Ascorbic Acid and Cancer: A Review

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.

---

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.

---

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

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.

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.

---

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

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.

---

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.

---

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.”

---

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.]

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.

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.

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 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).

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.

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.

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

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.

---

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.

---

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.

---

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.

Pauling’s Cancer

Medical Tribune, September 10, 1992.

[An examination of the final years of Linus Pauling’s life. Part 2 of 4.]

In February 1992, Linus Pauling announced publicly that he had cancer. His critics responded with sentiments that were, at times, distinctly unsympathetic. In their view, since Pauling had been advocating vitamin C as a preventative treatment for cancer for years, his diagnosis undermined those decades of work. Pauling retorted that most elderly men develop hyperplasia or cancer in their prostates, often by age 70. Pauling believed it was quite likely, although not provable, that his high intake of vitamin C delayed the inevitable by decades.

As Pauling continued to struggle with the limitations that his illness placed upon him, his new caretaker, ranch-hand Steve Rawlings, became an important part of his life. Rawlings did a lot of the day-to-day work of providing for Pauling while he was ill, a time period during which Pauling increasingly sought out the solace and solitude of his isolated home on the Pacific Coast. Linus Pauling Institute of Science and Medicine (LPISM) administrator Steve Lawson would later reflect on the importance of Pauling’s Big Sur residence at Deer Flat Ranch during the last few years of his life. In a 2011 interview, Lawson explained,

When he was in Palo Alto, Pauling’s time was sought by many people for many different reasons: old friends, colleagues, the public, the media. When he retreated to Deer Flat Ranch, he removed himself from that. I think he really loved that time alone down there. I know that he liked to watch some programs on T.V., some serialized programs. He read quite a lot. He loved to read mystery books. He was a rare individual in that there was really no division between what he did recreationally and what he did professionally. He was a scientist through and through, and derived pleasure from working on scientific problems. Often times if you go into someone’s bathroom, you’ll find a Prevention magazine, a Reader’s Digest, or Entertainment Weekly, or Time, or the newspaper. Pauling’s bathroom was stacked with scientific journals. He wasn’t physically vigorous [by the early 1990s], but he certainly didn’t seem fatigued.

With his time becoming increasingly precious, Pauling’s coworkers, friends, and family all felt that he should do what he most wanted to do with his days, and this had always been to focus on science. Freed from the responsibility of running the LPISM’s day-to-day operations, Pauling continued to work at Deer Flat Ranch in spite of his worsening health problems.

Of particular interest was the fact that, stricken with cancer himself, Pauling’s scientific fascination with the disease only intensified. Rather than remove himself from ongoing cancer research as his disease advanced, he instead committed even more fully to this cause in his final years. In particular, Pauling became increasingly interested in non-toxic methods of cancer therapy; methods, in other words, that were far less stressful on the body than are radiation or standard chemotherapy regimens.

In a paper co-authored with Drs. David Knight and Abram Hoffer, he worked to determine survival rates among over 2,000 cancer patients receiving high doses of vitamin C and other nutrients. He even flew to Tulsa, Oklahoma in October 1992 for a conference on alternative treatments of cancer. He likewise continued to work to convince American physicians of the value of vitamin C and lysine in preventing and treating heart disease, a notion that was gradually beginning to gain small slivers of recognition in the medical community.

---

Privately, Pauling was waging a personal war on his disease, exploring avenues of immunotherapeutic treatment that were unorthodox in the medicine of the time but which have, in recent years, begun to show great promise.

In a letter to medical writer and cancer consultant Ralph Moss, Pauling detailed a therapy involving autologous anticancer antigen preparation, or AAAP, of which he was somewhat skeptical but nonetheless interested in pursuing further. Working with friends and colleagues at Stanford Medical School to raise monoclonal antibodies against his prostate cancer cells, Pauling ultimately conducted what amounted to exploratory and self-experimental science to discern the potential value of AAAP.

Pauling’s first exposure to the idea of AAAP came from the work of Duncan McCollester, a medical doctor based in Irvington, New York, who advocated for a form of “Active Specific Immunotherapy.” This treatment involved the use of a manganese phosphate gel that was mixed with isolated portions of tumor tissue in which tumor antigens had been converted to a form capable of stimulating a cancer-destroying immune response in the patient upon re-administration on the forearm or thigh. McCollester dedicated a book on the subject to Pauling, even as he was struggling to receive FDA approval for the treatment.

David Stipp, a reporter for the Wall Street Journal, reported in August 1992 that a similar medical treatment had been developed by Cellcor, Inc. of Newton, Massachussetts. Cellcor offered customers a treatment for kidney cancer in which a patient’s own white blood cells were extracted, treated in such a way as to make them attack tumor cells, and then reintroduced into the patient’s cells. Known as autolymphocyte therapy, or ALT, the treatment had been available commercially in Atlanta, Boston, and Orange County, California since around 1990. However, at the time, medical officials disputed the efficacy of Cellcor’s anti-cancer therapy, arguing that not enough data had been collected to substantiate the company’s claims.

---

By July 1992, Pauling had decided to move forward with AAAP treatment, the ultimate goal being a vaccine that would combat his own illness while also providing useful data for the science of the future. Subsequently, a 1 gram section of cancerous tumor tissue that had been surgically removed from Pauling’s body was shipped to McCollester’s lab in New York. Upon entering the operation, Pauling’s surgeon had advised him that his entire tumor should be removed, rather than a small section. Pauling refused this request, arguing that a full resection would prevent him and others from observing the effectiveness of the AAAP treatment. In other words, rather than focusing on the fact that his own life was on the line, Pauling was still operating, first and foremost, in the mode of the scientist: he was running an experiment in which he himself was a test subject, and the stakes could not have been higher. In Pauling’s mind there were plenty of reasons for optimism.

---

Pauling notes his first AAAP injection on October 23, 1992.

By October, scientists at Stanford University, led by Dr. Ronald Levy, had successfully boosted the immune systems of a small group of B-cell lymphoma patients using a vaccine that had been genetically engineered from the patients’ own tumor tissues. In two of these nine patients, tumors vanished completely.

In generating the vaccines for each individual patient, the Stanford scientists created clones of the cancerous B-cells from each subject, and then separated out specific proteins – known as receptors – from the outer coatings of the B-cells. Using genetic engineering techniques, the scientists then added other proteins that boosted the immune system and created a synthetic version of the engineered receptors. The result was a tailor-made vaccine created from the B-cell receptors that used each patient’s immune system to attack cancer cells.

Pauling’s confidence in his anti-cancer antigen treatment was likewise elevated by other immunotherapy techniques then being developed by a team at the National Cancer Institute, as headed by Dr. Steven Rosenberg, Dr. French Anderson, and Dr. Michael Blaese. However, these studies were all specific to skin cancer, and were carried out on patients already in remission and receiving chemotherapy, or on patients with very small tumors. Pauling, by contrast, was already afflicted with advanced prostate cancer by the time that his condition was discovered, and he had not yet accepted any form of radiation therapy.

From October 1992 on, Pauling almost exclusively used the AAAP vaccine and vitamin C to treat his cancer. The vaccine traveled from McCollester’s lab in New York to a willing physician in California who had agreed to administer Pauling with the suggested injections- anywhere from 0.2 to 0.65 ml of vaccine a few times monthly. Pauling continued to receive these injections, which routinely caused tenderness and swelling, until January 1994, about seven months before he died.

Pauling’s Final Years

Pauling posing at lower campus, Oregon Agricultural College, ca. 1917.

[An examination of the end of Linus Pauling’s life, part 1 of 4]

In 1917, at sixteen years of age, Linus Pauling wrote in his personal diary that he was beginning a personal history. “My children and grandchildren will without doubt hear of the events in my life with the same relish with which I read the scattered fragments written by my granddad,” he considered.

By the time of his death, some seventy-seven years later, Pauling had more than fulfilled this prophecy. After an extraordinarily full life filled with political activism, scientific research, and persistent controversy, Pauling’s achievements were remembered not only by his children, grandchildren and many friends, but also by an untold legion of people whom Pauling himself never met.

Passing away on August 19^th 1994 at the age of 93, Pauling’s name joined those of his wife and other family members at the Oswego Pioneer Cemetery in Oregon. What follows is an account of the final three years of his life.

---

 

Linus Pauling, 1991.

In 1991, Pauling first learned of the cancer that would ultimately take his life. Having experiencing bouts of chronic intestinal pain, Pauling underwent a series of tests at Stanford Hospital that December. The diagnosis that he received was grim: he had cancer of the prostate, and the disease had spread to his rectum.

Between 1991 and 1992, Pauling underwent a series of surgeries, including the excision of a tumor by resection, a bilateral orchiectomy, and subsequent hormone treatments using a nonsteroidal antiandrogen called flutamide. During this time, Pauling also self-treated his illness with megadoses of vitamin C, a protocol that he favored not only for its perceived orthomolecular benefits, but also as a more humane form of treatment than chemotherapy or radiation therapy.

Pauling’s interest in nutrition dated to at least the early 1940s, when he had faced another life-threatening disease, this time a kidney affliction called glomerulonephritis. Absent the aid of contemporary treatments like renal dialysis – which was first put into use in 1943 – Pauling’s survival hinged upon a rigid diet prescribed by Stanford Medical School nephrologist, Dr. Thomas Addis.  At the time a radical approach to the treatment of this disease, Addis’ prescription that Pauling minimize stress on his kidneys by limiting his protein and salt intake, while also increasing the amount of water that he drank, saved Pauling’s life and led to his making a full recovery. Though his famous fascination with vitamin C would not emerge until a couple of decades later, Pauling’s nephritis scare instilled in him a belief that dietary control and optimal nutrition might effectively combat a myriad of diseases. This scientific mantra continued to guide Pauling’s self-treatment of his cancer until nearly the end of his life.

Pauling also believed that using vitamin C as a treatment would, as opposed to chemotherapy, allow him to die with dignity. Were his condition terminal and his outlook essentially hopeless, Pauling felt very strongly that he should be permitted to pass on without “unnecessary suffering.” Pauling’s wife, Ava Helen, had died of cancer in December 1981. She too had refused chemotherapy and other conventional approaches for much of her illness, a time period during which Linus Pauling had helped his wife the only way he knew how: by administering a treatment involving megadoses of vitamin C. This attempt ultimately failed and, by his own admission, Pauling never really recovered from his wife’s passing.

Nonetheless, Pauling continued to lead research efforts to substantiate the value of vitamin C as a preventive for cancer and heart disease in his capacity as chairman of the board of the Linus Pauling Institute of Science and Medicine (LPISM). By the time of his own diagnosis in 1991 however, the Institute was in a desperate financial situation, several hundred thousand dollars in debt and lacking the funds necessary to pay its staff.

---

 

In 1992, while he recovered from his surgeries and managed his illness, Pauling continued to act as chairman of the board of the LPISM. No longer able to live entirely on his own, he split his time between his son Crellin’s home in Portola Valley, California, and his beloved Deer Flat Ranch at Big Sur. When at the ranch, Pauling was cared for in an unofficial capacity by his scientific colleague, Matthias Rath. Pauling was first visited by Rath, a physician, in 1989, having met him years earlier in Germany while on a peace tour. Rath was also interested in vitamin C, and Pauling took him on as a researcher at the Institute. There, the duo collaborated on investigations concerning the influence of lipoproteins and vitamin C on cardiovascular disease.

Not long after Pauling’s cancer diagnosis, a professor at UCLA, Dr. James Enstrom, published epidemiological studies showing that 500 mg doses of vitamin C could extend life by protecting against heart disease and also various cancers. This caused a resurgence of interest in orthomolecular medicine, and it seemed that Pauling and Rath’s vision for the future of the Institute was looking brighter.

As it happened, this bit of good news proved to be too little and too late. LPISM had already begun to disintegrate financially, its staff cut by a third. The Institute’s vice president, Richard Hicks, resigned his position, and Rath, as Pauling’s protégé, was appointed in his place. Following this, the outgoing president of LPISM, Emile Zuckerlandl, was succeeded by Pauling’s eldest son, Linus Pauling Jr. Finally Pauling, his health in decline, announced his retirement as chairman of the board and was named research director, with Steve Lawson appointed as executive officer to assist in the day-to-day management of what remained of the Institute.

One day prior to his retirement as board chairman, Pauling signed a document in which he requested that Rath carry on his “life’s work.” Linus Pauling Jr. and Steve Lawson, however, had become concerned about Rath’s role at the Institute, and particularly on the issue of a patent agreement that Rath had neglected to sign. Adhering to the patent document was a requirement for every employee at the Institute, including Linus Pauling himself. When pressed on the issue, Rath opted to resign his position, and was succeeded as vice president by Stephen Maddox, a fundraiser at LPISM.

After this transition, Pauling met with Linus Jr. to discuss the Institute’s dire straits. Pauling’s youngest son, Crellin, had also became more active with the Institute as his father’s illness progressed, in part because he had been assigned the role of executor of Pauling’s will. Together, Crellin, Linus Jr., and Steve Lawson struggled to identify a path forward for LPISM. Eventually it was decided that associating the Institute with a university, and focusing its research on orthomolecular medicine as a lasting legacy to Pauling’s work, would be the most viable avenue for keeping the Institute alive. The decision to associate the organization with Oregon State University, Pauling’s undergraduate alma mater, had not been made by the time that Pauling passed away.

Vitamin C and Cancer: Rays of Hope

 

[Part 4 of 4]

Ridiculed by the medical profession for two decades, the tide began to shift for vitamin C and cancer starting in 1992. That year, the New York Academy of Sciences voted to discuss high-dose vitamins and nutrients at its annual meeting, devoting several sessions to the antioxidant properties of vitamin C and its potential value at higher-than-dietary amounts in preventing lung, stomach, colon, and rectal cancers.

Oddly, throughout the proceedings, one prominent name had been missing from the conversation, a point noted by a professor from Alabama who finally spoke up, saying,

For three days I have been listening to talks about the value of large intakes of vitamin C and other natural substances, and I have not heard a single mention of the name Linus Pauling. Has not the time come when we should admit that Linus Pauling was right all along?

---

Since 1996 the Linus Pauling Institute, relocated from California, has continued work on cancer from it’s new home at Oregon State University. Basing these contemporary orthomolecular studies on the hard sciences of cellular biology, molecular biology, and organic chemistry, the Institute continues to explore the cutting edge of health and nutrition research.

Working under Dr. Balz Frei, the current director of the Institute, as well as former LPI principal investigator Dr. Roderick Dashwood (now director of the Center for Epigenetics and Disease Prevention at Texas A&M University), OSU student Matt Kaiser has spent time analyzing the benefits of vitamin C treatment for colorectal cancer, which remains the third leading cause of cancer related deaths in the United States. The Pauling Blog has interviewed Kaiser in the past, and we met with him again recently to gain a better sense of trends in the community of researchers interested in vitamin C and cancer.

---

One primary question that begs further exploration is, why didn’t earlier studies find evidence of the value of vitamin C?

As it turns out, the problem appears to have been primarily located in the way that vitamin C was being administered. The 1979 Mayo studies to which Pauling so strongly objected had assumed that, since vitamin C was filtered out of the body after a certain point of blood saturation, higher doses need not be examined. This assumption – that excess vitamin C could not be absorbed and was simply excreted in the urine – was one of the most basic issues of contention that Pauling was never able to get past with the medical community. However, it now appears that the assumption applies only if vitamin C is taken as an oral supplement, a breakthrough that was first identified by Mark Levine, a Senior Investigator at the National Institutes of Health.

Matt Kaiser explains

Mark Levine realized in the 1990s that the way drugs are distributed and function in the body [pharmacokinetics] can drastically change the amount of vitamin C entering blood plasma. Eating vitamin C you can only get about 250 micromolar [a measure of vitamin C, or ascorbate— to use its chemical name— that can be concentrated in the blood stream]. With intravenous injection, the levels are much larger: 200 times. One millimole is a thousand micromoles, so 30 millimolar [of ascorbate in blood plasma] is a huge difference!

At these high pharmacological— or even super physiological— doses, Levine found that cancer cell populations dropped significantly. To understand why, it is important to know a bit about how cancer works.

Human DNA can wrap up tight (heterochromatin) or unwind into a loose, more open configuration (euchromatin). When it is wrapped up tight, the genetic information on the DNA cannot be expressed. This is because transcription, which is the process by which a cell reads and expresses the genetic code, requires access to DNA.

There are very specific times when DNA should be wrapped tight to maintain optimum health, and other times when one’s body needs to be able to use the instructions for cellular function that are contained in DNA. When DNA needs to be unwound, molecules called histone acetyltransferases (HATs) help to unwind it. When it needs to be wound up tight, the process is aided by histone deacetylases (HDACs).

HDAC overexpression is a hallmark of cancer cells, and hyperactive HDAC cells lead to messy, knotted DNA winding. This biological circumstance hinders the cell from reading important instructions found in DNA, which in turn prevents the production of important tumor suppressor proteins. At the same time, it leaves certain sections of the genetic code open that should not be expressed.

“Basically,” says Kaiser, “You remove the break from the car, and then you also step on the gas. And that’s cancer.”

---

Matthew Kaiser.

The prevailing theory of how vitamin C acts on tumors is that it functions as a “prodrug,” meaning that it stimulates biochemical processes that allow something else to kill the cancer cell, rather than acting on it directly. In this case, the active agent is hydrogen peroxide, which is produced in saturated tissues by excess vitamin C. “Vitamin C acts as the Trojan horse that allows hydrogen peroxide to enter the tumor site,” Kaiser explains. “You can’t inject it straight in; your body will react too strongly. Hydrogen peroxide is a reactive oxygen species…it tears cells apart.”

However, since working on the project, Kaiser has found that this consensus on how vitamin C fights cancer isn’t necessarily the whole story. Pharmacological levels of ascorbate appear to selectively reduce the presence of proteins that regulate reactive oxygen species, like hydrogen peroxide, in cancerous cells. Some of these same proteins also happen to promote cell growth, which is not something that one would wish for cancer cells to do. In addition to producing hydrogen peroxide, ascorbate actually inhibits the runaway HDAC production that makes cancer cells so dangerous.

“What makes it really hard, really complicated,” Kaiser laments, “is that this might not work the same way for different types of cancer cells in different locations. There’s still so much to understand about how vitamin C is having this protective effect…That’s what’s lacking and that’s why we need studies like this.”

---

And indeed, more studies are coming. In keeping with it’s mission to extend and promote what it calls “healthspan,” LPI hosts a bi-annual Diet and Optimum Health Conference, bringing together experts from around the world to talk about topics in orthomolecular medicine, among other fields. This year the conference, which was held at OSU in September, featured several speakers discussing vitamin C and cancer. One of them was Dr. Mark Levine, the NIH scientist who first showed the value of intravenous ascorbate.

Margreet Vissers and Anita Carr, of the University of Otago in New Zealand, also described their own advances on the subject. Vissers found in her studies that levels of 50 micromolar ascorbate in blood plasma (average dietary levels are between 40 and 80) had little to no protective effect against cancer. Doubling the amount to 100 micromolar, however, boosted a patient to the lowest level of the protective range. It would seem, then, that Pauling was right to suggest that mega doses might be important for optimum health.

Vissers also explained that, in animal models, ascorbate injected intravenously will peak after about twenty hours in both healthy tissue and in tumors. However, unlike the healthy tissue, tumor tissues hold onto the vitamin C and do not return to a natural baseline. This detail is important because it allows high doses of ascorbate to build up in tumor tissue, and these doses disproportionately kill cancer cells instead of healthy tissues for reasons that are still not fully understood.

Conversely, the dangers of using vitamin C, even in high intravenous doses, appear to be small. While some people harbor an enzymatic deficiency that can cause a severe negative reaction, most individuals simply cannot overdose on vitamin C. Even in the blood plasma, vitamin C usually reaches a saturation point and is filtered from the body.

At the LPI conference, Dr. Carr pointed out that this form of treatment also dramatically improves the quality of life of cancer patients as compared to chemotherapy. For one, vitamin C treatments involve significantly less pain, mental and physical fatigue, nausea and insomnia. As of March 2015, three clinical trials involving pharmacological levels of ascorbate have been conducted, all of them showing that it is well tolerated by patients and reduces chemotherapy-related toxicity.

Additionally, vitamin C at high doses is known to aid cognitive function, and these positive benefits work together to aid in social satisfaction for the patient. As Pauling pointed out in the 1970s, it is not only the disease that the doctor should be concerned about treating, but the patient as well.

---

Pauling in 1989 – an extraordinary life. Photo by Paolo M. Sutter.

So is Linus Pauling vindicated when it comes to vitamin C and cancer? The answer is complicated.

On the one hand, it would appear that vitamin C can serve as an important preventative and treatment for cancer. However, the method that Pauling advocated— taking large supplemental doses orally— is pretty clearly not an effective form of application. Rather, contemporary research indicates that the levels of ascorbate that are required to slow or stop tumor growth are far greater than that which can be achieved naturally by ingesting vitamin C; they can be accomplished only by intravenous injections of ascorbate. Furthermore, it is likely that this form of treatment will not replace, but instead will augment, existing protocols including chemotherapy.

But the broader trend is optimistic and, one might argue, validating. And with the Linus Pauling Institute and many others around the world continuing to investigate the potential for vitamin C and other nutrients to help people live longer and feel better, exciting new studies on optimum diet and effective treatments for diseases like cancer would appear to be on the near horizon.

Vitamin C and Cancer: Raising the Stakes

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

[Part 3 of 4]

By 1970, the year that Linus Pauling published Vitamin C and the Common Cold, the federal government’s “war on cancer” was soon to arrive. The National Cancer Act, passed in 1971, increased federal funding for treatment and prevention research, embracing cytotoxic treatment solutions like chemotherapy. That same year, Pauling began to push for investigations between nutrition and cancer, especially concerning vitamin C. Since the role of vitamin C in immune defense is arguably much less significant than Pauling supposed, the idea that intake of vitamin C should prevent or treat cancer seemed ludicrous to many physicians. Incredibly, evidence is now emerging that the opposite might be true.

In hindsight, there is a tendency for critics to see Pauling simply as a politically liberal proponent of alternative medicine; one who lashed out against a consumerist medical establishment that was firmly supported by conservative citizens, among others. However, proponents of alternative health and holism in the 1960s and 1970s prescribed to a broad range of political ideologies; Pauling was just one among many people who were searching for better preventative and alternative treatments.

In 1980, when Pauling was actively campaigning for a vitamin C treatment for cancer, Americans spent 13.1 billion dollars on cancer diagnosis and treatment. Five years later, a survey of over one-thousand individuals showed that a majority believed clinics using unorthodox cancer therapies should be permitted to operate in the U.S., and just over half said they would seek alternative treatment if seriously ill.

Pauling and his ideological positions are remembered now as having been central to the vitamin C “movement.” Perhaps this is because he was renowned in many arenas and easily attracted a great deal of media attention. Or perhaps, especially knowing his penchant for protesting against nuclear weapons testing and war, this was another issue on which Pauling was the most outspoken opponent of what he saw as a wrong to be made right.

---

Table from “Ascorbic acid and cancer: a review”, co-authored by Pauling and Cameron, 1979.

For Pauling, the continuing suffering of cancer victims was unnecessary, since a useful treatment was already cheap and readily available. He argued that,

The involvement of ascorbic acid (vitamin C) in the natural defense mechanisms is now known to be so great that we hope that a really significant control of cancer might be achieved by the proper use of ascorbic acid.

Of the studies that Pauling found so convincing, none were as crucial as those conducted at the Vale of Leven Hospital, near Glasgow, Scotland. There, Dr. Ewan Cameron found that mega doses of vitamin C (10 grams daily or more) seemed to slow and even reverse cancerous growth in some patients. He wrote to Pauling in 1971, who eagerly responded that this “attack” on cancer was the most promising application of vitamin C that he knew of.  Pauling, who had been studying the role of dietary vitamin C in issues of orthomolecular psychiatry such as schizophrenia, now shifted his focus to cancer.

Far from being the flaky alternative health guru that many came to see him as, Pauling’s work with vitamin C— like all his research on the subject of orthomolecular medicine (a field that he spearheaded)— was consistent with a biomedical model of molecular disease. Since Pauling saw this work as fitting within the framework of molecular biology, it was frequently unclear to him why the medical community resisted what was, to him, a straightforward and significant scientific endeavor.

Further complicating matters was the fact that Stanford University, Pauling’s academic home at the time, rejected his request for additional lab space to pursue cancer research. Now the target of regular media pummelings, Pauling’s ideas were becoming a potential source of bad press for the university. Refusing to take no for an answer, Pauling and his young lab assistant, Arthur Robinson, solicited private funding to continue their work on vitamin C outside of the university setting. Raising $50,000 in donations from wealthy supporters of vitamin therapies, the duo helped to found the Institute for Orthomolecular Medicine in 1973, subsequently renamed the Linus Pauling Institute of Science and Medicine (LPISM) one year later.

From 1973 to 1976, Pauling published co-authored articles with Cameron, who continued to study the effects of vitamin C on cancer from his base in Glasgow. And in 1975, Pauling and Robinson secured additional funds to begin their own animal testing. Two years later, the collaborators began reporting their results in the Institute’s newsletter.  In 1979 Cameron and Pauling likewise published an extensive review article in Cancer Research that cited previous studies corroborating their own conclusions. The duo published their book, Cancer and Vitamin C, that same year.

---

A sample of Pauling’s notes compiled in response to the Mayo Clinic trials, 1979.

Cameron and Pauling’s data seemed to show that vitamin C would be especially valuable for cancer patients. Whereas a daily intake of 10 g of vitamin C in a healthy individual would bring the vitamin C level in the blood to a saturation point that could not be exceeded by increasing or prolonging intake, cancer patients showed a different pattern. Known already to have abnormally low blood levels of vitamin C, the patients in fact achieved just over half the same level of vitamin C blood saturation found in healthy individuals subscribing to a daily intake of 10 grams. For those afflicted with cancer, it was seen as necessary to take 10 grams a day just to reach the normal level of vitamin C found in healthy individuals who did not take supplements at all.

To Pauling, this alone justified continued research on the matter. After persistently stating his case to Dr. Vincent De Vita, director of the National Cancer Institute, two rounds of trials were conducted through the Mayo Clinic to solve what the medical community perceived to be problems in Cameron’s studies. When the trials indeed failed to produce anything like Cameron’s results, funding effectively dried up for vitamin C research – a significant blow to LPISM’s functional well-being.

In response, Pauling and his supporters argued that the Mayo Clinic was missing the point. The Mayo trials had attempted to measure the effectiveness of vitamin C in a manner similar to drug treatments, because the advent of chemotherapy and antibiotics, and the biases of the pharmaceutical industry, had placed primary medical emphasis on the disease, and not on the patient. Pauling saw the results of the Mayo studies not as a definitive defeat, but as the triumph of a complex of interdependent federal and private organizations that held a vested interest in supporting the chemotherapy status quo.

---

Pauling had claimed that, with vitamin C, lifespan could be increased, tumors could regress, and even full recovery was possible. For many in the medical community, these were not only foolish assertions, they were dangerous as well.

Dr. Charles Moertel, chairman of the Department of Oncology at the Mayo Clinic, was particularly vocal in his rebuke, stating that

For such a message to be conveyed to desperate and dying people, with the endorsement of a Nobel laureate, the presumption must be that it is based on impeccable scientific methodology.

Moertel’s implication, of course, was that Pauling’s argument was instead based on unsound science and certainly lacked the scientific basis to challenge the use of chemotherapy.

Yet vitamin C retained a broad appeal because many saw the prevailing treatment, and its manifold side effects, as inhumane. John Cairn, head of the Mill Hill Laboratory of the British Imperial Cancer Research Fund, provided a voice to the other side the coin by calling out the survivorship data. To wit: in 1986, 200,000 patients were receiving chemotherapy and, by 1991, five year survival rates for colon cancer remained at just 53%. Cairn spoke for many in suggesting that, when it came to the prevailing course of treatment, “the benefit for most categories of patients has yet to be established.”

---

Ava Helen Pauling, June 1981.

For Pauling, the debate turned from the public to the personal when, at the height of his study of vitamin C, his wife Ava Helen was diagnosed with stomach cancer. Following Ewan Cameron’s advice, she took 10 grams of vitamin C daily, and did not receive chemotherapy.  Throughout her treatment, Linus clung to the belief that mega doses of vitamin C would work for Ava Helen, just as it had for Cameron’s success stories in Scotland.

“Daddy was convinced that he was going to save her,” remembered Linus and Ava Helen’s daughter, Linda. “And that was, I think, the only reason he was able to survive… He said to me after she died that until five days before, he thought he was going to be able to save her.”

Ava Helen Pauling passed away in December of 1981. And though he was badly shaken by his wife’s death, belief in the value of vitamin C in the fight against cancer did not fade from Pauling’s mind. Suffice it to say, the medical community remained whole-heartedly unconvinced.