Vitamin C (also known as ascorbic acid) is considered the most studied and yet the most controversial vitamin in history. It has been subjected to numerous research studies throughout the years. There are documented claims that Vitamin C provides benefit for heart disease, schizophrenia, diabetes, autoimmune disease, helping fight infections, cancer, and more. In fact there are virtually no areas in medicine where Vitamin C has not been used or studied at one point in time.

Enhancing chemotherapy effectiveness with simple Vitamin C? My clinical experiences

Generally it is not advised by the oncology community for patients with cancer to take any other form of treatment when they are receiving chemotherapy for fears that a negative interaction may occur. The rationale for this recommendation, in particular with vitamins, largely stems from fears of the antioxidant debate or from very limited information published. A recent article published October 1, 2008 in the journal Cancer Research further cast doubt on this subject area to a point that even a senior scientist here at the BC Cancer Agency publically discouraged patients to use Vitamin C together with chemotherapy. If I was an oncologist and trained only in conventional medical care, I could understand some of their concerns on this subject—in addition there is only a certain amount of free time in a day to personally investigate such subjects when dealing with patients with cancer—I understand this as well. However, for myself being a naturopathic physician, my training and expertise in the use of natural methods of healing, vitamins & minerals, etc. is definitely much more involved and extensive than an oncologist and most conventionally trained healthcare providers—it's one of my strengths and so my understanding on the subject is much more entrenched. Unfortunately, what people do not realize is this paper used a form of Vitamin C that is not even sold or used by people (i.e. dehydroascorbic acid) while when looking at the use of good old Vitamin C that everyone uses (i.e. ascorbic acid) with chemotherapy, there has been an overwhelming amount of positive research around the world. It is important to highlight that there already exists two research papers in humans (i.e. not test tube or mice like the one above), that compared the effects of oral Vitamin C (i.e. the regular stuff) together with and without chemotherapy in patients with cancer, none of which showing any evidence of interfering—and remember that's in humans! In addition, the use of Vitamin C by injection (i.e. an even stronger method of use) has also been used in people with cancer (i.e. again not in test tube or mice) and along with select chemotherapy agents, and the preliminary findings demonstrate that the combination works quite well together.

Throughout the years of helping patients with cancer, I have observed that some patients who were interested in pursuing Vitamin C (also known as ascorbic acid) as a means to help them fight their disease, in particular, pharmacological doses via intravenous injection, together or alongside chemotherapy often demonstrated very noteworthy responses. In fact, I have seen many cases where a patient is about to be removed from receiving a chemotherapy protocol because they showed signs that the tumour was not responding or was becoming more resistant to treatment. As a consequence the patient becomes a little more desperate and willing to try more unconventional approaches. The patient then begins to incorporate Vitamin C into their treatment protocol and from that point, the patient begins to show impressive signs of tumour response (i.e. shrinking). I have seen this kind of effect in lymphoma's as well (i.e. Non-Hodgkin's). Moreover, I have also seen where a patient has been more seriously hurt from a palliative chemotherapy combination cocktail (i.e. negative side-effects) and so a single agent is used to try and provide a more gentle level of treatment. The patient then decides to incorporate intravenous Vitamin C alongside the chemotherapy agent (i.e. Adriamycin) and from that point, the patient begins to respond and shrink the tumour unlike never before (and to the surprise of the oncologist).

Upon looking at the medical literature I was interested to find evidence that helped to support my observations in clinical practice that Vitamin C incorporated together with chemotherapy can make them synergize and work better (i.e. a term known as "chemo-sensitizing") and/or help to overcome chemotherapy resistance. I had managed to find 23 research papers from around the world incorporating a selection of more standard chemotherapy agents used together with Vitamin C and demonstrating just that! There was actually more using Arsenic Trioxide, an experimental chemotherapy medicine, however this is not a common agent at this time and so I did not include it in this analysis. There was one paper which demonstrated mixed effects (more on the positive side) depending on the cancer cell type used. There are also 2 human papers publishing their experiences using Vitamin C, by intravenous injection, and some of which together with chemotherapy demonstrating positive outcomes as well. The only real negative research paper I had found on this subject was only one (i.e. the latest article that has managed to get all the press), making a total of 27. There are 2 more human studies, as previously mentioned, that used oral Vitamin C either together with or without chemotherapy, however these trials did not demonstrate an effect either way (i.e. other than they are safe and help to decrease side-effects of treatment): however, this is not the basis for this paper.

In general, Vitamin C together with chemotherapy medicines has been shown in the scientific journals to:

• Reverse chemotherapy resistant cancer cells
• Increase the delivery of chemotherapy into cancer cells (helps to overcome drug resistance)
• Make the tumour cell membrane more permeable (enhanced drug delivery)
• Stabilize p53 genes, Bax, decrease Bcl-2 and telomerase activity (decreases drug resistance)
• Inhibit translocation of NF-kappaB and AP-1 (decreases drug resistance)
• inhibit Nrf2-mediated gene expression (decreases drug resistance)
• Activate the MLH1, c-Abl, and p73 signalling cascade (enhanced drug killing effect)

Note: it is important to also highlight that, on its own, Vitamin C—in particular by intravenous injection—also has chemotherapeutic effects and it also possess supportive properties for the rest of the body (unlike standard chemotherapy agents): however this is not the focus of this paper.

The researched chemotherapy agents used together with Vitamin C showing a positive effect have included the following:

• Arsenic Trioxide
• Cisplatinum (platinum-based)
• Cyclophosphamide (Cytoxan)
• Doxorubicin (Adriamycin)
• Dacarbazine (DTIC)
• Gemcitabine (Gemzar)
• Interferon-alpha 2b
• Imatinib (Gleevec)
• Mitomycin C
• Paclitaxel (Taxol)
• Etoposide
• 5-FU (fluorouracil)
• Tamoxifen
• Vincristine (Oncovin)

So you decide—1 negative paper, 1 neutral, or 23 positive papers (researched independently around the world)

The above information tends to paint a much different picture on the potential therapeutic properties of Vitamin C (i.e. ascorbic acid) acting as a means to improve the benefits of chemotherapy medicines (and vice versa)—I have seen this to be true in my clinical experience. It is the classic saying—"is the cup half full or half empty?". Some of the positive data have even shown to lower the chemotherapy dosage needed to produce the same effect of regular strength chemotherapy (i.e. cisplatin) when Vitamin C was added: more importantly, in the animal studies, they lived longer. Moreover, in cancer cells that were resistant to chemotherapy (i.e. Gleevec, Vincristine), the addition of Vitamin C reversed that effect. What alarms me is that none of these articles were even mentioned or referenced in the recent negative article—science should be about object reporting of the total evidence. It is important to highlight that the recent negative trial used a form of Vitamin C that is not even used in the common market place dehydroascorbic acid (a "rusted" form of Vitamin C). Good old basic Vitamin C (i.e. ascorbic acid) has been used by the vast majority of the positive data out there and more importantly by people—a very important difference which sheds some light in explaining the findings. At the University of Kansas Medical Center, intravenous Vitamin C is being studied together with chemotherapy for patients with ovarian cancer and preliminary published case reports appear quite promising (humans and not test tubes or mice). Other human clinical reports using Vitamin C together with various chemotherapy agents, again, do not show a negative effect—but rather the exact opposite (and of course there are also my personal experiences). Moreover, some research has shown that patients with cancer have lower levels of Vitamin C in their blood even though they consume more than non-cancer patients—they appear to need more as well!

While I understand that most oncologists are more hesitant on the idea of combining vitamins together with chemotherapy medicines, it is also possible that there may be a certain level of harm in this recommendation when looking at the bulk of the evidence. It is everyone's goal to improve the outcomes and quality of life in our patients, however, when being too restrictive, important tools or approaches can certainly be missed—the patient loses here.

The above information sheds some serious question on the more negative chemotherapy concerns that has been highlighted with respect to Vitamin C—it's a lot more complicated and involved! For example, there are some chemotherapy medicines that also possess antioxidant activity and yet produce cancer killing effects that do not hit the radar of concern (i.e. Etoposide, Oxaliplatin). Moreover, the majority of the medical community does not even realize that when Vitamin C is used in high or pharmacological doses (i.e. by injection), it operates more like a pro-oxidative medicine (i.e. and not an antioxidant) similar to some chemotherapy agents. It is not the intention of this paper to place the patient in the middle of a medical debate with this subject area but rather to simply provide honest information so that they can make good decisions (i.e. and have no regrets). I am regularly told by my patients who are upset they were never told about this kind of information to begin with or could not discuss it in better detail—a "no" answer is not enough for some and so this paper is for them.

I have found that while people believe that an either/or kind of approach is the safer course of action to take in cancer care, a combination of both at some level often works even better if the patient chooses to do so—hence the term "integrative cancer care".

The current negative paper on Vitamin C, using the dehydroascorbic acid form, should not be held in high regard: it is not even used by consumers. There exists an overwhelming amount of positive evidence to the contrary using simple Vitamin C (i.e. ascorbic acid)—the way nature intended.

Vitamin C and chemotherapy: DHA vs. AA—looking at the broader evidence

Hal Gunn, MD and Walter Lemmo, ND

Letter to the Editor: Heaney ML et al. Vitamin C Antagonizes the Cytotoxic Effects of Antineoplastic Drugs. Cancer Res 2008; 68:19:8031-8038

We read with great interest the paper by Heaney ML, et al (1), which demonstrates that dehydroascorbic acid (DHA), the oxidized form of Vitamin C, negatively impacts chemotherapeutic efficacy in leukemia and lymphoma cell lines and in a murine tumour model. In contrast, there is a larger body of evidence that has found that the reduced form of Vitamin C, ascorbic acid (AA) augments chemotherapy efficacy, reverses chemotherapy resistance in chemotherapy resistant cell lines, and increases drug accumulation in numerous in vitro and in vivo models (2-24). Moreover, the combination of AA with cisplatin in murine Dalton's lymphoma was found not only to increase chemotherapeutic efficacy but also to increase survival as well (22-23) and the same has also been shown with AA in combination with cyclophosphamide (24). The volume of research that supports the use of AA in combination with chemotherapy is even greater if the research of the use of AA in combination with Arsenic trioxide is included (35). There are also two human randomized trials comparing chemotherapy with and without AA. These clinical trials did not show signs of interference (25, 26).

While some cell lines appear to be more sensitive to AA chemotherapy combinations than others, there are likely other factors that explain the difference between the positive impact of the use of AA in combination with chemotherapeutic agents listed above and the negative impact of the use of DHA in combination with chemotherapy found by Heaney et al. There are important interplays between AA & DHA to consider, which may explain this paradox. Unlike DHA, AA is an electron donor, which is important in signal transduction pathways (27). Flooding both the extracellular and intracellular pool with DHA may disrupt important homeostasis, which includes AA's ability to induce cell death through the release of apoptosis-inducing factor from the cancer cell mitochondria (28). In fact, research by Koh WS et al., demonstrates that AA's ability to inhibit leukemic cell growth is dependent on its concentration in culture medium rather than in its intracellular concentration (29). No AA was found in the culture supernatant treated with DHA. Interestingly, in this study, the growth of leukemic cells was dose-dependently inhibited by AA but not by DHA. As Heaney,et al. had mentioned, AA is the principle form of Vitamin C in the serum, which may also hold some significance and potential chemo-modulatory impact on cell membranes and also on cell mediated immunity. In other words, treatment with DHA may negatively impact chemotherapeutic response even though the reverse may be true with AA treatment.

Patients with cancer have lower serum AA levels even when intakes are greater than controls (30, 31). Data also suggests that cancer patients have serum and CSF ascorbyl radical formation (i.e. free radical stress). The oxidized form of Vitamin C (i.e. DHA) may be an added stress, especially during chemotherapy (32), consistent with the findings of Heaney et al. In humans, AA in combination with chemotherapeutic agents have not shown adverse effects in randomized trials and in clinical reports (25-26, 33-35). As the general public consumes AA (for which the weight of the evidence suggests a positive impact on chemotherapy in cell-line and murine tumour models) rather than DHA, more research should be done with AA in combination with chemotherapy in animal models to better understand the current findings and their implications with respect to Vitamin C use during chemotherapy.

References

1. Heaney ML et al. Vitamin C Antagonizes the Cytotoxic Effects of Antineoplastic Drugs. Cancer Res 2008; 68:19:8031-8038
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Please visit the intravenous page to learn more on how Vitamin C is applied as an intravenous therapy agent.