High Dose Vitamin C & Cancer - Cancer Treatments - from Research to Application (2024)

Background:

L-ascorbic acid (C₆H₈O₆), known as Vitamin C,has a variety of functions in humans, some of which are not yet fully understood. It wasdiscovered in 1930 byAlbert Szent-Györgyi(Hungarian, half Romanian by descent), who as a result of this discovery received Nobel Prize in Physiology or Medicine in 1937. Note, that Albert Szent-Györgyiis the same scientist who about 20 years latter discovered the anti cancer effects of Methylglyoxal, discussed recently on this website in the following posthttps://www.cancertreatmentsresearch.com/?p=1471.

Vitamin C plays a vital role in the production of collagen, which is the principal connective tissue protein found in tendons, arteries, bone, skin and muscle. However, humans can not synthesize ascorbic acid due to the absence of the enzyme L-gulonolactone oxidase. Hence, in humans ascorbic acid has to be supplemented through food and/or as tablets.The two major forms of vitamin C in the diet are L-ascorbic acid and L-DHA. (Ref.)

Nobel laureate Linus Pauling began a long clinical collaboration with the British cancer surgeon Ewan Cameron in 1971 on the use of intravenous and oral vitamin C and as a result they proposedtheuse of high doses of ascorbic acid (> 10 g/day) to cure and prevent cold infections and in the treatment of cancer (Ref.).

The anti cancer mechanism suggested by Pauling and Cameron was essentially related to the tumor microenviroment. They argued that cells are normally restrained from proliferating by the highly viscous nature of the intercellular space and that cancer cells may escape from this due to an enzyme calledHyaluronidase which normally would be not there if enough Vitamin C would exist in the body. (Ref.1, Ref.2).

Its amazing how all things are connected. Just a few weeks ago I was discussing aboutHyaluronidase in another post (https://www.cancertreatmentsresearch.com/?p=1489) and now I realize that Vitamin C has one of its major anti cancer mechanisms related to thesame.

However, in addition to this mechanism, Vitamin C has other anti cancer actions highly relevant which also supports its use next to chemo therapy. Indeed, it is widely accepted now, at least within the scientific world, that while at lower concentrations Ascorbic Acidfunctions primarily as an antioxidant and can protect cells from oxidative stress, at higher concentrations Ascorbic Acid acts as a pro-oxidant that imposes oxidative stress and induces cell death (Ref.). The specific mechanism that leads to its pro oxidant anti cancer action will be discuses in more details below, in the “Mechanism” section.

In order to achieve the high dose required to exert its anti cancer action, Vitamin C has to be administrated intravenously. This is because when administrated orally, Vitamin C is absorbed only in very low amounts (Ref.). This low oral bio availability is also one of the reasons why some of the earlier clinical trials of Vitamin C in cancer have failed (Ref.).

As a side note, if intravenous administration is not an option, usingliposomal vitamin C formulation may be a way to achieve same plasma levels of Vitamin Cas that achieved via the intravenous route. Liposomal vitamin C can be bought online or formulated at home and administrated via the oral route. Here is a website where it is explained in detail how Liposomal vitamin C can be formulated at home http://qualityliposomalc.com/

Given its low toxicity and low cost, next to its serious anti cancer potential intravenous high dose Vitamin C wasrapidly adopted by private clinics across the world to treat various disease including cancer. At the same time, academic research has been also preformed, indeed supporting the relevance of Vitamin C therapy in the the following areas:

Heart Disease (Low dose Vitamin C) (Ref.1,Ref.2, Ref.3)
High Blood Pressure (Ref.1, Ref.2)
Common Cold
Cancer (Ref.1, Ref.2., Ref.3 and many more)
Reducingchemotherapy side effects (Ref.)
Antiviral (Ref.)
Osteoarthritis
Treating allergy-related conditions, such as asthma, eczema, and hay fever (called allergic rhinitis)
Decreasing blood sugar in people with diabetes
Boosting immunity
High-dose ascorbic acid was also recommended as a treatment in surgical critically ill patients with septic shock (Ref.)
Etc.

After reviewing the literature, to me the followingaspects are clear:

There is enough scientific evidence to believeVitamin C can kill cancer cells.
Chemo sensitivity tests indeed indicate effectiveness of Vitamin C in about 70% of the tested cancer patients (see fig enclosed in the following posthttps://www.cancertreatmentsresearch.com/?p=1321)
There are multiple reports publishedindicating anti cancer potential of Vitamin C in humans (see below section “Case reports in humans”)

However, it also appers that when zooming-out and looking not at specific reports only but at large number of patients treated with high dose intravenous Vitamin C, theanti cancereffects become lessvisible (Ref.). Yes, somepatients benefit from Vitamin C, a feware even cured, but manyneed to search for othersoptions.

So my questions is: Why this conflicting evidence?Why in theory andlaboratory experiments high dose Vitamin Cseems to be effectivefor most tumor typeswhile in real life it shows great results only for a few? Why some Vitamin C treatments are successful and other not in patientsthat all should respond to Vitamin C based on cancer type and e.g. chemosensitivity analysis?

Off course we can argue that even if it is effective for a few that is still highly relevant since we are speaking about life and about patients that are left with no options. But my question is what do we still need to understand and do in order to increase the success rate of high dose Vitamin C?

One simple answer to the above question can be related to theVitamin C source. It can degrade relatively fast (becoming yellowish solution) and preparation just before administration may be the best.

However, I believe a major answers may be found in this scientific report, published in 2014 in the prestigious journal Nature: Extracellular iron diminishes anticancer effects of vitamin C: An in vitro studyhttp://www.nature.com/articles/srep05955.

Essentially, the article argues thatthat the anticancer/cytotoxic effects of Vitamin C are completely abolished by ironexistent in the blood as the Vitamin C reacts with the Iron in the blood before reaching its target, i.e. the tumor, which would be the case for most of the patients. As a result, the authors suggest that in order to increase the chance of success of the Vitamin C therapy, the patient would have to be treated with Iron chelators prior to the Vitamin C therapy. The authorst suggested the use ofIron chelator such asDisulfiram (a safe and FDA approved drug used to support the treatment of chronic alcoholism), but other substances such as Baicalein, an extract from a plant named Scutellaria Barbata(known to also have anti cancer effects specifically in breast cancer) is also an Iron chelator (Ref.). Whole plantScutellaria is available online as a supplement. On the same line, avoiding foods reach in Iron before/during Vitamin C therapy may be a good idea. Combining Vitamin C therapy with Gallium therapy may be another good idea. Using EDTA IV to chelate iron prior to Vit C IV may be yet another good idea (Ref.1, Ref.2).

The fact that patients presenting Glucose-6-phosphate dehydrogenase (G6PD) deficiency have been subjects to Vitamin C induced anemia (Ref.) is a demonstration of the pro-oxidant effect of high dose Vitamin C on the blood cells of cancer patients which supports the suggestions of the paper above in that there is a need for Iron chelation prior to high dose Vitamin C. This will not only protect the blood of patients but also increase the chance that Vitamin C reaches the tumor and is effective as an anti cancer treatment.

Next to this, due to the mechanisms of action, I think there are a few more ways to improve the chance of success for high dose Vitamin C therapy, which I intend to discuss at the end of the “Mechanism” section of this post.

Update November 6th, 2018: One other answer to the question about effectiveness could be related to the administration protocol of Vit C. In contrast to the days of great results reported by theNobel laureate Linus Pauling, when Vit C was given daily in a dose of about 10g or more/day (which we could call metronomic approach), today Vit C is mainly used in high doses, given a few times per week at clinics around the world. As will be discussed in the “Mechanism” section below, these two different approaches lead to two totally different mechanism that may indeed induce totally different results in patience.

That is one point. The other point is that we have to realize, when looking at a specific case it may be difficult to conclude if Vit C helped to extend life or not. This is why clinical trials are made where statistics is generated over many patients, to understand the benefit of a drug. Looking at extensive statistics generated byLinus Paulingmany decades ago, the benefits of Vit C are clear.

In conclusion, high dose Viatmin C (intravenous) has a greatpotential to fight cancer while being cheap, accessible and safe. As a result I would clearly considerit as a part of an anti cancer treatment strategy. However, according to the discussion above, in order to get the most out of it I would pay specific attention at the source, administration procedure and the whole treatment strategyaround that.

Note: After publishing this post, I have received messages from readers asking if I am notpositive about Vitamin C. I am actually positive and as a results we (my wife) are using it. But with this post I intendedto highlight not only the potential of Vitamin C but also the challenges we need to address in order to make use of itspotential and be successful.

Update April 3rd, 2018: Thanks to Ergin for indicating this article “O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate.”https://www.ncbi.nlm.nih.gov/pubmed/28366679 published in the Cancer Cell, one of the top scientific peer-reviewed journals reporting major advances in cancer research and oncology. This is a well researched article published in 2017 and co-authored by 35 medical doctors and scientists from USA stating the following:

“Despite advances in treatment strategies, 5-year overall survival in NSCLC and GBM has not significantly increased over thelast 20 years. Here, we demonstrate that pharmacological ascorbate represents an easily implementable and non-toxicagent that may increase treatment efficacy when combined with standard-of-care radio-chemotherapy in NSCLC andGBM. Furthermore, the mechanism by which ascorbate is selectively toxic to cancer cells versus normal cells is shownto involve alterations in redox-active iron metabolism mediated by mitochondrial O2- and H2O2. As fundamental defectsin oxidative metabolism leading to increased steady-state levels of O2- and H2O2 emerge as targetable hallmarks of cancercells, the current findings support a generalized mechanism for the application of pharmacological ascorbate in cancertherapy.”

The above is an as clear statement as it can get in a scientific setting, coming from35 medical doctors and scientists.

Successfulcase reports in humans:

Ascorbic Acid as a Therapeutic Agent in Cancerhttps://pdfs.semanticscholar.org/347d/06a951484965fe458ca12e5a8287e23565a1.pdf

This is a report by the british cancer surgeon Ewan Cameron and the Nobel laureate Linus Pauling, Ph.D., on many many positive results in humans after using daily 10g or more of Vitamin C.

Effects of High Doses of Vitamin C on Cancer Patients in Singapore: Nine Caseshttp://www.ncbi.nlm.nih.gov/pubmed/26679971Click hereto access a pdf form of the article.

Introduction. Intravenous high-dose vitamin C therapy is widely used in naturopathic and integrative oncology; however, a study reviewing its effects has never been performed in Singapore. This article serves to document administration of supportive vitamin C therapy for cancer patients in Singapore. Methods. The clinical response of 9 cancer patients of differing stages to the regular administration of large doses (25-100 g/d) of intravenous vitamin C (IVC; ascorbic acid) is outlined. Tumor pathology and patient health were verified by doctors who do not practice vitamin C treatment. Results. Cases suggesting survival beyond prognosis, improvement in quality of life, safe coadministration with and improved tolerance of conventional therapy, and deterioration in clinical condition following withdrawal of vitamin C therapy are documented clinically. Some patients experience the Jarisch-Herxheimer reaction—the release of endotoxin from microorganism death resulting in pimples, fever, and body odor—for a few hours after the therapy, but these are resolved quickly with no lasting effects. Conclusion. Randomized trials of IVC therapy are recommended because it has minimal side effects and has shown promising results.

Intravenously administered vitamin C as cancer therapy: three caseshttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC1405876/

Early clinical studies showed that high-dose vitamin C, given by intravenous and oral routes, may improve symptoms and prolong life in patients with terminal cancer. Double-blind placebo-controlled studies of oral vitamin C therapy showed no benefit. Recent evidence shows that oral administration of the maximum tolerated dose of vitamin C (18 g/d) produces peak plasma concentrations of only 220 μmol/L, whereas intravenous administration of the same dose produces plasma concentrations about 25-fold higher. Larger doses (50–100 g) given intravenously may result in plasma concentrations of about 14 000 μmol/L. At concentrations above 1000 μmol/L, vitamin C is toxic to some cancer cells but not to normal cells in vitro. We found 3 well-documented cases of advanced cancers, confirmed by histopathologic review, where patients had unexpectedly long survival times after receiving high-dose intravenous vitamin C therapy. We examined clinical details of each case in accordance with National Cancer Institute (NCI) Best Case Series guidelines. Tumour pathology was verified by pathologists at the NCI who were unaware of diagnosis or treatment. In light of recent clinical pharmaco*kinetic findings and in vitro evidence of anti-tumour mechanisms, these case reports indicate that the role of high-dose intravenous vitamin C therapy in cancer treatment should be reassessed.

A case report fromGangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea, published at the end of 2015:

We report a case of regression of multiple pulmonary metastases, which originated from hepatocellular carcinoma after treatment with intravenous administration of high-dose vitamin C. A 74-year-old woman presented to the clinic for her cancer-related symptoms such as general weakness and anorexia. After undergoing initial transarterial chemoembolization (TACE), local recurrence with multiple pulmonary metastases was found. She refused further conventional therapy, including sorafenib tosylate (Nexavar). She did receive high doses of vitamin C (70 g), which were administered into a peripheral vein twice a week for 10 months, and multiple pulmonary metastases were observed to have completely regressed. She then underwent subsequent TACE, resulting in remission of her primary hepatocellular carcinoma.http://www.ncbi.nlm.nih.gov/pubmed/26256994

Hereis an article published in 2000 including several case reports, most of which lead to complete remission:

A case report on adenocarcinoma of his right kidney:One of us (HDR) reported positive effects of vitamin C therapy in a patient with adenocarcinoma of the kidney in 1990.4 This report described a 70-year-old white male diagnosed with adenocarcinoma of his right kidney. Shortly after right nephrectomy, he developed metastatic lesions in the liver and lung. The patient elected not to proceed with standard methods of treatment. Upon his request, he began intravenous vitamin C treatment, starting at 30 grams twice per week. Six weeks after initiation of therapy, reports indicated that the patient was feeling well, his exam was normal, and his metastases were shrinking. Fifteen months after initial therapy, the patient’s oncologist reported the patient was feeling well with absolutely no signs of progressive cancer. The patient remained cancer-free for 14 years. He died of congestive heart failure at the age of 84.
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Another case report inmetastatic renal cell carcinoma patient publish in 1998:The patient was a 52-year-old white female from Wisconsin diagnosed with non-metastatic disease in September 1995. In October 1996, eight metastatic lung lesions were found: seven in the right lung and one in the left (measuring between 1-3 cm). The patient chose not to undergo chemotherapy or radiation treatments. The patient was started on intravenous vitamin C and specific oral nutrient supplements to correct diagnosed deficiencies and a broad-spectrum oral nutritional supplement in October, 1996. The initial dose of intravenous vitamin C was 15 grams, subsequently increased to 65 grams after two weeks. The patient was given two infusions per week. Intravenous vitamin C treatments were continued until June 6, 1997. An x-ray taken at that time revealed resolution of all but one lung metastases. The patient discontinued intravenous vitamin C infusions at that time and continued taking the broad-spectrum oralnutritional supplement. A radiology report on a chest x-ray taken January 15, 1998, stated that no significant infiltrate was evident, and there was resolution of the left upper lobe lung metastasis. In February, 1999 a chest xray showed no lung masses, and the patient reported being well at that time.
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for more case reports please read the following referencehttp://www.orthom*olecular.org/library/jom/2000/pdf/2000-v15n04-p201.pdf

A 12 Week, Open Label, Phase I/IIa Study Using Apatone® for the Treatment of Prostate Cancer Patients Who Have Failed Standard Therapy http://www.medsci.org/v05p0062.htm

Purpose: To evaluate the safety and efficacy of oral Apatone® (Vitamin C and Vitamin K3) administration in the treatment of prostate cancer in patients who failed standard therapy.
Materials and Methods: Seventeen patients with 2 successive rises in PSA after failure of standard local therapy were treated with (5,000 mg of VC and 50 mg of VK3each day) for a period of 12 weeks. Prostate Specific Antigen (PSA) levels, PSA velocity (PSAV) and PSA doubling times (PSADT) were calculated before and during treatment at 6 week intervals. Following the initial 12 week trial, 15 of 17 patients opted to continue treatment for an additional period ranging from 6 to 24 months. PSA values were followed for these patients.
Results: At the conclusion of the 12 week treatment period, PSAV decreased and PSADT increased in 13 of 17 patients (p ≤ 0.05). There were no dose-limiting adverse effects. Of the 15 patients who continued on Apatone after 12 weeks, only 1 death occurred after 14 months of treatment.
Conclusion: Apatone showed promise in delaying biochemical progression in this group of end stage prostate cancer patients.

High-Dose Intravenous Vitamin C Combined with Cytotoxic Chemotherapy in Patients with Advanced Cancer: A Phase I-II Clinical Trialhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388666/

Phase I clinical trial of i.v. ascorbic acid in advanced malignancyhttp://annonc.oxfordjournals.org/content/19/11/1969.full

Two patients at the 0.6-g/kg dose (one with prostate cancer and the other with epidermoid carcinoma) received greater than six cycles of ascorbic acid with stable disease (less than a 20% reduction and less than a 20% increase in the sum of the two perpendicular diameters of the target lesion and the appearance of no new lesions).

High-Dose Vitamin C Promotes Regression of Multiple Pulmonary Metastases Originating from Hepatocellular Carcinoma.https://www.ncbi.nlm.nih.gov/pubmed/26256994

Innovation vs. quality control: an ‘unpublishable’ clinical trial of supplemental ascorbate in incurable cancer.https://www.ncbi.nlm.nih.gov/pubmed/1787807

A computerized data bank was created recording the details of all cancer patients attending three district general hospitals in West Central Scotland over a 4.5 year period 1978-1982. At the conclusion of the trial, the records of 2804 individual patients were available for study, of whom 1826 had reached an incurable stage. 294 of these incurable cancer patients had received supplemental ascorbate at some stage in their illness, whereas 1532 had not, and served as controls. Analysis showed that the ascorbate-supplemented patients had a median overall survival time (343 days) almost double that of the controls (180 days). Our difficulties in having this simple, but important, observation published are briefly recounted in the introduction.

Reticulum cell sarcoma: two complete ‘spontaneous’ regressions, in response to high-doseascorbic acidtherapy. A report on subsequent progress.https://www.ncbi.nlm.nih.gov/pubmed/1749589

In 1975, we reported the remarkable case of a 42-year-old man with histologically proven widely disseminated reticulum cell sarcoma who, in a remarkably short time, appeared to enjoy not one, but two, complete spontaneous regressions of his fatal illness. Both these regressions coincided exactly in time with intravenous high-dose ascorbate administration, and it seemed reasonable to conclude that this unconventional therapy must have been responsible for his excellent responses. For those interested in spontaneous regressions of cancer and the possible mechanisms, we now report his subsequent progress some 17 years later.

O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. https://www.ncbi.nlm.nih.gov/pubmed/28366679

Although the small number of subjects prevent a statistically significant assessment of efficacy (11 subjects; 2 subjects were removed from longevity analysis due to limited protocol dictated therapy due to unrelated co-morbidities), average progression free survival (PFS) currently stands at 13.3 months (median: 9.4 months) vs. the historical median PFS of 7 months (Stupp et al., 2005a), and average overall survival (OS) is currently 21.5 months (median: 18.2 months) vs. historical median of 14 months. Furthermore, 4 subjects remain alive, with 1 showing no evidence of disease based on MR imaging (Figures 7A, 7C).

Mechanism:

Numerous reports are available in literature on cytotoxic and anti-carcinogenic effect of ascorbic acid and its derivatives in different tumor model systems. However, the molecular mechanisms underlying the anti-carcinogenic potential of ascorbic acid are not completely elucidated. Below aresome of themajor mechanisms that may be associate withanti-carcinogenic effect of ascorbic acid:

Pauling and Cameron believed that the mechanism behind the anti cancer activity of Vitamin C is the following:
- Cells are normally restrained from proliferating by the highly viscous nature of the intercellular space.
- In order to proliferate, cells must escape from this restraint by depolymerizing the glycosaminoglycans(including Hyaluronic acid) in their immediate environment.
- This process is accomplished by the release of the enzyme hyaluronidase and is kept in check by physiological hyaluronidase inhibitor.
- Hyaluronidase inhibitor is an oligoglycosaminoglycan that requires ascorbic acid for its synthesis, and perhaps incorporates residues of ascorbic acid. Note that the role ofHyaluronic acid in cancer was specifically discussed in a previous post on this websitehttps://www.cancertreatmentsresearch.com/?p=1489The authorsarguedthat this hypothesis provides an explanation for the pathogenesis of scurvy. It explains the increased requirement for ascorbic acid that occurs in many cell proliferative diseases, including cancer. It indicates the existence of a basic underlying mechanism in many pathological states and suggests a common pattern of treatment. (Ref.)
- Therefore providing Vitamin C,oligoglycosaminoglycan inhibitsHyaluronidase and cancer cells remain isolated, and at some point die.
  .
The second major mechanism refers to the pro oxidant action of Vitamin C and is the following:
- Epithelial tumors appear to rely on superoxide (inflammation) which is produced bynon-neoplastic stromal cells (Ref.) to oxidize the ascorbic acid (AA) to DHA (Ref.).
- Because of the structural resemblance of dehydroascorbic acid (DHA, the oxidized form of vitamin C) to glucose, DHA can enter the tumor cells through the GLUT transporters and accumulate inside (Ref.).
  - Therefore there are two steps that have to happen in order for AA to exert its anti cancer effect: 1) stromal cells/fibroblast oxidizing AA to DHAby superoxide anions produced by the cells in the stromal (Ref.); 2)DHA to enter the cancer cells via GLUT1. (Ref.)
- When dehydroascorbate acid enters cancer cells, glutathione turned the dehydroascorbate back into ascorbic acid (vitamin C), which is not allowed to move out of cancer cells, i.e. is not transportable through the bidirectional GLUTs.
  - This by itself is an anti cancer mechanims as the conversion of AA in DHA will consumeglutathione required in the cancer cell to cope with the usual high levels of ROS in cancer cells
- This ascorbic acid is converted to dehydroascorbate again and produces H₂O₂, which destroy cancer cells (viareaction with the elevated Cooper (Ref.) and Iron concentrations in tumors, leading to generation of ROS).
- The fact that High Dose Vitamin C acts as a pro-oxidant is not just a theory. Instead, the fact that patients presenting Glucose-6-phosphate dehydrogenase (G6PD) deficiency have been subjects to Vitamin C induced anemia (Ref.) is a demonstration of the pro-oxidant effect of Vitamin C in high dose (anemia happens in this case as the blood cells of these patients can not produce anti-oxidants at the level high enough to cancel out the pro-oxidant action of high dose Vitamin C).
  .
Other relevant mechanisms:
- high doses of ascorbate can reduce inflammatory cytokine levels in cancer patients
- Antiangiogenesis effects: Suppression of NO (nitric oxide) generation appeared to be one of the mechanisms by which AA mediated angiostatic effects (Ref.)

As promised above here are a few more ideas to improve the effectiveness of Vitamin C (next to the iron chelation):

prior to Vitamin C administration, increase blood oxygen in order to support the AA conversion to DHA (e.g. ozon theraphy, etc.)
avoid sugar prior to Vitamin C administrations in order to potentially activate even more GLUT1 receptors through which DHA enters cancer cells
avoid any potential GLUT1 inhibitors prior to Vit C administration. One such GLUT1 inhibitor is Caffeine (Ref.). Others are listed here.
avoid anti oxidant therapies around Vit C administration
include pro oxidant therapies such as 3BP, DCA, etc.

Pharmaco*kinetics:

Hoffer, et al.reported that when 1.5 g/kg of vitamin C was administered in humans, plasma concentrations over 10 mM could be maintained for 4.5 hours (Ref.)

Other relevant points:

pH influences the stability of ascorbic acid. It exhibits maximal stability between pH 4 and 6 (Ref.)
DHA is very unstable.DHA taken up or generated in the matrix must be reduced back to ascorbate, otherwise, in physiological conditions, it is lost within minutes.

Toxicity and potential Side effects:

High-dose vitamin C therapy should be avoided in patients with renal failure or renal insufficiency, and in patients undergoing dialysis(Ref.).

Due to the chelating effect of IVC, some patients may complain of shakiness due to low calcium or magnesium. An additional 1.0 mL of MgCl added to the IVC solution will usually resolve this. If severe, it can be treated with an IV push of 10 mL’s of calcium gluconate, 1.0 mL per minute. (Ref.)

Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme that represents the first step in a intracellular process producing antioxidants used by the cells to protect against pro-oxidants. Some people are G6PD deficient, which means their cells are less able to produce antioxidants. This is why when these people are exposed to pro-oxidants injected in their blood, they are highly likely to end up having strong anemia with low haemoglobin level, since the first cells exposed to the pro-oxidants are the blood cells. G6PD deficiency is a hereditary X-linked recessive disorder with an estimated worldwide prevalence of at least 329 million people. (Ref.).

In low dose, Vitamin C is protective for such people since low dose Vitamin C is antioxidant. However, in high dose Vitamin C is a pro-oxidant and in patients presenting G6PD deficiency it may induce anemia. Indeed, there are case reports of hemolytic anemiain G6PD deficient individuals following high dose IVC administration (Ref.1,Ref.2). This is why, prior to high dose IVC administration all patients have to perform a test for G6PD deficiency.However, most cancer clinics are not screening their patients for this deficiency as they are not aware of it. So, patients themselves have to have an eye on potential anemia induced by high dose Vit C. Otherwise, as haemoglobin decreases cancer patients may think that is due to the evolution of cancer.

Synergy:

Vtamin K2 and K3 (Ref.1) IndeedMenadione is known to induce extensive GSH depletion (Ref.).

Combining a glycolisis inhibitor such as Vit C, with a mitochondria inhibitor such as Doxycicline seems to lead to great anti cancer effectiveness: “Vitamin C and Doxycycline: A synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs)” (Thanks Alternmed for the reference.)

High DoseVitamin C Administration:

“Typical” High DoseIntraVenousVitamin C

Today, Vitamin C is administrated at a dose of about 1.5g/kg/day, or in a range between 50g and 100g/day. Usually it is started at a lower level, at about 15g/day and increased during a few administrations to the target dose. In general, it is administrated 2 to 3x/week but foractive cancers, an initial recommendation of 21 days of daily IVC therapy is used by some (Ref.). Note that this approach that is used in most of the cancer clinics around the world is different compared to that used during the time ofLinus Pauling.

The Vitamin C solution is pushed in an IV bag and administrated at a rate of 0.5 g/min so that 50g will be administrated during 100 min.Rates up to 1.0 gram/minute are generally tolerable, but close observation is warranted. Patients can develop nausea, shakes, and chills. (Ref.)

For reference, 50g Vitamn C are administrated in 50o ml IVbag and 100g Vitamn Cin a 1000 ml IVbag. Some clinics are using NaCl IV bag but in general it is recommended that for doses greater than 15 g, the diluent should besterile water to achieve a theoretical osmolarity between 500 and 900 mOsm/L (Ref.).

Sodium ascorbate is clear and dehydroascorbate is yellow – so if the solution turn yellowish it meanssodium ascorbate started to degrade. To avoid thedegradation during the IV administration, the IV bag should be warped in an opaque foil such as aluminium foil (in case it is not already opaque.

Here is a good administration protocol discussion: Vitamin C Research – IVC Protocolhttps://riordanclinic.org/research-study/vitamin-c-research-ivc-protocol/

Using EDTA IV to chelate iron prior to Vit C IV may be agood idea (Ref.1, Ref.2). Actually, EDTA increases the pool of labile iron inside cancer cells, which is important for the effectiveness of high dose Vitamin C (high dose Vitamin C produces hydrogen peroxide that interacts with labile iron to generate hydoxyl radicals that kill the cancer cell (Ref.).

Note: Sometimes combined with DMOS & B17 in the same bottle – “Manner co*cktail”

E.g. 9 grams of Laetrile [Amygdalin/ B-17], 25-50 grams of Ascorbic acid [vitamin C], 10-15 ml. of DMSO (Ref.)

Protocols referenced:
Cathcart: http://www.vitamincfoundation.org/pdfs/civprep.pdf
Riordan: https://riordanclinic.org/wp-content/uploads/2015/11/RiordanIVCprotocol_en.pdf
Kansas University: https://drive.google.com/file/d/0B_EpU6QZ4EZtYWhFZEIxZGF6eEk/view?usp=sharing

(Thank you to my friend Fred for thelinks above, on the various protocols)

Here is an example of a treatment protocol when Vitamin C was used in combination with chemo therapy:

“The IVC infusion protocol was previously described [26]; it is based on a well-known protocol developed by Riordan et al [43,44]. Vitamin C infusates were prepared using ascorbic acid 500 mg/mL for injection USP (supplied as single-use 50 mL glass ampules) as a gift from Alveda Pharma Canada, Ltd. The stock solution was diluted in sterile water to achieve an osmolarity of approximately 900 mOsm/L. Any air bubbles formed during preparation were promptly evacuated. The solutions were delivered to the clinical research unit covered by an opaque bag, allowed to come to ambient temperature, and infused by calibrated infusion pump within one hour of preparation. Water and other drinks (preferably sugar-free) were provided and the patients encouraged to consume them freely before, during and after IVC infusions. The dose of vitamin C was 1.5 g/kg body weight when the body mass index (BMI) was 30 kg/m2 or less, and normalized to the body weight corresponding to BMI 24 kg/m2 for patients with a BMI > 30. The vitamin was infused at a constant rate over a period of 90 minutes for doses up to 90 g, and over a period 120 minutes for doses > 90 g. IVC was infused three times (at least one day apart) on week days during weeks when chemotherapy was administered (but not on the same day as intravenous chemotherapy) and any two days at least one day apart during weeks when no chemotherapy was given.”http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388666/

The “Ewan Cameron andLinus Pauling” approach:

Because of the main ‘pro-oxidant’ paradigm of high dose Vitamin C, it is generally believed that ‘more is better’. However, in contrast to the approach in which Vit C is given at a very high dose a few times each week, as used today,the best anticancer action seems to be the one observed byEwan Cameron andLinus Pauling, where patients were given a daily dose of about 10g or more (Ref.1, Ref.2). More specifically, they administered 10 g/d intravenous Vitamin C for approximately 10 days, followed by 10 g/d oral vitamin C thereafter. Their work showed significantly enhanced survival in these patients compared with two retrospective cohorts of 1,000 patients who did not receive vitamin C. (Ref.). Therefore, a lower dose (such as 10g/day) at a higher frequency of administration (i.e. daily) appears to be more beneficial based on the available studies. Continuous intravenous ascorbate seems to be safe (Ref.).

Here is a way to estimate blood Ascorbate concentrations in patients receiving High-Dose Intravenous Ascorbate, with teh simple use of commercially available fingerstick blood glucose: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725640/

Source:

Most compounding pharmacies including those listed here:https://www.cancertreatmentsresearch.com/?page_id=945

The price for a 25g vial – solution for IV – is around 15 to 20 euro. Taking 50g at one in a cancer clinic may cost between 100 to 200 euro.

Formulation:

If ready made IV Vitamin Cis not available, the IV solution can also be formulated “in house”:

Dr. Cathcart’s youtube lecture on IV/C prep is the best tutorial on “do it yourself” IV/C. https://www.youtube.com/watch?v=Zgi-7xPrCAgAnd an updated version of his written document: http://www.vitamincfoundation.org/pdfs/civprep.pdf

One of the best Vitamin C powder to be formulated for IV usage seems to beQuali-C brand. If thereare better suggestions on other brands please let me know.

The best is to formulate before the administrationhttp://www.ncbi.nlm.nih.gov/pubmed/9760591

References:

On the cytotoxicity of vitamin C and metal ionshttp://onlinelibrary.wiley.com/doi/10.1111/j.1432-1033.1983.tb07804.x/full

Cameron E, Pauling L: Ascorbic acid and the glycosaminoglycans.http://www.karger.com/Article/Abstract/224733

A new concept of a basic mechanism involved in cell proliferation is presented. It is suggested that cells are normally restrained from proliferating by the highly viscous nature of the intercellular . In order to proliferate, cells must escape from this restraint by depolymerizing the glycosaminoglycans in their immediate environment. This process is accomplished by the release of the enzyme hyaluronidase and is kept in check by physiological hyaluronidase inhibitor. There is some evidence that physiological hyaluronidase inhibitor is an oligoglycosaminoglycan that requires ascorbic acid for its synthesis, and perhaps incorporates residues of ascorbic acid. This hypothesis provides an explanation for the pathogenesis of scurvy. It explains the increased requirement for ascorbic acid that occurs in many cell proliferative diseases, including cancer. It indicates the existence of a basic underlying mechanism in many pathological states and suggests a common pattern of treatment. We conclude that ascorbic acid may have much greater therapeutic value than has been generally assigned to it.

Vitamin C in human health and disease is still a mystery? An overviewhttps://nutritionj.biomedcentral.com/articles/10.1186/1475-2891-2-7

Stromal cell oxidation: a mechanism by which tumors obtain vitamin C.http://www.ncbi.nlm.nih.gov/pubmed/10493506

Human tumors may contain high concentrations of ascorbic acid, but little is known about how they acquire the vitamin. Certain specialized cells can transport ascorbic acid directly through a sodium ascorbate cotransporter, but in most cells, vitamin C enters through the facilitative glucose transporters (GLUTs) in the form of dehydroascorbic acid, which is then reduced intracellularly and retained as ascorbic acid. Mice with established hematopoietic and epithelial cell xenografts were studied for the accumulation of injected ascorbic acid and dehydroascorbic acid. Most hematopoietic and epithelial tumor cell lines can only transport vitamin C in the oxidized form (dehydroascorbic acid) in vitro; however, when grown as xenografts in mice, they rapidly accumulated vitamin C after administration of radiolabeled ascorbic acid. The involvement of the GLUTs in vitamin C uptake by the xenografted tumors was demonstrated by competitive inhibition with D-glucose but not L-glucose. Because the malignant cells were not capable of directly transporting ascorbic acid, we reasoned that the ascorbic acid was oxidized to dehydroascorbic acid in the tumor microenvironment. Tumor accumulation of vitamin C in animals injected with ascorbic acid was inhibited by coadministration of superoxide dismutase, implying a role for superoxide anion in the oxidation of ascorbic acid. Whereas the epithelial cancer cell lines could not generate superoxide anion in culture, the minced xenograft tumors did. Our studies show the transport of dehydroascorbic acid by GLUTs is a means by which tumors acquire vitamin C and indicate the oxidation of ascorbic acid by superoxide anion produced by cells in the tumor stroma as a mechanism for generating the transportable form of the vitamin.

Intravenously administered vitamin C as cancer therapy: three caseshttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC1405876/

Cancer and vitamin C: a discussion of the nature, causes, prevention, and treatment of cancer with special reference to the value of vitamin Chttp://agris.fao.org/agris-search/search.do?recordID=US8128113

Aspects of the nature, causes, prevention and treatment of cancer are examined with emphasis on the value of vitamin C. The view is put forward that routine high intakes of ascorbic acid play a role in cancer by increasing the natural resistance of the patient; resistance of healthy tissues to metastasis by a malignant tumor may be the most important element in cancer progress and outcome. Extension evidence (clinical trials and case histories) supporting a therapeutic role for vitamin C in cancer treatment, especially if begun early, is presented. Increased ascorbate intakes by healthy individuals may also act to prevent the development of cancer. A discussion of the mechanisms of action of vitamin C, including its function in the immune system, provides insight into how the vitamin may work in the prevention and treatment of cancer

Vitamin C, Linus Pauling was right all along. A doctor’s opinionhttp://www.medicalnewstoday.com/releases/12154.php

Anti-cancer effects of vitamin C revisitedhttp://www.nature.com/cr/journal/v26/n3/full/cr20167a.html

Vitamin C was first suggested to have cancer-fighting properties in the 1930s and has been the subject of controversy ever since. Despite repeated reports of selective cancer cell toxicity induced by high-dose vitamin C treatment in vitro and in mouse models, the mechanism of action has remained elusive.

Vitamin C injections ease ovarian-cancer treatmentshttp://www.nature.com/news/vitamin-c-injections-ease-ovarian-cancer-treatments-1.14673

A clinic, expect in Vitamin C administration:https://riordanclinic.org/research-studies/

Orthom*olecular.com:http://orthom*olecular.org/index.shtml

Ascorbic Acid and a Cytostatic Inhibitor of Glycolysis Synergistically Induce Apoptosis in Non-Small Cell Lung Cancer Cellshttp://journals.plos.org/plosone/article?id=10.1371/journal.pone.0067081#pone.0067081-Chen2

Vitamin C attack http://www.nature.com/nchembio/journal/v12/n1/full/nchembio.1995.html

Vitamin C halts growth of aggressive forms of colorectal cancer in preclinical studyhttp://meyercancer.weill.cornell.edu/news/2015-11-05/vitamin-c-kills-colorectal-cancer

Pharmacologic ascorbic acid concentrations selectively kill cancer cells: Action as a pro-drug to deliver hydrogen peroxide to tissueshttp://www.pnas.org/content/102/38/13604.short

Human pharmaco*kinetics data indicate that i.v. ascorbic acid (ascorbate) in pharmacologic concentrations could have an unanticipated role in cancer treatment. Our goals here were to test whether ascorbate killed cancer cells selectively, and if so, to determine mechanisms, using clinically relevant conditions. Cell death in 10 cancer and 4 normal cell types was measured by using 1-h exposures. Normal cells were unaffected by 20 mM ascorbate, whereas 5 cancer lines had EC₅₀ values of <4 mM, a concentration easily achievable i.v. Human lymphoma cells were studied in detail because of their sensitivity to ascorbate (EC₅₀ of 0.5 mM) and suitability for addressing mechanisms. Extracellular but not intracellular ascorbate mediated cell death, which occurred by apoptosis and pyknosis/necrosis. Cell death was independent of metal chelators and absolutely dependent on H₂O₂ formation. Cell death from H₂O₂ added to cells was identical to that found when H₂O₂ was generated by ascorbate treatment. H₂O₂ generation was dependent on ascorbate concentration, incubation time, and the presence of 0.5-10% serum, and displayed a linear relationship with ascorbate radical formation. Although ascorbate addition to medium generated H₂O₂, ascorbate addition to blood generated no detectable H₂O₂ and only trace detectable ascorbate radical. Taken together, these data indicate that ascorbate at concentrations achieved only by i.v. administration may be a pro-drug for formation of H₂O₂, and that blood can be a delivery system of the pro-drug to tissues. These findings give plausibility to i.v. ascorbic acid in cancer treatment, and have unexpected implications for treatment of infections where H₂O₂ may be beneficial.

Oxalic acid excretion after intravenous ascorbic acid administrationhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482487/

In our study, ascorbic acid was rapidly administered shortly after the infusate was prepared, whereas parenteral nutrition solutions are commonly infused over 12 to 24 hours, during which time considerable ascorbic acid degradation is known to occur.The present data are important because they indicate a remarkable lack of severe hyperoxaluria after massive intravenous doses of ascorbic acid in people with normal renal function.

Vitamin C and Doxycycline: A synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs)

Here, we developed a new synthetic lethal strategy for further optimizing the eradication of cancer stem cells (CSCs). Briefly, we show that chronic treatment with the FDA-approved antibiotic Doxycycline effectively reduces cellular respiration, by targeting mitochondrial protein translation. The expression of four mitochondrial DNA encoded proteins (MT-ND3, MT-CO2, MT-ATP6 and MT-ATP8) is suppressed, by up to 35-fold. This high selection pressure metabolically synchronizes the surviving cancer cell sub-population towards a predominantly glycolytic phenotype, resulting in metabolic inflexibility. We directly validated this Doxycycline-induced glycolytic phenotype, by using metabolic flux analysis and label-free unbiased proteomics.

Next, we identified two natural products (Vitamin C and Berberine) and six clinically-approved drugs, for metabolically targeting the Doxycycline-resistant CSC population (Atovaquone, Irinotecan, Sorafenib, Niclosamide, Chloroquine, and Stiripentol). This new combination strategy allows for the more efficacious eradication of CSCs with Doxycycline, and provides a simple pragmatic solution to the possible development of Doxycycline-resistance in cancer cells. In summary, we propose the combined use of i) Doxycycline (Hit-1: targeting mitochondria) and ii) Vitamin C (Hit-2: targeting glycolysis), which represents a new synthetic-lethal metabolic strategy for eradicating CSCs.

This type of metabolic Achilles’ heel will allow us and others to more effectively “starve” the CSC population.

Intravenous Vitamin C for Cancer Therapy – Identifying the Current Gaps in Our Knowledgehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115501/

Innovation vs. quality control: an ‘unpublishable’ clinical trial of supplemental ascorbate in incurable cancer.https://www.ncbi.nlm.nih.gov/pubmed/1787807

A computerized data bank was created recording the details of all cancer patients attending three district general hospitals in West Central Scotland over a 4.5 year period 1978-1982. At the conclusion of the trial, the records of 2804 individual patients were available for study, of whom 1826 had reached an incurable stage. 294 of these incurable cancer patients had received supplemental ascorbate at some stage in their illness, whereas 1532 had not, and served as controls. Analysis showed that the ascorbate-supplemented patients had a median overall survival time (343 days) almost double that of the controls (180 days). Our difficulties in having this simple, but important, observation published are briefly recounted in the introduction.

Ascorbic Acid as a Therapeutic Agent in Cancerhttps://www.ncbi.nlm.nih.gov/pubmed/1787807

Vitamin C and Cancer: Is There A Use For Oral Vitamin C?https://www.isom.ca/article/vitamin-c-cancer-use-oral-vitamin-c/

Ascorbic Acid in Colon Cancer: From the Basic to the
Clinical Applicationshttps://www.mdpi.com/1422-0067/19/9/2752/pdf

Given the safety and potential benefits of intravenous ascorbic acid (AA) administration in cancer patients, there is merit in further exploring this therapeutic concept. In this review, we discuss the potential benefits of intravenous AA administration on colorectal cancer and we specifically focus on its effect on glycolysis in mutant and wild type RAS. We perform a PubMed and Ovid MEDLINE search using ascorbic acid, intravenous vitamin C, KRAS mutation, BRAF mutation and colorectal cancer (CRC) as keywords. At the cellular level, colorectal cancer cells undergo a metabolic shift called the Warburg effect to allow for more glucose absorption and utilization of glycolysis. This shift also allows AA to enter which leads to a disruption in the Warburg effect and a shutdown of the downstream KRAS pathway in mutated KRAS colon cancer cells. At the clinical level, AA is associated with tumour regression in advanced disease and improved tolerability and side effects of standard therapy. Based on these findings, we conclude that further clinical trials are needed on a larger scale to examine the therapeutic benefits of AA in colon cancer.

Oral vitamin C supplementation to patients with myeloid cancer on azacitidine treatment: Normalization of plasma vitamin C induces epigenetic changes https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6798470/

Intravenous vitamin C in the supportive care of cancer patients: a review and rational approach https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5927785/

We propose a pragmatic approach for the administration of IV and oral vitamin C as a supportive therapy, including recommendations to ensure safety before and after chemotherapy. In the post-adjuvant and advanced incurable settings, IV C with radiation treatment is not discussed.

Targeting cancer vulnerabilities with high-dose vitamin C https://www.nature.com/articles/s41568-019-0135-7

Over the past century, the notion that vitamin C can be used to treat cancer has generated much controversy. However, new knowledge regarding the pharmaco*kinetic properties of vitamin C and recent high-profile preclinical studies have revived interest in the utilization of high-dose vitamin C for cancer treatment. Studies have shown that pharmacological vitamin C targets many of the mechanisms that cancer cells utilize for their survival and growth. In this Opinion article, we discuss how vitamin C can target three vulnerabilities many cancer cells share: redox imbalance, epigenetic reprogramming and oxygen-sensing regulation. Although the mechanisms and predictive biomarkers that we discuss need to be validated in well-controlled clinical trials, these new discoveries regarding the anticancer properties of vitamin C are promising to help identify patient populations that may benefit the most from high-dose vitamin C therapy, developing effective combination strategies and improving the overall design of future vitamin C clinical trials for various types of cancer.

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