Cameron and Pauling’s Attack on Conventional Views of Cancer

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Announcement published in the LPISM Newsletter, Spring 1979.

[An examination of “Ascorbic Acid and Cancer: A Review,” published in 1979. This is part 2 of 2.]

Linus Pauling and Ewan Cameron began their paper “Ascorbic Acid and Cancer: A Review” – published with Brian Leibovitz in Cancer Research in March 1979 – by detailing the history of research on ascorbate and establishing a connection between cancer and scurvy. This line of thinking was predicated on the observation that cancer patients, like scurvy patients, were abnormally deficient in Vitamin C. The authors, in turn, traced this observation back to the importance of Vitamin C in maintaining the balance of the intercellular matrix. They likewise emphasized that cancer is a disease that originates in the body, emanating from the patient’s own cells.

The paper next identified the two main traits of cancer: abnormal cell proliferation and invasiveness. Keeping these characteristics in mind, the authors hypothesized that the release of an enzyme, hyaluronidase, contributed to occurrences of cancer. Hyaluronidase breaks down the gel-like substance that surrounds cells, they argued, and creates a pathway that allows cells of any kind to continue multiplying. In healthy individuals, this process is self-limiting. When the process goes completely unchecked however, cells can become malignant and invade the surrounding tissue. Pauling and Cameron believed this to be the likely mechanism for metastasis, the point in a cancer’s progression at which survival rates plummet.

While they knew that it was highly unlikely that a simple infusion of Vitamin C would cure a cancer patient – as it would do in the case of scurvy – Pauling and Cameron theorized that an infusion of this sort would contribute to the inhibition of hyaluronidase, thus keeping cell proliferation in check. As they repeatedly emphasized in their review, Vitamin C’s main benefit was to increase host resistance to diseases that caused unrestrained cell proliferation. What Vitamin C did not do was guarantee complete remission.

Once they had described ascorbic acid’s defensive role, the authors moved on to its limited ability to take the offensive. One function that increased Vitamin C was believed to carry out was the capacity to “encapsulate” a tumor or disseminated tumors to the point where they were no longer malignant. As Pauling pointed out to his colleagues, when his wife Ava Helen was first diagnosed with stomach cancer and surgeons went in to remove her tumor, they noted that the mass had unusual presentation for its location and appeared to be encapsulated. Ava Helen had been taking large doses of Vitamin C for several years before she was first diagnosed, and her husband attributed the nature of her tumor and the ease of its removal to her intake of Vitamin C.


Central to the review paper were the clinical results that Ewan Cameron had compiled at the Vale of Levin Hospital in Alexandria, Scotland. Cameron had begun to see positive results early on, but found that his studies were somewhat skewed because so many of his patients were terminal and ended up dying regardless of their treatment. Cameron was worried that his data did not present much of an argument in favor of Vitamin C, a situation that was further muddied by the fact that, “the terminal stages of cancer are a compound of so many human, individual, pathological and even emotional variables, as to be nearly impossible to quantify.”

In an effort to provide what the authors believed to be a more accurate picture of Vitamin C’s treatment benefits, Cameron’s later studies measured survival time in ascorbic acid patients and compared them with non-ascorbic acid patients. This comparison revealed that a patient on supplemental ascorbic acid survived, on average, four times as long as a patient with a similar prognosis who had not received ascorbic acid.

In conducting his trials, Cameron encountered the additional barrier of patients who failed to adhere to the Vitamin C regimen once they were released from the hospital. Cameron called this mode of behavior the “reverse placebo” effect, noting that some patients, when left to their own devices, would discontinue their ascorbic acid intake because it was “just Vitamin C.” Believing that it would be treated with greater respect if it sounded more like a drug, Cameron half-jokingly suggested that pharmacies rename Vitamin C as “Pauleron” to dissuade patients from underestimating its potential.


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In the final section of their review paper, Pauling and Cameron warned of unexpected and unexplained potential consequences associated with ascorbic acid therapy. In particular, some of Cameron’s patients, after showing marked improvement for several weeks or even months, succumbed to what Pauling called a “whirlwind” of cancer. Autopsies later revealed sudden massive tumor growth and dissemination.

Interestingly, most of these “whirlwind” tumors contained a large volume of necrotic cancer cells. Pauling put forth two possible explanations for this, which he included in the review. One explanation was that, though necrotic cancer cells can be less harmful than live cancer cells, the inflammation caused by their presence might cause rapid tumor growth or become toxic to the patient in such a large volume.

A second explanation, which he thought more plausible, was based on the understanding that abruptly discontinuing Vitamin C caused ascorbate levels to plummet. In this circumstance, if ascorbic acid was inhibiting tumor growth as believed, a drastic and sudden decrease in the treatment could lead to rapid, unrestrained tumor growth.

Pauling couldn’t provide solid evidence for either possibility, but he felt that both supported the review’s hypothesis. In the first instance, ascorbic acid could be killing the cancer cells. In the second, the negative consequences of withdrawing ascorbic acid inversely suggested the benefit of continued ascorbic acid use.

Pauling and Cameron concluded their review by listing areas of ascorbate research that were encouraging but had, to date, only received preliminary investigation. Specifically, the paper pointed out that no trials had been conducted to consider the effects of ascorbate in general cancer management.


The Cameron, Pauling and Leibovitz review provoked mixed reactions. Many readers, particularly aspiring physicians, were intrigued and encouraged by the results. On the other hand, quite a few others remained skeptical and focused on the aspects of treatment that Vitamin C could not promise to provide. Shortly after the review came out, Pauling received a letter from a medical student who reported that the paper had been torn out of archived copies of Cancer Research at both Cornell Medical College and the Sloan-Kettering Cancer Center. Pauling confirmed that this had happened at both locations, but was unable to persuade anyone to rectify the situation.

In the fall of 1979, a handful of months after the review was published, the Mayo Clinic released the results of its own clinical trial, which concluded that Vitamin C did not contribute to longer survival times, nor did it offer any therapeutic benefit for cancer patients. When the results were published in the New England Journal of Medicine, Cameron wrote a letter to the editor providing a rebuttal of sorts.

In Cameron’s letter, he pointed out that the Mayo Clinic hadn’t followed the same procedures as those used at the Vale of Leven. Importantly, in Cameron’s trial, only 5% of patients had received recent chemotherapy treatment. By contrast, in the Mayo Clinic trial, only 5% of patients hadn’t received recent chemotherapy. Cameron also suggested that patients, fearful that they were in the control group and not receiving supplemental ascorbate, were dosing themselves with Vitamin C, as it was easy to obtain outside of the trial setting. If this was indeed the case, the Mayo Clinic data likely supported the Cameron-Pauling hypothesis.

Despite Cameron’s centrality to the debate, the editor of the New England journal refused to print his letter, a decision that only increased the levels of skepticism surrounding Cameron and Pauling’s work.


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In publishing their review and the papers that led up to it, Pauling and Cameron sought to update the popular view of cancer as an invasion of foreign cells that needed to be entirely destroyed to produce clinical success. Once people accepted a new view of cancer, Pauling believed that attitudes toward cancer treatment would also change.

Perhaps most importantly, Pauling and Cameron wanted physicians to stop assuming that troubling side effects were a sign of a treatment’s success and instead to begin concentrating more on the overall health of patients. Though they focused primarily on Vitamin C, the duo hoped that their review would encourage researchers to gather more evidence for an orthomolecular approach to cancer, one that would emphasize vitamins and natural methods as opposed to cytotoxic chemicals.

Although Pauling and Cameron’s perspective was not widely accepted during their lifetimes, researchers today are increasingly focusing on alternatives to chemotherapy and radiation. Immunotherapy, still in its infancy during Pauling’s life, has now become a standard treatment for certain cancers. Additionally, researchers have been able to show that high-dose Vitamin C, administered intravenously at even higher levels than Pauling and Cameron had attempted, does indeed provide therapeutic benefits in some cancers.

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Ascorbic Acid and Cancer: A Review

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Ewan Cameron, Ava Helen and Linus Pauling. Glasgow, Scotland, October 1976.

[Ed Note: Today’s post is the first installment of a two-part look at Linus Pauling, Ewan Cameron and Brian Leibovitz’ extensive 1979 review of the published literature pertaining to research on ascorbic acid and cancer.]

Students of Linus Pauling’s life will know full-well that Pauling expended significant energy over his latter decades advocating for the use of ascorbic acid, or Vitamin C, in the treatment of cancer. One of his lengthier research endeavors, and certainly among his most controversial, Pauling’s interest in and advocacy of ascorbic acid therapy prompted a wide array of responses from scientists, journalists, and patients, among many others.

Pauling’s views also attracted the disdain of most medical professionals. One notable exception to this theme was Ewan Cameron, a Scottish surgeon who became so invested in the work that he eventually relocated to California to join the staff of the Linus Pauling Institute of Science and Medicine.

Prior to his immigration, Cameron had shared a rich correspondence with Pauling through which the colleagues bounced ideas off one another and even co-wrote papers. Cameron, who was head of his department at the Vale of Leven Hospital in Alexandria, was permitted to run a clinical trial testing the efficacy of ascorbic acid treatments on terminal cancer patients. He then relayed his data to Pauling, who studied the Alexandria results and contributed his thoughts on the chemical mechanisms that might be underlying them.

In 1979, Pauling, Cameron and a third author published a major literature survey titled “Ascorbic Acid and Cancer: A Review.” Appearing in the March 1979 edition of Cancer Research, the paper marked a crescendo of the duo’s eight years of work in the cancer field; work which they attempted to bolster using all of the previous and ongoing studies that they could find.

The survey, which took up ten journal pages and included 358 references, was published with the hope that it might serve to counter some of the skepticism that its authors were encountering, while also inspiring new researchers to turn their own attentions toward the potential benefits of ascorbic acid. As was typical during this period of Pauling’s career, the reception that the paper received was mixed at best.


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One of the 1,000+ references gathered by Brian Leibovitz for use in “Ascorbic Acid and Cancer: A Review.”

Pauling and Cameron first began toying with the idea of a grand literature review in 1976. Having struggled mightily with both the medical community and mainstream publishers for five years, the duo had, by 1976, finally managed to get a few papers into print. Encouraged by these successes, the co-authors agreed that gathering all available research on Vitamin C and cancer, and presenting it in one paper, would make for a very useful contribution to a decidedly nascent field.

There was a secondary ambition in play as well. Though brimming with ideas, the resources available to the two scientists were scarce and, as a result, they had arrived at an impasse of sorts. Lying at the heart of the matter was the fact that basically all of the leading medical journals had refused to publish the clinical work that Cameron and Pauling had conducted, because they hadn’t been able to follow a proper double-blind study protocol. Instead, Cameron had matched his ascorbic acid patients – by age, sex, and cancer type -with previous patients who had been treated at the Vale of Levin hospital but hadn’t received ascorbic acid.

Likewise, Cameron believed so strongly in the benefits of ascorbic acid that he refused to withhold it from incoming cancer patients who might otherwise populate a control group for his study. In his correspondence with Pauling, Cameron confided that to withhold ascorbic acid treatment from sick patients would stand as a violation of the Hippocratic Oath.

(Oddly enough, Dr. Thomas Addis – the doctor whose conservative therapies saved Pauling from an almost certain death sentence when he was diagnosed with glomerulonephritis in the 1940s – argued against the use of ascorbic acid for exactly the same reason. To discontinue traditional methods of cancer treatment he believed to be effective came at the cost of his patients, and Addis refused to do it.)

Memorial Sloan-Kettering Cancer Center in New York had conducted its own trial in 1974, but Cameron and Pauling suspected that there were problems with the scientific design of that study as well. Preventing this from happening again, especially as Pauling and Cameron were gaining increased attention from the medical community, was another motivation for publishing the review. Finally, the research that they had gathered also helped the co-authors in preparing a new book, Cancer and Vitamin C, which came out in 1979, only a few months after the review was published.


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Brian Leibovitz

In putting together their article, Pauling and Cameron enlisted the additional help of Brian Leibovitz, a graduate student at Stanford who had worked at LPISM from 1975 to 1977. Leibovitz’ main task was straightforward: obtain reprints of anything related to ascorbic acid and cancer. Pauling also requested that Leibovitz look into other papers that focused on the environment shared by cells, as he and Cameron both believed that the intercellular environment held important – if, as yet, undiscovered – resources for treating cancer.

Leibovitz expressed great dedication to the multi-year project, continuing to collect references even after finishing up at LPISM and moving to Oregon. In the end, Leibovitz gathered over a thousand sources; for his work, his name appeared on the review as a third co-author.


Once it had been completed, Pauling encountered trouble finding a home for the review. Originally a friend had offered to have it published in Cancer Research, but upon seeing the manuscript, the editor complained that the paper was much too long. In response, Cameron worked on shortening the text while Pauling looked into other avenues for publication, including The Journal of Preventative Medicine and Cancer Reviews.

While Cancer Reviews was kind enough to respond that they were not interested in publishing anything on ascorbic acid, The Journal of Preventative Medicine did not reply at all. Just as the authors were about to give up, the editor of Cancer Research got back in touch, suggesting a series of changes and promising to publish the survey once it met with the requirements that he had outlined.

Intravenous Vitamin C: The Current Science

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Jeanne Drisko with Murray Susser. Both Drisko and Susser are past presidents of the American College for Advancement in Medicine.

[Part 2 of 2]

At her public lecture, “Intravenous Vitamin C: Does it Work?” delivered at the Linus Pauling Institute’s Diet and Optimum Health Conference in September 2017, Dr. Jeanne Drisko of the University of Kansas Medical Center, Kansas City, provided an overview of current research on the potential impact of intravenous vitamin C in treating disease.

She began this portion of her talk by reflecting on the factors that have continued to propel her own scientific interest in the topic, despite the headwinds generated by critics of the work. For one, Drisko has taken heart in the fact that intravenous vitamin C is used in many clinics around the world. Indeed, at a 2006 integrative medicine conference, Drisko and colleague Mark Levine took a survey of participants and found that some 8,000 patients had received intravenous vitamin C from doctors attending the meeting. Because Drisko maintains contacts in both conventional and alternative medical circles, she knows that naturopaths have been using intravenous vitamin C as well.

Drisko then pointed out that one barrier to more widespread acceptance of vitamin C as a cancer treatment is that, conventionally, it does not make sense to administer it in tandem with chemotherapy, since vitamin C is known to be an antioxidant and chemotherapy is a prooxidant. That said, Levine and Drisko’s colleague in Kansas, Qi Chen, have found that when vitamin C is given intravenously, it actually works as a prooxidant because it produces hydrogen peroxide. As such, it actually becomes a very good compliment to chemotherapy. Moreover, studies conducted by Drisko and others have found no evidence of conflict arising as a result of vitamin C dosages given alongside chemotherapy. On the contrary, researchers have reported a synergistic relationship in many cases.

In explaining why this is so, Drisko noted that when vitamin C is injected into a vein, it takes on the form of an ascorbyl radical, which she described as a “very promiscuous and active molecule that likes to interact with transition metals” like copper and iron. These interactions lead to the formation of hydrogen peroxide, which is quickly turned into water and oxygen by the enzymes glutathione peroxidase and catalase, such that levels of hydrogen peroxide in the bloodstream are promptly rendered as unmeasurable.

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However, when vitamin C gets into the extracellular fluid it also becomes hydrogen peroxide. The difference in this case is that glutathione peroxidase and catalase do not intervene and the hydrogen peroxide is not broken down into water and oxygen. Instead, the hydrogen peroxide diffuses throughout the extracellular fluid, bathing the cells.

While the presence of hydrogen peroxide in the cells might seem unsafe, Levine’s cell culture tests have found that hydrogen peroxide caused harm only to cancer cells. In reporting his results, Levine explained that the glutathione peroxidase and catalase enzymes are not as efficient in attacking cancer cells because they direct their activity towards reproduction rather than other processes. The fact that glutathione peroxidase and catalase are not active in the extracellular fluid renders vitamin C as a pro-drug and hydrogen peroxide as an actual drug.


Drisko’s research portfolio on the use of intravenous vitamin C includes the first randomized controlled trial involving ovarian cancer patients, work that was published in 2014. The trial studied two groups of patients: one group received standard care, which included carboplatin and paclitaxel chemotherapy for six cycles. The other group received this same care along with 75 to 100 gram doses of intravenous vitamin C.

The trial made clear that this form and dosage of vitamin C therapy is safe to administer. It also yielded a statistically significant improvement in how certain types of patients felt during their cancer treatment. Drisko called this a “feel good effect” which she believes is neurological. This same impact, however, was not observed in patients suffering from more advanced stage three and stage four cancers. Drisko is currently following up on these results by looking at the role that vitamin C might play in brain chemistry.

While her work has generated positive results, Drisko is also aware that vitamin C should not be used in all cases. Importantly, vitamin C is known to be potentially harmful when given in large doses under certain conditions. One such case is in individuals suffering from a deficiency of Glucose-6-Phosphate Dehydrogenase, or G6PD. On its own, G6PD can cause anemia, but when combined with high levels of vitamin C it leads to hemolysis, or the destruction of red blood cells. As a matter of standard protocol, Drisko checks her own patients for G6PD deficiencies, but she knows of others who have been unaware of this biological conflict and who have had to send patients to the emergency room.

Drisko will likewise opt against administering intravenous vitamin C when a patient reports a history of oxalate kidney stones, which can form as a result of excessive vitamin C intake. For individuals who have gone ten years or more since their last instance of oxalate kidney stones, Drisko administers vitamin C, but she does so cautiously, monitoring kidney functions and liver enzymes throughout the process.


Another barrier to studying intravenous vitamin C is that it is a difficult substance to measure since it is processed by the body so quickly. To get around this difficulty, Drisko developed a finger stick method that emerged from her interactions with a diabetic ovarian cancer patient. Over the course of these interactions, Drisko found cause to contact a glucometer manufacturer who told her that, because vitamin C and glucose molecules are so similar, the glucometer would indicate levels of both. Making use of this similarity, Drisko started taking finger stick glucose readings both before and right after her patients received their doses, and using this process she is now able to ascertain a rough estimate of how much vitamin C has been absorbed by the body.


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Qi Chen

In attempting to achieve greater certainty about appropriate dosage levels of vitamin C to administer, Qi Chen and Mark Levine have conducted experiments wherein they give intravenous vitamin C to mice and rats with tumors. This work is a follow-up to Levine’s original studies in the 1990s, which showed that vitamin C given orally could not be absorbed above a 10 millimolar concentration. In their more recent invesigations, Levine and Chen have found that blood concentration levels of 20 to 30 millimolar can be achieved as a result of intravenous application. They also found that the tumors in their mice studies would take up the vitamin C and that hydrogen peroxide formed in the tumors and subcutaneous tissue, but not in the blood.

Drisko gives her patients two to three infusions of vitamin C per week in advanced cases. Ideally, the vitamin C would be administered as the fluid loading dose for chemotherapeutic drugs, but it is often difficult to carry out both vitamin C and chemotherapy treatments on the same day because patients are already burdened by a busy treatment schedule and the facilities providing the two types of treatments are often not in the same location. (A new dosing device that attaches to the hip, developed by Channing J. Paller at Johns Hopkins, could help to get around some of these barriers.) Drisko’s treatment schedule uses a “stair-step” methodology wherein doses ranging from 0 to 100 grams are able to achieve 20 millimolar blood concentrations.

The appropriate duration of vitamin C treatment for cancer is still an open question. What is known is that it takes at least a couple of months before effects start to show. This stands in stark contrast to chemotherapy, which makes a much quicker impact.


Drisko concluded her talk by sharing the hopeful story of a woman who had participated in her ovarian cancer trial. This patient had been part of the group that had received the standard chemotherapy treatment only. She had subsequently relapsed very quickly and was believed to have only months to live. In her conversations with Drisko, the patient expressed a strong desire to live long enough to give her grandson a present at Christmas, and she requested that Drisko give her vitamin C in addition to her chemotherapy, since she was no longer part of the trial.

Initial CT-PET images showed that the woman was suffering from an accumulation of fluid, or ascites, full of cancer cells that were pushing against her organs. At the start of her intravenous vitamin C treatment in 2004, a second CT-PET scan showed both the malignant ascites as well as a residual tumor that could not be removed surgically.

Subsequent scans after Drisko began her treatment showed gradual improvement. In 2007, the pictures included fewer ascites and the tumor was somewhat smaller, trends that continued to be seen in 2012. By 2014, calcification appeared in the tumor and around the fluid, with further calcification showing in 2015. In essence, what the scans were revealing was an eight-year process of “turning her cancer into a scar.” While this is only a single example, it is a powerful one, and may prove to be harbinger of medical breakthroughs to come.

Intravenous Vitamin C: The Historical Progression

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Jeanne Drisko

[Part 1 of 2]

Jeanne Drisko, MD, Director of Integrative Medicine at the University of Kansas Medical Center, Kansas City, was a featured speaker during the public session of the Linus Pauling Institute’s Diet and Optimum Health Conference, held September 13-16, 2017.  She delivered a public lecture titled “Intravenous vitamin C and cancer treatment: Does it work?” Dr. Maret Traber, a principal investigator at LPI, introduced Drisko, describing her as a “leading expert on intravenous vitamin C.”

Drisko began her talk by tracing the history of vitamin C research, noting the ways in which previous studies had made her own research possible. The first person Drisko spoke of was Nobel laureate Albert Szent-Gyӧrgyi (1893-1986), who isolated ascorbic acid while working at Cambridge University and the Mayo Foundation between 1927 and 1930. Drisko then pointed out that, in the 1940s, vitamin C was used widely in clinical settings to treat pertussis, or whooping cough, along with other bacterial and viral infections. Importantly, these treatments were not administered orally. At the time, pharmaceutical preparations of vitamin C were not of a quality that could be administered intravenously, so they was injected into the muscles.

The use of vaccines was also on the rise during this period and Drisko pointed out that the development of the polio vaccine was particularly connected to the clinical fate of vitamin C. Albert Sabin (1906-1993), who had developed an oral polio vaccine, also carried out trials on the effects of vitamin C injections on primates. Sabin found no benefit and suggested that focus turn toward vaccines instead. It was at this point, Drisko explained, that the use of vitamin C injections went “underground,” drifting well outside of the medical mainstream.

One individual who remained interested in the promise of vitamin C was Frederick Klenner (1907-1984), who began using intravenous ascorbic acid at his North Carolina clinic in the 1940s. Drisko described Klenner as keeping “vitamin C use alive,” by administering both muscular and intravenous injections, while the broader medical community turned elsewhere. In particular, Klenner used vitamin C to treat children suffering from polio and found that even advanced cases could be approached successfully. During this time, Klenner also trained other practitioners in the methods that he was pioneering at his clinic.


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Ewan Cameron, Ava Helen and Linus Pauling. Glasgow, Scotland, October 1976.

Next, Drisko turned to Linus Pauling. To begin, Drisko noted that since Pauling was already well known, his interest in oral vitamin C was written off by many who were familiar with his prior work. Others, however, did look to Pauling as an authority, and among them was the Scottish surgeon Ewan Cameron (1922-1991), who contacted Pauling after reading some of his papers in the early 1970s. In his initial correspondence, Cameron informed Pauling that he had been giving about ten grams of vitamin C to cancer patients and had observed that they tended to live longer. As a result of their shared interest, Pauling and Cameron decided to collaborate on a series of papers investigating the potential clinical import of large doses of vitamin C.

As they delved deeper into this work, Pauling became convinced of the need to carry out more rigorous trials. Lacking the funds to do so, he instead turned to the National Institutes of Health. Fatefully for Pauling, Charles Moertel (1927-1994), an oncologist at the Mayo Clinic who was eager to debunk the effectiveness of vitamin C, agreed to lead the NIH investigation. Specifically, Moertel carried out a double-blind placebo-controlled trial in which ten grams of vitamin C were administered orally, and he found no benefit. (He was not aware that Cameron had been injecting vitamin C intravenously.) Moertel published his results in the New England Journal of Medicine and the press picked it up. Once the negative conclusion had been widely circulated, subsequent mainstream interest in the medical application of vitamin C suffered a near fatal blow.


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Mark Levine

Research on intravenous vitamin C began to re-emerge during the 1990s, led in part by NIH scientist Mark Levine. Levine’s nutrition experiments were novel, and did not emerge from the types of medical training that he could have been expected to received. For context, Drisko described her own education, wherein courses on nutrition were optional and held on Saturday mornings. She attended them because she was interested, but she also went along with the convention of the time; one emphasizing that nutrition was of lesser importance relative to other aspects of medical practice.

Levine, on the other hand, did not follow this line and decided to study vitamin C in depth. In the trials that he carried out at the National Institutes of Health, Levine tracked patients deprived of vitamin C and showed that they had indeed become vitamin C deficient. He followed this by administering oral doses of vitamin C, which demonstrated repletion. At the end of his trial, Levine also administered one gram of vitamin C intravenously. He was not allowed to administer a higher dose to his subjects, due to fears of toxicity, but it was his guess that ten gram doses would yield peak blood levels of vitamin C.

Ultimately, Levine demonstrated that oral vitamin C was not capable of yielding maximal vitamin C blood levels, because the body does not absorb oral doses well and excretes it very quickly. Intravenous administration, on the other hand, bypassed these metabolic processes, leading to higher blood levels. With Levine’s work in mind, Drisko summarized the difference between Cameron’s research and Moertel’s Mayo Clinic trial: “Cameron gave a drug and the Mayo Clinic gave a vitamin.”


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Hugh Riordan

Drisko’s mentor, Hugh Riordan (1932-2005), was another individual responsible for keeping vitamin C research alive. The founder of what is now known as the Riordan Clinic in Wichita, Kansas, Riordan belonged to a group of orthomolecular physicians who saw vitamins as providing restoration of a healthy baseline in all humans.

After Levine published his paper on vitamin C absorption, Riordan went to visit him in Maryland to convince him to continue following this path of inquiry. The two ultimately collaborated on several case studies and welcomed others into their fold, a progression that helped incubate today’s group of researchers investigating the use of intravenous vitamin C.

As of 2016, the intravenous vitamin C group included Qi Chen, who works on basic research at the University of Kansas with Drisko; John Hoffer at McGill University, who explores the effects of high doses of vitamin C on cancer; Garry Buettner and Joseph Cullen at the University of Iowa, who looks at the redox capacity of vitamin C in patients undergoing radiation therapy; and Ramesh Natarajan at Virginia Commonwealth University, who is researching the use of vitamin C in the treatment of sepsis.

Drisko noted that there are differences in the lines of research followed within the current group. On the one hand, her cancer trials use megadoses of vitamin C at 75 to 100 grams. Natarajan, on the other hand, only uses 4 or 5 grams in the ICU for sepsis.  For Drisko, these differences emphasize that there is still a lot of research to be done to understand exactly what is going on.


At present, attitudes toward vitamin C within the medical community can be mostly lumped into two categories. One is comprised of “early adopters,” as Drisko defines herself, who continue to carry out research to refine vitamin C treatments. The other consists of those who adhere more closely to the conclusions of the Moertel study, and who thus believe that claims supporting the effectiveness of vitamin C have been disproven. The distance between these two groups was characterized by Drisko as a “gulf of disapproval.”

However, current trends suggest that the gulf is being bridged. While some state medical boards still restrict the therapeutic use of vitamin C, Drisko and others have succeeded in garnering increasing levels of support from both colleagues and institutions. Shifts in funding opportunities are also beginning to emerge: though Drisko was unable to secure federal dollars for her work on ovarian cancer, the Gateway for Cancer Research non-profit stepped in to provide crucial support. With evidence of the efficacy of the treatment building from a growing number of trials, the possibility of obtaining federal grants is becoming more realistic. Likewise, drug companies are now looking at ways to patent vitamin C therapy, and some vitamin C treatment patients have succeeded in receiving reimbursement from their insurance companies.

Next week, we will provide an overview of the science underlying this renewal in optimism about the potential to fight disease with intravenous ascorbic acid.

Normal Expression of Human Beta-Actin (Cloned at LPISM) Acts as a Tumor Suppressor – A Novel Hypothesis

[Guest post written by John Leavitt, Ph.D., retired Senior Scientist at LPISM in Palo Alto CA from 1981 to 1988; living in Woodstock CT.]

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In 1980, Klaus Weber at the Max-Planck Institute and I published the amino acid sequence of human beta- and gamma-cytoplasmic actins. In 1981, after we completed this work, Klaus asked me “What are you going to do next?” I told him that I was moving to the Linus Pauling Institute of Science and Medicine in Palo Alto, California, and that I was going to clone the human beta-actin gene. My reason was that I had discovered a mutation in beta-actin that was associated with a tumorigenic human fibrosarcoma cell line. I wanted to test the hypothesis that this mutation contributed to the tumorigenic potential of this fibrosarcoma.

In 1984, I published the cloning of multiple copies of both the normal (wildtype) human beta-actin gene and multiple copies of the mutant gene. These actins are the most abundant proteins of all replicating mammalian cells and most other cells, down to yeast. (My story of meeting Dr. Pauling, moving from the National Institutes of Health to the LPISM, and our work on the role of this actin mutation in tumorigenesis in our model system was recounted in an article posted at the Pauling Blog in 2014.) In 2013, Schoenenberger et al. at the Biozentrum in Basel, Switzerland, reproduced all of our findings in a different cell system, a rat fibroblast model system, and extended our findings (see our review of their work).

A year ago, in June 2015, Dugina et al published a paper that proposed that altering the ratio of these two actins regulated either suppression or promotion of cancerous cell growth (more work needs to be done). I was very surprised by this idea – even though our work at LPISM had suggested this, I hadn’t thought of putting our observations into the language of “tumor suppression” and “tumor promotion.” Perhaps this was because, in the 1980s, hundreds of so-called “oncogenes” (tumor promoters) and tumor suppressor genes were being cataloged, and our findings were suggesting that a so-called “housekeeping” gene could do the same.

Indeed, Dugina and colleagues even stated this, somewhat simplistically, at the beginning of their Discussion section if their paper:

Until recently non-muscle cytoplasmic β- and γ-actins were considered only to play structural roles in cellular architecture and motility. They (the two isoforms) were viewed as products of housekeeping genes and β-actin was commonly used as internal control in various biochemical experiments.

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It didn’t go unnoticed by me that this paper failed to cite any of our papers, which had produced fundamental knowledge about human cytoplasmic actins. For example, instead of citing our 1980 paper on the amino acid sequences of human cytoplasmic beta- and gamma-actins, the Russian authors cited a paper on the sequences of bovine actins. Furthermore, these authors were apparently unaware of our discovery of actin mutations leading to tumorigenesis and several examples of null alleles of human beta-actin genes associated with tumors.

I communicated by email with the senior author of this paper, Pavel Kopnin at the Blokhin Russian Cancer Research Center in Moscow, not to complain about these omissions, but to tell him that I liked his hypothesis and to explain why. He thanked me and opined that he had had trouble persuading reviewers to publish the paper. I told him that our findings supported his hypothesis and would have made his argument stronger. He apologized for not citing our work and said that he had not reviewed the literature that far back, which amounted to twenty-eight years since our last paper from LPISM was published in 1987 (this made me feel old).

As early as March 1980, I had suggested in writing that altering the ratio of beta- and gamma-actins might contribute to the causation of cancer. This paper was published in the major journal, Journal of Biological Chemistry (see the figure below, last sentence of the abstract). If Dugina et al. were to consider filing a patent on this idea as an invention, our paper would have to, at least, be considered as invalidating prior art along with the rest of our work at LPISM up to 1987.

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Both our work at LPISM and Schoenenberger’s work in Basel indicate that the mutation in one of two alleles of the beta-actin gene produces a stable, but defective, form of beta-actin. If Dugina’s hypothesis is correct, it is tempting to suggest that the function of the mutation site in beta-actin controls suppression of tumor formation. I recommended to Pavel Kopnin that his lab pursue this and it is my impression that his lab will continue to work on this hypothesis.

In our model system, we isolated a derivative cell line from the original mutated human fibrosarcoma cell line that exhibited even faster tumor formation (Leavitt et al, 1982). In this second cell line, the mutant beta-actin gene had acquired two additional mutations that made the mutant beta-actin labile with a fast turnover rate in the cell (Lin et al, 1985). As the result of this change, the ratio of stable beta- to gamma-actin changed from approximately 2:1 to approximately 1:1. Furthermore, we found that the two remaining stable forms of beta- and gamma-actin up-regulated in synthesis to maintain a constant normal amount of actin in the cell.

In addition, when we transferred additional mutant human beta-actin genes into immortalized but non-tumorigenic human fibrosarcoma cells, we found that both beta- and gamma-actin from the endogenous normal genes were down-regulated to maintain a constant stable amount of actin in the cell. Thus, we found and reported that beta- and gamma-actin levels in living cells auto-regulated the activities of their own endogenous genes to maintain a constant level of actin in the cell along with a constant ratio of these actins as well (Leavitt et al, 1987a; and Leavitt et al, 1987b). This finding was later confirmed by other laboratories.

These final observations lend support to the idea that maintaining a normal ratio of fully functional cytoplasmic beta- and gamma-actins may be required for the maintenance of the normal, non-neoplastic cellular phenotype. By contrast, mutations and deletions that alter the ratio of functional cytoplasmic beta-actin to gamma actin could lead to tumorigenesis. Hopefully, Pavel Kopnin and others who are aware of our work at LPISM will explore further the role of cytoplasmic actins in maintenance of the normal, non-neoplastic state.

L-Plastin is One of 70 Signature Genes Used to Predict Prognosis of Breast Cancer Metastasis

[Guest post written by John Leavitt, Ph.D., retired Senior Scientist at LPISM in Palo Alto CA from 1981 to 1988; living in Woodstock, CT.  Leavitt has contributed several posts to the Pauling Blog in the past, all of which are collected here.]

John

John Leavitt

On August 24, 2016, the New York Times summarized the results of a Phase 3 clinical study of 6693 women with breast cancer. The outcome of this extensive clinical study was published in the New England Journal of Medicine on August 25, 2016. The clinical trial had been initiated ten years earlier on December 11, 2006 in Europe, (2005-002625-31) and on February 8, 2007 in the United States (NCT00433589). The study examined seventy select genes (seventy breast cancer “signature genes”) out of approximately 25,000 genes in the human genome that, when assayed *together* using a high density DNA microarray, predict the need for early chemotherapy.

In other words, the study asked which of the 6,693 tumors were “high risk” and likely to metastasize to distant sites within a five-year period, and which of these tumors were “low risk” and likely not to metastasize to distant sites in five years. One stated purpose of the study was to determine the need for chemotherapy, which can be very toxic and cause unnecessary harm to the patient, in treating breast cancer. The study found that a certain pattern of elevated or diminished expression of the seventy signature genes can predict a favorable non-metastatic outcome without chemotherapy for five years (while undergoing other forms of therapy such as surgery and irradiation).

One of the seventy selected genes is L-plastin (gene symbol “LCP1” and identified by the blue arrow in the figure below).

List of 70 signature genes

In 1985, my colleagues and I identified this protein in a cancer model system and named it “plastin” (Goldstein et al., 1985). We cloned the gene for human plastin while at the Linus Pauling Institute of Science and Medicine in 1987, and discovered that there were two distinct isoforms encoded by separate genes, L- and T-plastin (Lin et al, 1988). In 2014, in a piece published on the Pauling Blog, I described in some detail the discovery of L-plastin and its subsequent cloning.

A second figure, which is included below, summarizes information about L-plastin in a gene card published by the National Center for Biotechnology Information. This card shows that “LCP1: is the gene symbol for L-plastin and also identifies alternative names for L-plastin. Except for the inappropriate expression of L-plastin in tumor cells, this gene is only constitutively active in white blood cells (hematopoietic cells of the circulatory system). We used very sensitive techniques to try and detect L-plastin in non-blood cells such as fibroblasts, epithelial cells, melanocytes, and endothelial cells, but could not detect its presence in these normal non-hematopoietic cells of solid tissues.

Plastin Gene Card

The L-plastin gene card.

The clinical study reported on in the New York Times and New England Journal of Medicine shows that if L-plastin is not elevated in synthesis and modulated in combination with other signature genes, there should be little or no metastasis in five years. However, if L-plastin, in combination with other signature genes, is elevated in the early stage tumor, then the tumor is a high risk for metastasis and should be treated with chemotherapy.

plastin gels

The above figure consists of a pair of two-dimensional protein profiles that show the difference in expression of L-plastin and its phosphorylated form (upward arrows) between a human fibrosarcoma (left panel) and a normal human fibroblast (right panel).

My colleagues and I also found that L-plastin elevation is likewise a good marker for other female reproductive tumors like ovarian carcinoma, uterine lieomyosarcoma and choriocarcinoma (uterine/placental tumor), as well as fibrosarcomas, melanomas, and colon carcinomas. Abundant induction of L-plastin synthesis was likewise observed following in vitro neoplastic transformation of normal human fibroblasts by the oncogenic simian virus, SV40 (see Table IV in Lin et al, 1993).

The abundant synthesis of L-plastin that we found normally in white blood cells (lymphocytes, macrophages, neutrophils, etc.) suggested to me that the presence of L-plastin in epithelial tumor cells like breast cancer cells contributes to the spread of these tumor cells through the circulatory system to allow metastasis at distant sites. Indeed, both plastin isoforms have now been linked to the spread of tumors by metastasis, an understanding that is summarized in another Pauling Blog article from 2014 and, more recently, in other studies.

The End of Pauling’s Life

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Linus Pauling giving an interview at Deer Flat Ranch, September 1993.

[Part 3 of 4]

After a sigmoidoscopy in 1993 revealed that Linus Pauling’s rectal tumor was still growing, the reality set in that he was not likely to survive his cancer. It was at this point that Pauling began to seriously consider which of his possessions should be turned over to family and which should be transferred to his archival collection at Oregon State University.

The same year, it was decided that it would be a good idea to arrange a special symposium, sponsored by Caltech and the Linus Pauling Institute of Science and Medicine, on or near his 93rd birthday. Speakers would consist of former graduate students and postdocs. Pauling had once imagined that an event of this sort would be appropriate for his 100th year, a birthday that he had fully intended to achieve.

Throughout 1993, Pauling strived to be as active as possible, giving interviews in person or over the telephone, and entertaining many visitors at Deer Flat Ranch. At the end of May, Pauling and a collection of friends, family, and co-workers also gathered to celebrate the Linus Pauling Institute of Science and Medicine’s 20th anniversary.

However, as time moved forward and his illness worsened, Pauling attended to his scientific writing and correspondence at a decreasing rate. On two occasions, he returned to Palo Alto to attend scientific meetings, giving a short talk at one, and the last scientific paper that he authored himself was written in November-December of 1993. Much of his time was taken up with scheduled visits to his doctors in San Luis Obispo and Cambria, or simply resting at Deer Flat Ranch, his sanctuary on the Pacific Ocean.


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Pauling delivering his last lecture at the International Symposium on Biological NMR, Stanford University, March 25, 1994.

In January 1994, Pauling’s physicians decided that steps needed to be taken to shrink his tumor, and Pauling relented to a course of chemotherapy, during which he attributed his lack of negative side effects to his taking routine megadoses of vitamin C. When Pauling learned that the cancer had spread to his liver, however, his hope to live to be one-hundred years old were lost. He stopped taking vitamin C completely, and gave up writing in his research notebook – a brief note about his work on nuclear structure appears in January and the pages after it are blank.

During the last months of his life, Pauling met with friends and family, while also attending to some less pleasant business. LPISM administrator Steve Lawson and Linus Pauling, Jr. journeyed to Deer Flat Ranch during this time to mediate ongoing litigation between the Institute and Matthias Rath, who had initiated a lawsuit against his former employer. Even at the deposition, which was given from his bed, Pauling welcomed Rath warmly.

Pauling’s final public appearance came on June 19, 1994, at the conference that he had requested be organized a year earlier, and which his son Crellin had arranged. This event, which was ultimately hosted by The Pacific Division of the American Association for the Advancement of Science, was titled “A Tribute for Linus Pauling” and was held at San Francisco State University. Pauling’s ranch hand Steve Rawlings attended as Pauling’s nurse, bringing him into the assembly in a wheelchair. Upon entering however, Pauling stood and insisted on walking into the room, receiving applause from the gathering as he made his way to his chair. An array of speakers including Harden McConnell, Alexander Rich, Frank Catchpool, Richard Kunin, and Crellin Pauling delivered moving talks detailing Pauling’s major contributions to science, human health, and world peace.


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A final family photo session, on Pauling’s 93rd birthday. Seated to Pauling’s left is his sister, Pauline, who lived to the age of 101.

Pauling’s daughter Linda was at Deer Flat Ranch with her husband and children on August 18, 1994, when Pauling suffered a stroke that left him comatose. Pauling’s sons Crellin and Linus Jr. arrived the next day and were both at the ranch with him on the evening that he died. His passing came at the end of a beautiful summer day, as the sun was just beginning to set over the Pacific. At the end of his life, Pauling wore on his wrist an opal bracelet that he had once given to his late wife, Ava Helen, as a gift.

In Palo Alto, Steve Lawson had just sat down for dinner when he received a call from Linus Pauling Jr., informing him of the sad news. Immediately, Lawson got in his car and went back to the Institute, faxing pre-written obituaries to the media. Copies went to CBS, the New York Times, NBC, CNN, the San Francisco Chronicle, the San Jose Mercury-News, and half a dozen more outlets. But by the time that Lawson had faxed the third news organization, the phone started ringing. He later recalled

In those days, we had an old fashioned phone system where you could see a number of little pegs that would light up for an incoming line, and I think there were as many as six incoming lines. Before long every light was lit and blinking: it was the New York Times, it was CBS, it was everybody under the sun that wanted statements.

Pauling’s passing was reported the next day through packages of stories in the New York Times and the Los Angeles Times that were immediately picked up by news services and syndicated around the globe. The Pasadena Star-News ran its own article a few days later, as did the Medical Tribune and the scientific journal Nature. Personal letters flooded in to the Pauling children and the Institute from every corner of the globe: France, the United Kingdom, Russia, Japan, Italy, Australia, South America, the Philippines, and all across the United States. Universities and organizations worldwide, including Caltech and the American Association for the Advancement of Science, all sent heartfelt letters conveying their sadness at the loss of a great man.


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In the months and years that followed, Pauling’s life was honored around the world in a wide variety of ways. The Alpha Chi Sigma chemistry fraternity, which is based in Indianapolis, dedicated the Library Room of its house to Pauling. A fossil leaf from an extinct species of citrus tree was also named after him: Linusia paulinga. 

Later on in 1994, shortly after Pauling’s death, Steve Lawson started receiving unmarked packages in the mail, containing nearly exact replicas of Pauling’s Nobel Prizes. A week or two after they had arrived, Pauling’s son Peter, then living in Wales, called and cryptically asked if Lawson had received anything “unusual” in the mail. As it turned out, Peter had gone to the Nobel Academies and had duplicate medals struck in an alloy for family members and for the Institute to hold as keepsakes.

Later still, with the help of Pauling’s daughter Linda and officials at Oregon State University, Lawson and others planned a Linus Pauling Exhibition, which was sponsored by the Japan-based peace organization, Soka Gakkai International. Intended as a mechanism to educate the public about Pauling’s work and to introduce school children to Pauling as a role model, the exhibit focused on all facets of Pauling’s career as a humanitarian, as an activist, as a scientist, and as a medical researcher. Over the course of several years, millions of people visited the exhibit in Europe, Japan, and many locations in the United States, including Washington D.C., San Francisco, and Boston. The exhibit was created by a team of designers who, when it had finished touring, donated all of its elements and infrastructure to Oregon State University.