeks). Specifically, on days 1, 2, 3, 4, 5, 8 (Monday, Tuesday, Wednesday, Thursday, Friday, and Monday), and 9 (Tuesday), he gets infusions of chemotherapy. On days 1, 3, 5 (Monday, Wednesday, and Friday), and 9 (Tuesday), he also receives infusions of 75 g of ascorbate (vitamin C). These are administered in the same infusion session, one after the other. Then he takes nothing after day 9 until the end of the 28-day cycle, when he repeats his treatment.
“Currently, there is no cure for my situation. So, treatments will continue. But there may be modifications in the future, but we are in unknown territory. So what can be done is unknown,” Buettner told Medscape Medical News.
“The big thing is that I am feeling good; my blood counts have been in or near the normal range. Can’t ask for more,” he continued.
Sitting in an infusion chair at the Holden Comprehensive Cancer Center at the University of Iowa, with a cold liter bag of high-dose pharmacologic ascorbate (extremely high-dose vitamin C) — brown-bagged to shield it from fluorescent lights — Buettner talks about mechanisms and millimolar concentrations with the calm precision of someone who has spent decades in this exact chemistry.
“The cancer drug I’m getting hinders putting methyl groups on DNA,” Buettner explains, referring to his chemotherapy agent azacitidine. “And the system that takes those methyl groups off relies on vitamin C [ascorbate] to function optimally. So I thought, let’s make sure I have plenty of vitamin C so that system works at full capacity.”
The distinction between vitamin C as a nutritional supplement and pharmacologic ascorbate as a drug is key to understanding why this field has been so hard to communicate and so easy to dismiss. What researchers at the University of Iowa, the University of Kansas, and a few other institutions are studying bears almost no resemblance to the vitamin C tablets sold in drug stores. We are talking about doses 150-190 times higher, given intravenously, 2-3 times a week — sometimes for years.
Prajwal Dhakal, MBBS, hematologist and oncologist at University of Iowa Health Care in Iowa City, has been treating Buettner, which included okaying him receiving the ascorbate infusions. Dhakal recently began recruiting for a clinical trial of ascorbate with chemotherapy for patients with MDS.
A Complicated History
To understand where things stand today, it helps to understand the confusion left by earlier efforts. In the 1970s, Linus Pauling championed oral vitamin C as a cancer treatment. However, Mayo Clinic randomized trials in the 1980s found no benefit and were published in The New England Journal of Medicine. For most of the oncology community, that was that.
“There’s a lot of inertia against vitamin C,” said Bryan Allen, MD, PhD, director of radiation oncology research at the University of Iowa and a leading investigator of high-dose ascorbate clinical studies in humans. “Even if we show the data, they just don’t believe it.”
The flaw in those early trials, researchers now understand, was the route of administration. Oral vitamin C cannot reach the blood levels needed to produce a pharmacologic effect. Mark Levine, MD, at the National Institutes of Health (NIH), recognized this and revived interest in high-dose intravenous ascorbate in the mid-2000s, connecting with Buettner and eventually with Joseph Cullen, MD, a surgeon at the University of Iowa. What followed was a decade-long effort to rebuild the rationale from cells to animals to patients.
“When Levine gave a formal talk to our scientists and physicians, they understood it,” Buettner recalls. “They got it.”
The Mechanism: More Than Just Antioxidants
One of the persistent misconceptions about high-dose vitamin C in oncology is that it acts as an antioxidant — and that giving an antioxidant alongside chemotherapy or radiation would blunt those treatments’ cancer-killing effects. For years, this concern kept medical oncologists at arm’s length.
The reality is more nuanced. When pharmacologic ascorbate is infused intravenously, plasma concentrations in the body can rise into the near 20 mM range, according to a randomized phase 2 study of patients with stage IV pancreatic cancer published in Redox Biology. This concentration is orders of magnitude higher than the roughly 0.06 mmol/L normally found in blood and cannot be achieved through oral intake. At these levels, vitamin C behaves very differently from its familiar antioxidant role.
Levine, Buettner, and colleagues co-authored a paper, published in Proceedings of the National Academy of Sciences, which found that pharmacologic ascorbate acts as a prooxidant, generating hydrogen peroxide in the extracellular fluid surrounding tumors. The authors of this and other papers think this is how pharmacologic ascorbate works when people take it.
Tumor cells, which often harbor elevated pools of redox-active iron and exist under higher baseline oxidative stress, appear particularly vulnerable to this chemistry, according to a study of high-dose ascorbate in preclinical and animal models of non-small cell lung cancer and glioblastoma, published in Cancer Cell by the Iowa researchers. In this setting, the hydrogen peroxide produced by high-dose ascorbate damaged lipids, proteins, and DNA.
While the mechanism of action proposed for pharmacologic ascorbate — the generation of hydrogen peroxide that selectively damages tumor cells — has been strongly demonstrated in cell culture and animal models, direct proof of the full mechanism operating within human tumors remains limited. A study in humans published in Cancer Chemotherapy and Pharmacology showed that pharmacologic ascorbate produces the same millimolar plasma concentrations required for the hydrogen-peroxide mechanism.
What Human Trials Show
The most compelling human evidence of improved survival from pharmacologic ascorbate to date comes from research on pancreatic cancer.
The study of patients with pancreatic cancer mentioned earlier was conducted by researchers at Iowa. Cullen, who led the research, and his colleagues, added 75 g of pharmacologic ascorbate three times weekly to standard gemcitabine and nab-paclitaxel as first-line therapy in metastatic pancreatic cancer. The results were striking enough that the data safety monitoring board stopped enrollment early: patients receiving ascorbate showed roughly double the progression-free and overall survival (16 months vs 8 months) of those on chemotherapy alone.
“Double the survival — to me, that’s not heard of before,” said Qi Chen, PhD, at the University of Kansas Medical Center, Kansas City, Kansas, who trained directly under Levine at the NIH. “Even if you prolonged survival for 2 or 6 months in pancreatic cancer, that would be viewed as significant.”
Cullen noted an unexpected secondary finding: ascorbate patients tolerated chemotherapy substantially better.
“Patients who got ascorbate got almost twice as much chemotherapy for twice as long,” he said. Whether the survival benefit stems from ascorbate’s direct antitumor effect, its protection of normal tissue enabling more chemo, or both remains unclear. “Who cares?” Cullen said. “I’ll take it for the win.”
In glioblastoma, Allen led a University of Iowa phase 2 trial of roughly 50-60 patients treated with pharmacologic ascorbate plus radiation and temozolomide. The study, published in Clinical Cancer Research in 2024, showed that about 20% had significantly improved overall survival vs the historical control group (19.6 months vs 14.6 months, respectively). Embedded within that trial was a notable biomarker finding: patients whose tumors had higher baseline levels of redox-active iron had substantially better progression-free and overall survival, suggesting tumor iron content may predict who benefits most. Allen’s group is currently conducting a phase 1 trial testing that theory. His team is also analyzing results of a phase 2 trial combining radiation, chemotherapy, and ascorbate for patients with non-small cell lung cancer. They hope to publish these findings this year.
Chen and colleagues at the University of Kansas have also recently concluded a small pilot trial in patients with muscle-invasive bladder cancer who were ineligible for standard neoadjuvant cisplatin. Instead, they received high-dose ascorbate plus gemcitabine and carboplatin. It found that four of the 12 patients experienced significant downstaging, with three achieving complete pathologic response. The rationale for its use in bladder cancer is especially appealing on biological grounds: ascorbate is excreted in urine, thereby concentrating it at the tumor site.
Researchers in Guangzhou, China, from the Sun Yat-sen University Cancer Center completed the phase 3 VITALITY trial in colorectal cancer of ascorbate with FOLFOX ± bevacizumab. Overall results did not show a survival benefit, but a subgroup of KRAS-mutated patients — who represent the vast majority of pancreatic cancer cases — showed a trend toward improvement, though the trial was also criticized for insufficient ascorbate dosing levels.
What We Don’t Know
For all the encouraging signals, the field’s honest practitioners are clear-eyed about limitations.
“We currently do not have good predictors of whether cancers will be sensitive or resistant to pharmacologic ascorbate,” said Channing Paller, MD, oncologist at Johns Hopkins Medicine, Baltimore. She led a trial of docetaxel with or without ascorbate in heavily pretreated prostate cancer that showed no benefit — a result attributed in part to late-line patient selection and failure to verify adequate ascorbate blood levels were achieved.
“In advanced prostate cancer, there was a lack of clinical benefit,” she noted, “but none of these patients received ascorbate as first-line therapy.”
Dosing point matters, according to experts. Allen, Cullen, Chen, and Buettner all emphasized that achieving plasma concentrations of at least 15-20 mM is essential. Trials that don’t measure blood levels or use insufficient doses cannot be considered valid tests of the hypothesis.
Kathy D. Miller, MD, breast oncologist at Indiana University School of Medicine, Indianapolis, raised the following methodological concern that hangs over the field.
“Single-arm phase 2 trials cannot demonstrate a survival benefit without a concurrent control group,” she emphasizes, commenting that patients who reach academic trial centers, meet eligibility criteria, and enroll tend to be healthier at baseline — and tend to live longer regardless of what they receive. It is the same selection bias that once made uncontrolled bone marrow transplant trials in breast cancer look falsely promising.
“Phase 3 clinical trials showing overall survival benefit are needed for pharmacologic ascorbate to be evaluated in mainstream cancer treatment,” Miller explained.
The Funding Problem
So why hasn’t a rigorous phase 3 trial happened? One reason is that vitamin C cannot be patented, so no pharmaceutical company stands to profit from proving it works. A single dose of pharmacologic ascorbate costs roughly $150-$200 during the Iowa trials — compared with $15,000 or more per dose for many immunotherapies.
Cullen said he has a plan ready and five or six willing sites. What he lacks is funding. A Columbia University oncologist has expressed interest in co-leading a phase 3 pancreatic cancer trial, and the Medical College of Wisconsin, Milwaukee, has already participated in earlier ascorbate studies — suggesting that a multicenter infrastructure exists if resources can be secured.
Safety and Practical Considerations
Adverse events with pharmacologic ascorbate are substantially milder than those of most systemic cancer therapies. Paller compared the profile to an intravenous fluoroquinolone, not a cytotoxic agent. The main signals across the Iowa trials were transient hypertension from the hyperosmolar bolus, modestly increased seizure risk in brain tumor patients (likely from fluid shifts in the setting of mass effect), and a small risk for kidney stones.
According to Paller, prescreening should include G6PD deficiency (low activity can precipitate hemolysis), renal insufficiency, and a history of nephrolithiasis. Brooke M. Katzman, PhD, and colleagues also reported in the Journal of Diabetes Science and Technology that high-dose ascorbate can interfere with certain strip-based glucose meters — a practical concern for patients who routinely self-monitor blood sugar.
Where Things Stand
The oncologists interviewed for this story view pharmacologic ascorbate as a promising area for further investigation in well-designed clinical studies.
What’s at stake is a randomized phase 3 trial to confirm a phase 2 study that appeared to double survival in one of oncology’s most lethal diseases, Buettner said.
Allen is chair of research in radiation oncology at the University of Iowa. Buettner is a professor emeritus of radiation oncology at Iowa. Paller is an associate professor of oncology at Johns Hopkins. Miller is a professor of oncology at Indiana University. None of these individuals has any financial disclosures relevant to this work.
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