This month we will discuss the research and clinical results of Nina Mikirova, Ph.D. and Ron Hunninghake, M.D. in the clinical use of IVC against cancer. Their studies have been systematic and thorough over the decades. Nearly all their peer-reviewed studies can be downloaded free for your additional information (and your physician’s).
I consider this to be one of the most important areas of research that I have covered in my 35 years that I have had the privilege of writing this column.
The study that we will focus on showed that high-dose vitamin C can reduce the rate of progression of the prostate cancer biomarkers, prostate specific antigen (PSA) and Alkaline Phosphatase (ALP). Increasing the frequency of IVC treatments is even more effective (1). I will try to balance the biochemistry against the readability. The biochemistry can be skipped over if you’re not interested, but it is included so that physicians and researchers can check its validity. You may find the results of the studies very interesting.
Dr. Nina MikirovaDr. Nina Mikirova is director of research at the Riordan Clinic in Wichita, KS, and graduated from Moscow State University in Russia with a Ph.D. in physics and mathematics. She has earned a degree in statistics in the United States. After 15 years as the senior researcher and chief engineer at the Institute of Bio-Medical Problems in Russia, she joined the Riordan Clinic in 1997. At that time, the institute staff had been researching the potential of high dose intravenous vitamin C therapy in cancer treatment. Dr. Mikirova’s efforts have included in vitro studies, animal studies and pharmacokinetic analyses.
Dr. Mikirova has published numerous articles including more than 50 in the area of translational medicine and 50 articles in the field of bio-medical aspects of solar radiation. Her areas of research focus include: effect of high dosage intravenous vitamin C on inflammation, cytokines, angiogenesis, gene expression and viral infection; potential of using high dose IVC alone or as an adjuvant therapy to treat cancer; effects of nutrients on levels of progenitor and stem cells in circulation; energy metabolism and functioning of mitochondria in cancer and normal cells; effects of micronutrient supplementation on inflammation and cardiovascular risk factors.
She is a 2014 recipient of the Riordan Clinic’s Pearl Maker award, which recognizes individuals for their actions to further the mission of stimulating an epidemic of health worldwide.
Passwater: Dr. Mikirova, Dr. Ron Hunninghake and you have done a significant amount of very important cancer research at the Riordan Clinic. Why did you choose to do your cancer research at the Riordan Clinic?
Mikirova:Well, it was a perfect fit for me. Both Dr. Hugh Riordan’s and Dr. Hunninghake’s clinical results and their attention to details were compatible with research as well as good clinical results. Even the history of the clinic showed an excellent compatibility for cancer research. The founder of our clinic, Dr. Riordan, was a pioneer in the field of complementary and alternative medicine. He was a strong supporter of orthomolecular medicine, the practice of preventing and treating disease by providing the body with optimal amounts of natural substances.
Dr. Riordan was constantly looking for effective ways to eliminate illness. As he wrote in one of his books, (Medical Mavericks, volume 3), his first direct experience with orthomolecular medicine occurred when he was a medical student (2). He had developed a strep throat, and for treatment, he saw a very knowledgeable doctor who offered him two choices. He could take either the new antibiotic aureomycin or could take vitamin C. As a medical student with tight finances, he chose vitamin C for 50 cents instead of antibiotic for $9, and it worked just as the doctor had said it would.
Dr. Riordan considered that orthomolecular-based therapy is effective in many ailments. He had friendship with and was influenced by many orthomolecular doctors, such as Drs. Fowler Poling, Carl Pfeiffer, Robert Cathcart, Roger Williams and Linus Pauling. According to the memories of his son Dr. Neil Riordan, his belief in the usefulness of massive doses of vitamin C in cancer was started at the first treatment of the patients with cancer. A 70-year–old man with the kidney cancer that metastasized to his liver and lungs came to the center specifically seeking Dr. Riordan’s help. Since no treatment was available from standard doctors, the man had been given a very short time to live. Dr. Riordan treated the man, twice a week, in his own office, with high-dose vitamin C protocol that he developed at the center, which was based upon the work of Dr. Linus Pauling. After six weeks, the patient was seen again by the radiologist. The radiologist reported that the tumor had shrunk. After twelve weeks, the tumors were undetectable, and six months later the patient was cancer free (2).
Passwater:Many of us are delighted to see your retrospective study of IV vitamin C and prostate cancer. The report published in July 2017 concludes that your study “demonstrated the clinical benefit of IV vitamin C for prostate cancer patients“ (1). It is a seminal study that should open a lot of eyes.
The Riordan Clinic has been using IV vitamin C as adjuvant in treating cancer for some time. Before we discuss your recent study, please give our readers an overview of the Riordan Clinic experience with IV vitamin C and cancer?
Mikirova:Dr. Riordan launched a major research initiative to look for the causes of cancer and non-toxic ways to treat it. He found vitamin C to be selectively toxic to cancer cells if present in the blood at sufficient levels. Tumor-toxic dosage levels could only be attained by intravenous administration.
He named the research project RECNAC, the acronym of the word “cancer” spelled backward and it stands for “Research Encompassing Comprehensive Novel Approach to Cancer.” The first phase was completed in 2000. The researchers validated the use of the IV vitamin C for cancer therapy. Using in vitro studies, it was demonstrated that at a high enough dose vitamin C can kill cancer cells while not affecting normal cells. Riordan Clinic researchers were the first to demonstrate plasma levels of vitamin C could be achieved in cancer patients which were selectively toxic to cancer cells and not normal cells (3,4). In decades of vitamin C research, RECNAC generated and published many scientific articles on vitamin C and cancer. RECNAC inspired the formation of RECNAC II at the University of Puerto Rico (5).
In 1997 the IVC treatment was patented by Drs. Neil Riordan and Hugh Riordan; the title of the patent is “Intravenous ascorbate as tumor cytotoxic chemotherapeutic agent” (6). Other important results of the research group studies included: synergism between vitamin C and alpha-lipoic acid (4), inhibition of angiogenesis (forming new blood vessels) in tumors by vitamin C (7), effect of ascorbate on immune function (8), and Phase I trial of the safety of the proposed treatment (9). All publications of our research group can be found on the website www.riordanclinic.org. The treatment protocol is also published in the book “The Orthomolecular Treatment of Chronic Disease,” edited by Andrew W Saul, Ph.D., which is also downloadable free from our website (10).
Passwater:What else did the RECNAC data show?
Mikirova:Vitamin C can benefit cancer patients in several ways. Some of the observations from the RECNAC studies include: vitamin C can be toxic to tumor cells without harming normal cells and vitamin C can reduce the side effects of chemotherapy. RECNAC also showed that vitamin C can suppress chronic inflammation, which plays a key role in tumor development. RECNAC established the safety of high-dose vitamin C. As an example, high-dose IV vitamin C has not caused a kidney stone here at The Riordan Clinic in over 40 years during more than 90,000 infusions of vitamin C.
Passwater:In 2005, the role of vitamin C against cancer was given additional validation by a National Institutes of Health study led by Dr. Mark Levine which was published in the Proceedings of the National Academy of Sciences (11). Do you have any comments on the 2005 publication? The article concludes, “These findings give plausibility to IV vitamin C in cancer treatment…”
Mikirova:I think that Dr. Mark Levine’s and Dr. Jeanne Drisko’s research groups do exceptional work on the study of high dose vitamin C in the treatment of cancer. Recently, they demonstrated that the combination of parenteral ascorbate with the conventional chemotherapeutic agents carboplatin and paclitaxel synergistically inhibited ovarian cancer and reduced chemotherapy-associated toxicity in patients with ovarian cancer and conducted a phase I/IIa study to investigate pharmacokinetic interaction between IVC and gemcitabine.
Passwater:Dr. Mikirova, what are some of the possible mechanisms for high-dose vitamin C to kill cancer cells?
Mikirova:Vitamin C has been studied for decades for its potential role in preventing chronic diseases. It also has a variety of properties that have generated interest in using it against cancer. The anticancer mechanisms of vitamin C are not fully understood. Several mechanisms have been proposed. Vitamin C enhances natural killer cell activity, increases collagen synthesis, inhibits capillary tubule formation (angiogenesis), and reduces inflammation in cancer patients.
At very high concentrations, vitamin C shows cytotoxicity against cancer cells and the ability to reduce tumor growth in vivo. Clinical trials to date indicate that high dose (on the order of ten to 100 grams) intravenous vitamin C therapy can enhance anti-cancer effects of chemotherapy and improve quality of life in cancer patients.
There are a lot of studies that analyzed the mechanism of vitamin C antitumor activity. The first proposed mechanism was that vitamin C is strengthening the collagen structure and inhibits hyaluronidase (enzymes that increase tissue permeability).
Later, it was demonstrated that vitamin C at high plasma concentration may function as a pro-oxidant. Currently, this is the most “popular” proposed mechanism and was explained in detail in the previous column with Dr. Hunninghake. This occurs in the presence of free transition metals, such as copper and iron. The difference in sensitivity between normal and cancer cells towards vitamin C may be due to low levels of antioxidant enzymes and high endogenous levels of reactive oxygen species (ROS) in cancer cells. The relative lower activities of catalase, glutathione peroxidase, and peroxiredoxins in cancer cells could potentially contribute to less efficient removal of H2O2 and increased sensitivity to vitamin C-induced cytotoxicity.
Another mechanism that has been proposed is the alteration of intracellular metabolism in cancer cells by disrupting the redox (reduction/oxidation) balance. Increased reliance of cancer cells on glycolysis suggested that following IVC treatment, elevated uptake of oxidized vitamin C may cause oxidative stress by depleting glutathione. The high-dose vitamin C may block the energy flux in glycolysis and the tricarboxylic acid cycle (TCA cycle, also known as the Krebs cycle or citric acid cycle) and consequently inhibit adenine triphosphate (ATP) production.
In addition, in recent years there were studies showing that vitamin C influences gene expression and epigenetic phenomena. Besides its role as antioxidant, vitamin C is essential for the activity of a family of mono- and dioxygenases enzymes by providing the electrons required to keep the prosthetic metal ions in the reduced/active form.
Vitamin C at high doses can cause the downregulation of several gene expressions that are involved in cancer proliferation, survival and angiogenesis. For example, vitamin C is a regulator of hypoxia-inducible factor 1 (HIF-1), because HIF-1a prolyl hydroxylase is stimulated by vitamin C, low vitamin C levels would reduce HIF-1a hydroxylation and thus stabilize HIF-1a, thereby promoting HIF-dependent gene transcription and tumor growth.
We studied the effect of pharmacological concentrations of vitamin C on several gene expressions by using an animal model (12). Our results support the previous studies and showed significant difference in expression of gene p53, a gene that protects a cell from one step on the path to cancer. When gene p53 mutates to cause a loss or reduction in its function, the cell can progress to cancer. There was considerable difference in expression of gene p53 in tumor tissue between treated and non-treated groups, and reduction of p53 gene expression by size and spreading of tumors.
The experimental data demonstrated that the maximum vitamin C dosage reduced expression of HIF. Reduced expression of tumors promoting genes, such as HIF, and increased expression of tumor suppression gene such as p53 support the hypothesis that high dose vitamin C can act as a potential agent for the suppression of tumor development.
Passwater:The data on gene expression are extremely important, but I am also interested in more of your immune data. Earlier you mentioned a role of inflammation. Please elaborate.
Mikirova:Inflammation plays a key role in many diseases including tumor development, and also affects tumor proliferation. Inflammation also affects angiogenesis, metastasis, and resistance to therapy.
Several studies indicate that inflammation is a marker of high cancer risk and poor treatment outcome. There are particularly strong negative correlations between a marker of inflammation [C-reactive protein (CRP) levels] and cancer survival in a wide variety of cancer types.
Key features of cancer-related inflammation include leukocyte infiltration, cytokine build-up, tissue remodeling, and angiogenesis. These leukocytes secrete proinflammatory cytokines as well as chemokines (small cytokines that facilitate movement). While immune cells may repress tumor growth in some cases, there is increasing concern that inflammatory microenvironments caused by infiltrating leukocytes can facilitate cancer development. We had complete data for 45 patients who went through the Riordan IVC protocol. Our analysis of the markers of inflammation in these cancer patients showed that high-dose intravenous vitamin C treatment reduces inflammation in cancer patients. According to our data, positive response to treatment, as demonstrated by CRP measurement, was found in 70% of patients (8).
It is interesting, therefore, that in our 2017 study, prostate cancer patients showed the most benefit (in terms of reduced Prostate Specific Antigen (PSA) and CRP levels) from IVC therapy.
A potential effect of IVC in reducing inflammation is also supported by our serum cytokine data, which demonstrate that levels of pro-inflammatory cytokines decrease during IVC therapy.
Cytokines play an important role in tumor angiogenesis and inflammation. We conducted a study to investigate the effect of treatment by intravenous vitamin C on cytokines and tumor markers, by using protein array kits allowing assessment of 174 cytokines in 12 cancer patients before and after a series of IVC treatments. The analysis of the data showed that the treatment resulted in normalization of many cytokine levels. We were able to show that average scores for inflammatory and angiogenesis- promoting cytokines decreased over the course of treatment (13).
Passwater:What is especially interesting in your 2017 study is that you tracked the changes in prostate cancer biomarkers PSA and ALP over time and found that their rate in increase could be reduced with IVC therapy and reduced moreso by increasing the frequency of IVC treatments.
Let’s look at the details of the 2017 study. It was a retrospective study conducted using clinical data from the Riordan Clinic database from 1994 through 2015 (2).
Mikirova:Since the Riordan Clinic has been treating cancer patients with IVC for decades, we have a potentially useful database of patients with prostate cancer treated by IVC. We examined our historic data for prostate cancer patients given IVC, with a focus on tracking changes in PSA levels and — where data are available — alkaline phosphatase levels (ALP). PSA is a reliable, sensitive, easy-to-measure, and widely used biomarker for prostate cancer. There is some indication that declines in PSA levels are predictive of longer patient survival. ALP is especially useful as an indicator of osteoblastic activity, and may in fact be a better predictor of survival than PSA.
Passwater:More than 80% of the men who died from prostate cancer and were autopsied have been found to have metastasis (spread) to the bones. The cancer cells that then grow in the bones cause the release of bone growth factors which is why ALP is a good biomarker to follow. Prostate cancer patients having elevated levels of ALP have been associated with shorter survival and ALP has been shown to be a predictor of early death.
Mikirova:We collected data from 180 prostate cancer patients, when available, on the following patient characteristics at diagnosis and during the courses of IVC therapy: tumor stage, Gleason biopsy score, serum prostate specific antigen, alkaline phosphatase levels, and location of metastases. PSA, ALP, and C-reactive protein (CRP) levels were analyzed in prostate cancer patients given IVC therapy during several years. Most of the patients were treated by IVC after conventional treatment: surgery, chemotherapy, or radiation. Sixteen patients refused conventional treatment and chose alternative treatment.
For all patients treated by IVC the periods of analysis were chosen when patients did not have conventional treatment. In general, IVC was administered in accordance with the Riordan IVC protocol. Briefly, new cancer patients were given a 15-gram vitamin C infusion for their first dose, followed by a 25-gram infusion on day two. Dosage was then gradually adjusted upward by the physician, based on patient tolerance for the treatment and the plasma vitamin C levels attained, to maximum doses between 50 grams and 100 grams.
As the result of analysis, we found that PSA, CRP, and ALP correlate with tumor staging as measured by Gleason biopsy scores. Moreover, peak plasma ascorbate levels attained during the patient’s first IVC infusions are reduced in patients with elevated PSA and CRP levels. There were some subjects who were treated with IVC for a regular and prolonged period and for whom PSA levels were monitored at regular intervals. In these subjects we were able to analyze how IVC treatments affected PSA levels and PSA velocity. In doing so, we define the PSA velocity (the change in PSA concentration), and the IVC treatment frequency (the number of IVC treatments between PSA measurements). Tracking the changes in PSA with time in patients indicated that the rate of increase in this marker over time can be reduced by incorporating IVC therapy and by increasing the frequency of IVC treatments.
The other parameter we investigated in detail was ALP, a marker of bone formation that can be used to some degree to track bone metastases in prostate cancer patients. Alkaline phosphatase is one of the older biochemical tools for investigating and monitoring prostate cancer, and a reliable indicator of osteoblastic activity and bone metastases. In these patients, the onset of IVC therapy, and the increasing of its frequency, led to reductions in ALP values. PSA levels also tended to track ALP levels for these subjects.
As the PSA concentration varies depending upon tumor differentiation, tumor volume, and the extent of disease, the relationship between the PSA rate of change and frequencies of IVC treatment may indicate some inhibitory effect of the treatment on the cancer. The rate of change in concentration of the PSA marker, is thought to be an important prognostic parameter. Several reports suggest that PSA doubling time can be used to predict the aggressiveness of the disease and may be useful in identifying patients at risk for progression after prostatectomy or radiation therapy.
Our preliminary observations concerning IVC therapy and ALP levels were encouraging. ALP levels have been associated with the progression of skeletal metastases in patients with prostate cancer and have also been shown to be significant predictors of early death. While osteoclastic processes are a potential target for prostate cancer therapy, chemotherapeutic drugs aimed at inhibiting these processes offer only a few months advantage over placebo in prolonging survival time, and often carry side effects such as osteonecrosis of the jaw, hypocalcemia, and deterioration of renal function. IVC therapy is unlikely to have such severe side effects and may act as an adjuvant to reduce side effects of other agents. Furthermore, ascorbic acid induces formation of collagen matrix and enhances osteoblast differentiation. Since cancer patients are ascorbate deficient and have an abnormal demand for ascorbate due to oxidative stress, using vitamin C as an adjuvant to support these processes may help prevent metastasis in prostate cancer patients.
As the result of the study, we underlined the possibility of ALP decline, which is a marker of suppression of osteoblast bone formation marker, suppression of the rate of PSA growth, and the dependence of the suppression of the rate of PSA growth on the frequency of the high dose vitamin C treatment. Both these dependencies resulted from the analysis of the data, demonstrating the clinical benefit of IVC for prostate cancer patients.
This study was ultimately limited by the small number of patients in our database who had sufficiently detailed information about analyzed parameters, frequent PSA, and ALP measurements, in addition to consistent participation in the IVC protocol. A controlled study using a larger population of prostate cancer patients would allow for a more rigorous assessment of the promising trends reported in these studies (2, 14).
Passwater:The Riordan Clinic experience plus that of the other clinics and researchers strongly suggests that an all-out effort is warranted to follow up on these promising leads. Are there clinical studies that confirm the efficacy of high dose vitamin C in the treatment of cancer patients and any indication that these studies may be followed up by a larger prospective study?
Mikirova:Despite years of research and thousands of patients who have been treated with intravenous vitamin C, the question of efficacy remains. In the past years published data has supported many of the actions of IVC, its pharmacokinetics and dynamics and particularly possibility of high dose vitamin C antagonize or synergize the effects of various chemotherapy agents. These data are presented and summarized in several reviews (15-17).
Several trials were designed to determine the effect of escalating doses of vitamin C when combined with chemotherapy: gemcitabine in stage IV pancreatic cancer patients and carboplatin and paclitaxel in ovarian cancer (18-20).
The preclinical studies and clinical trials confirmed efficacy and demonstrated synergy with chemotherapeutic agents. IV vitamin C can reduce the severity of cancer symptoms and the unpleasant side-effects of chemotherapy and radiotherapy, in particular, nausea, loss of appetite, fatigue, depression, sleep disorders and dizziness. Improvements in physical, cognitive, emotional and social functioning, as well as an improvement in overall health were also observed. IV vitamin C has an effect on prolongation of the survival time of cancer patients.
There were also clinical studies that could not prove or neither prove nor disprove IVC’s value in cancer therapy (for example, study 21).
Passwater:Has your 2017 publication brought about any changes to the published Riordan Clinic protocol?
Mikirova:The optimal administration schedule of high-dose vitamin C is still being discussed in the literature in terms of dosing and frequency. The long intervals between treatments can decrease the therapeutic effect of the treatment, as the intravenous vitamin C has a short half-life and rapid excretion. The results of our study demonstrating that the increased frequency of the treatment is more effective, were previously suggested and used by our doctors in practice. The schedule-dependence and the optimal vitamin C dosing and frequency were also discussed in the publication of the research group RECNAC-2.
Passwater:As I have discussed in many previous columns, there are no safety concerns with oral vitamin C. Are there safety issues with intravenous vitamin C due to osmotic and fluid bolus concerns specific to IVC therapy?
Mikirova:Intravenous high-dose vitamin C has caused very few side effects in clinical trials (nausea, vomiting, headache, dry mouth, flushing, diarrhea and minor edema). The injected solution of high dose intravenous vitamin C is hypertonic, but it does not cause problems as the rate of infusion is very low (0.5-1 gram/min). In addition, as the solution of IVC injection is balanced to pH close to normal by components that have sodium, patients treated by high-dose IVC need to be tested for electrolyte balance to minimize electrolyte abnormalities. The most serious electrolyte disturbances involve abnormalities in the levels of sodium, potassium or calcium. In our protocol we recommend testing these electrolytes after several IVC treatments.
High-dose IV vitamin C may be harmful in patients with certain risk factors. In patients with a history of kidney disorders, kidney failure has been reported after ascorbic acid treatment. Case reports have shown that patients with an inherited disorder called glucose-6-phosphate dehydrogenase (G6PD) deficiency should not be given high doses of vitamin C, due to the risk of hemolysis.
Since vitamin C may make iron more easily absorbed, high doses of the vitamin are not recommended for a condition in which the body takes up and stores more iron than it needs (hemochromatosis).
Passwater:Oral vitamin C doesn’t cause hemolysis or hurt a renal disease patient and the Riordan Clinic protocol for IVC guards against harm with IVC.
How can someone who is not close to the Riordan Clinic locate a physician who can administer the Riordan protocol? Is IVC treatment covered by insurance?
Mikirova:For patients who are not close to the Riordan Clinic, we can help to locate a physician who can administer IVC. In our clinic each year we have “The IVC & Chronic Illness Symposium,” which offers training on the treatment of cancer by IVC and on the care and treatment of the vast array of chronic illnesses. The participants receive the certificate that they successfully completed the Riordan IVC Academy and are certified in the Riordan IVC protocol. The database of certified practitioners is available at the Riordan Clinic. It is important to inform patients that the IVC treatment is not covered by insurance.
Passwater:Dr. Mikirova, thank you for discussing your research with IV vitamin C and cancer over the years. Hopefully, others are following up on Riordan Clinic research and many lives will be saved.WF
References
- Mikirova, N. and Hunninghake, R. Changes in the rate of PSA progression and the level of alkaline phosphatase during high dose vitamin C treatment of patients with prostate cancer. Functional Foods in Health and Disease 2017; 7(7) 511-528.
- Riordan, M.D, Hugh Desaix. “Medical Mavericks, Vol. 3” (2005)
- Riordan NH, Riordan HD, Meng XL, Li Y, Jackson JA. (1995). Intravenous ascorbate as a tumor cytotoxic chemotherapeutic agent. Medical Hypotheses, 44, 207-213.
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- Mikirova, NA, Ichim, TE and Riordan, NH Anti-angiogenic effect of high doses of ascorbic acid. J Transl Med, 2008; 6: 50. Published online 2008 Sep 12. doi: 10.1186/1479-5876-6-50.
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