Promising Effects of High-Dose Parenteral Ascorbate in Ovarian Cancer
Oral ascorbate, or vitamin C, has been shown to be ineffective in cancer clinical trials. However, recent studies have indicated that millimolar concentrations of ascorbate achieved in blood and tissue with intravenous dosing is associated with cancer cell killing without harm to normal tissue. In studies reported in Science Translational Medicine, Ma et al investigated the anticancer effects of millimolar concentrations of ascorbate and found benefits of high-dose intravenous ascorbate treatment in mouse models of ovarian cancer and in a phase I/IIB study in patients with ovarian cancer.
Study Details
Recent studies have indicated that ascorbate at millimolar concentrations produces local pro-oxidant effects by mediating hydrogen peroxide formation, resulting in cancer cell death. In the current study, investigators assessed downstream mechanisms of ascorbate-induced cell death. Their findings showed that millimolar concentrations of ascorbate acted as a pro-oxidant, inducing DNA damage and depletion of cellular adenosine triphosphate, activated the ataxia telangiectasia mutated (ATM)/adenosine monophosphate-activated protein kinase (AMPK) pathway, and resulted in mTOR inhibition and death of ovarian cancer cells.
Effects in Mouse Models
In ovarian cancer mouse models, treatment with carboplatin/paclitaxel and high-dose parenteral ascorbate reduced tumor weight by 94% compared to controls and completely prevented ascites formation, and reduced tumor weight (P = .0062) and ascites volume (P = .48) significantly more than carboplatin/paclitaxel. Further, the triple combination and the combinations of ascorbate with carboplatin and ascorbate with paclitaxel showed improved effects compared with carboplatin/paclitaxel alone.
All regimens containing ascorbate showed inhibition of mTOR and phosphorylated mTOR in tumors, with the greatest inhibition in the triple-therapy group. AMPK phosphorylation was enhanced in tumors treated with ascorbate alone or in combination with the chemotherapeutic drugs; while carboplatin/paclitaxel treatment induced p-AMPK, the strongest effect was with the triple combination. Large increases in H2AX, a marker for DNA damage, and its phosphorylated form (pH2AX) were also observed with the triple combination.
Promising Effects in Phase I/IIA Trial
In a pilot phase I/IIA trial, 27 patients with newly diagnosed stage III or IV ovarian cancer were randomly assigned to treatment with conventional carboplatin/paclitaxel with (n = 13) or without (n = 14) high-dose intravenous ascorbate, with carboplatin/paclitaxel being administered for 6 months and ascorbate for 12 months. Intravenous ascorbate was given in a dose-escalating protocol with a final dose of 75 or 100 g per infusion depending on peak plasma concentration; the target peak plasma concentration was 350 to 400 mg/dL. Patients received ascorbate infusion twice weekly.
Patients were followed for survival for 5 years. Two patients in the chemotherapy-alone group wanted to receive intravenous vitamin C and withdrew.
Among the 25 evaluable patients, there were no grade 5 treatment-related events. Inclusion of ascorbate did not increase rates of grade 3 (P = .49) or grade 4 (P = .85) adverse events, but significantly reduced rates of grade 1 (P = .00000070) and grade 2 (P = .028) adverse events, with decreases being observed in almost all categories of toxicity evaluated, including neurotoxicity, bone marrow toxicity, infection, hepatobiliary/pancreatic toxicity, toxicities in the renal/genitourinary, pulmonary, and gastrointestinal systems, and dermatologic toxicity.
There was a trend toward improved overall survival with the addition of ascorbate and a prolongation in median time to disease progression or relapse of 8.75 months (25.5 vs 16.75 months). Neither comparison achieved statistical significance since the trial was not statistically powered to detect efficacy. The authors stated, “These results might also have been improved with more frequent ascorbate dosing.”
The authors concluded, “On the basis of its potential benefit and minimal toxicity, examination of intravenous ascorbate in combination with standard chemotherapy is justified in larger clinical trials.”
Jeanne Drisko, MD, and Qi Chen, PhD, of University of Kansas Medical Center, are the corresponding authors for the Science Translational Medicine article.
The work was supported by Gateway for Cancer Research Foundation and grants from University of Kansas Endowment, University of Kansas Research Institute, and National Institutes of Health.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
