The Vitamin Myth, Myth

An article by Paul Offit, MD, published in The Atlantic Monthly, July 19, 2013, reports the lack of evidence supporting the use of micronutrient supplements. Dr. Offit is a recognized infectious disease expert, co-developer of the rotavirus vaccine and a professor at the University of Pennsylvania. He is the author of 2013 book, “Do you Believe in Magic, the Sense and Nonsense of Alternative Medicine.”

The article begins by examining the illustrious career of Linus Pauling, PhD. Recipient of two Nobel prizes, Dr. Pauling’s contributions to science cannot be overstated as he is credited with originally describing the ionic bond and the discovery of the molecular basis of sickle cell disease. Later in his career, Dr. Pauling became interested in Vitamin C and its potential for chemo prevention and maintenance of cardiovascular health.

Unfortunately, the article deteriorates from an interesting discussion to a diatribe directed against micro-nutritional supplementation with Dr. Pauling’s focus on vitamin C as the principle point of departure. Where Dr. Offit may have missed his mark isn’t that he raises questions about micro-nutrition but that he selectively utilizes negative studies to support his position to the exclusion of any and all more favorable findings.

To examine but a few of the points: Vitamin C is a profoundly important micronutrient, which is likely deficient in many American’s diets. The USRDA measured in tens of milligrams may well underestimate the human body’s requirements, characterizing instead the minimum amount required to avoid scurvy, that age-old disease of English mariners successfully managed with the consumption of citrus fruit (ergo the moniker of limey). As mankind evolved we lost the capacity to synthesize vitamin C (lacking the enzyme L-gulano-gamma-lactone oxidase) and now must rely on ingestible sources. Thus, Dr. Pauling’s attention to this vital micronutrient served us well in forcing a reexamination of the biologically relevant daily requirements.

Although, Drs. Pauling and Cameron’s (a Scottish surgeon), and Dr. Moertel’s, subsequent American studies did not establish vitamin C as a therapeutic, the choice of oral vitamin C in this pharmacologic application should have been recognized as an inadequate delivery mechanism in light of the diminishing absorptive efficiency of the human gastrointestinal tract associated with high dose oral administration. To wit, the therapeutic application of vitamin C, it could be argued, ultimately requires other vehicles for administration. More to the point, however, was Dr. Pauling’s original examination of primate diets, which included vitamin C rich foods and not vitamin C tablets. Albert Szent-Gyorgi, the co-discoverer of ascorbic acid, long held that the bioflavonoids in Vitamin C rich fruits participated in critical antioxidant reactions.

Above and beyond Dr. Offit’s pillorying of Dr. Pauling, is his inclusion of several ill-conceived clinical-proofs-of-concept that failed to support vitamin supplementation for cancer prevention.  The CARET study, which provided cigarette smokers and patients with asbestos exposure, high doses of beta carotene (30 mg/day) and retinyl palmitate (25,000 IU/day) identified an increased incidence and death rate from of lung cancer. In retrospect, any biochemist should have known that carotenoids serve both as antioxidants and prooxidants depending upon ambient oxygen-free radical conditions. Placing high concentrations of beta carotene into the circulation of cigarette smokers and asbestos exposed individuals was tantamount to throwing gasoline on a fire.

Similarly, the prostate cancer prevention study, SELECT, chose alpha-tocopherol as its vitamin E supplement and went on to report a higher incidence of prostate cancer in the treatment arm. Once again, the choice of a comparatively inactive tocopherol (the alpha form) that, in high doses, diminishes the bioavailability of the more active gamma tocopherol and tocotrienols, reflected a poorly conceived design and an inadequate understanding of the underlying biochemistry.

Dr. Offit’s article adds heat, but little light to this discussion. We should remember that micro-nutritional supplementation is designed to replace those trace elements and chemical species that would normally be found in a human diet. We evolved from scavengers, hunters and gatherers whose diet varied by season and included dozens, even hundreds of foodstuffs that few Western civilizations consume today. It is the intention of intelligently constructed micro-nutritional supplements to replace these deficient nutrients.

There is ample evidence to support intelligent dietary supplementation and a growing body of evidence that suggests that many, if not most, modern human maladies reflect our diets and lifestyles. Epidemiology is a difficult field under the best of circumstances. It took Doll and Peto decades to prove that cigarette exposure caused cancer, a simple fact that today is accepted by every grade school child in America.

It was Mark Twain who quipped that “There are three kinds of lies: lies, damned lies and statistics.” Perhaps he should have considered including nutritional epidemiology as a fourth.

Functional Profiling Leads to Identification of Accurate Genomic Findings

The 2013 American Society of Clinical Oncology annual meeting, held May 31 – June 1, in Chicago, afforded the opportunity to report three studies.

Crizotinib (Xalkori)
Mechanism of Action

The first, “An examination of crizotinib activity in human tumor primary culture micro-spheroids isolated from patients with advanced non-small cell lung cancer,” reports our experience using the EVA-PCD platform to examine the drug crizotinib. This small molecule originally developed as an inhibitor of the oncogenic pathway MET, was later found to be highly active in a subset of cancer patients who carried a novel gene rearrangement for anaplastic lymphoma kinase (ALK). It was this observation that lead to the drug (sold under the name Xalkori) being approved for the treatment of advanced ALK positive lung cancer. The subsequent observation that this same drug inhibited yet another gene target known as ROS-1 found in a subset of lung cancer patients, has led to its use in this patient population.

Our exploration of crizotinib activity identified a series of patients who received the drug and responded dramatically. This included both ALK positive and ROS-1 positive patients. One patient however, appeared highly sensitive to the drug in our studies, but was found negative for the ALK gene rearrangement by genomic analysis. We repeated our functional analysis only to the find again, the same high degree of crizotinib sensitivity. I felt confident the patient should receive crizotinib, but at the time the drug was not yet commercially available and he didn’t qualify for the protocols, as he was ALK negative.

I scoured the country looking for a way to get the patient treated with crizotinib. From Sloan Kettering to UCLA, no one could help. And then, in collaboration with my abstract co-author Ignatius Ou from UC Irvine, we decided to repeat the ALK analysis. That proved to be a very good idea. For the patient was indeed positive for ALK gene rearrangement by second analysis and subsequently responded beautifully to a treatment for which he would not otherwise qualify. Once again, phenotype trumped genotype. (The complete story of this patient can be found in Chapter 19 of Outliving Cancer.)

A final patient in the series represented a particularly interesting application of functional analysis. The patient, a young woman with an extremely rare pediatric sarcoma, had failed to respond to multiple courses of intensive chemotherapy and her family was desperate. As she approached the end of her third year in high school, it looked unlikely that she would reach her senior year. A portion of her tumor was submitted for analysis. The results confirmed relative resistance to chemotherapeutics, many of which she had already received and failed, but showed exquisite sensitivity to crizotinib. Indeed, our inclusion of crizotinib in the analysis reflected our intense effort to identify any activity for this previously refractory patient.

We reported our findings to the pediatric oncologist and encouraged them to consider an ALK rearrangement analysis, despite this particular pathway not being on anyone’s radar prior to our study. The result – a positive gene rearrangement. This led to a successful petition to the drug company for the use of this agent for an off-label indication. The response was prompt and dramatic, and remains durable to this day, nearly a year later. Again, the phenotypic analysis guided us to the correct genomic finding.

Our other presentations at this year’s meetings will be reported in future blogs.