Monday, January 21, 2013

Do Antioxidants Block Cancer Treatment?

     This blog is based on a suppositional paper written by Dr. James Watson, of DNA fame, and published in Open Biology. He argues that the presence of antioxidants in cancer cells blocks anticancer treatments. The only clinical evidence of which I am aware that supports his thesis is the study of Finnish male smokers which showed that those who took antioxidant supplements had a higher incidence of lung cancer, and there also are several studies of cancer cells in vitro that seem to demonstrate a similar effect of antioxidants.

     Dr. Watson's paper is long and highly technical, so I will summarize the key points here and try to interpret them for the reader who is not heavily involved in cancer research. I might just begin by remarking that no interventional diet study involving the addition of antioxidants to the daily diet (beta carotene, Vitamin E, selenium, Vitamin A, and Vitamin C) has been shown to prolong the human life span. I will also touch on the possible reason for the benefit of aspirin in cancer prevention and why tests are now being done to see if the diabetes drug metformin has anti-cancer properties.

     Most agents used to kill organ (non bone-marrow) cancers, including Xrays and chemotherapy, work by generating ROS, or reactive oxygen species (such as OH-) which block key steps in the cell cycle and thereby hasten apoptosis, or cell self-destruction. The presence of ROS also generates a hypoxic environment in the cell, which drives a conversion of the cell from an epithelial to a mesenchymal type. But at the same time, in self-protection, the presence of ROS causes the cell to generate antioxidants, which render the cell resistant if not immune to both ionizing radiation and chemotherapy. In addition, mesenchymal cells are more prone to travel and metastasize. So the presence of ROS is both an accelerator and a brake.

     The presence of the Myc gene  activator can drive cancer cells forward, as can the presence of inflammatory cytokines such as interleukin-6. It is therefore theorized than the cancer-preventing property of daily aspirin (most convincingly demonstrated in colon cancer) derives from its anti-inflammatory and cytokine suppressing effect. And it has been shown that the turning off of Myc drives cancer cells towards apoptosis.

     Now in mouse models of cancer, the anti-diabetic drug metformin preferentially killed mesenchymal stem cells, which cells are the most resistant to chemotherapy and the most prone to metastasize. The reason for this is probably its blocking of oxidative phosphorylation. There are currently a number of ongoing studies where metformin is being added to standard anticancer chemotherapies in humans to look for an enhanced killing effect.

     To summarize Dr. Watson's thesis, and again I refer the interested reader to his paper, anticancer chemotherapy and Xrays generate ROS. The presence of ROS has a two-fold effect: it drives the cancer cell  towards apoptosis, or cell death, and at the same time it induces antioxidants which render the cell resistant to further anticancer treatment as well as inducing a transformation to a mesenchymal stem cell. It is not known if the antioxidants themselves drive this change in addition to inducing resistance to treatment.

     Based on this theory, and the limited data to date, it would seem prudent to avoid adding antioxidants to your diet which in theory would increase the antioxidant levels in every cell in your body by diffusion. Remember the study of Vitamin E, touted as an oxidant, which showed (in two different studies) that an increase in the intake of Vitamin E increased the rate of cardiac events and heart attacks.





Thursday, January 3, 2013

BMI, Overweight, and Longevity

     A recent article in the Journal of the American Medical Association (JAMA, 2013;309: 71-82) created quite a stir when it concluded that adults who were overweight but not obese had a 6% lower all-cause mortality rate. Nutritionists rushed to say that this did not mean that you should gain weight, although if the study had shown the reverse I am sure they would have unanimously recommended weight loss. This was not the first study to reach this conclusion, so I thought I should review it here, along with examining exactly what the BMI purports to measure since all obesity labels were based on the BMI (Basal Metabolic Index) results.
     The BMI was first defined by Quetelet in the 1800's as a surrogate number for estimating the amount of body fat. It is defined as mass(kg)/height (m) x height, i.e. the mass divided by the square of one's height. Since your mass increases with your total body volume, it scales with the cube of your height, so it is immediately obvious that only dividing by the square of the height will overestimate the total body fat of taller individuals. Similarly, muscular athletes have very little total body fat, but since muscle has mass, the BMI will  overestimate their total body fat as well. It is trivial to note that since most elderly patients have some degree of osteoporosis and therefore lighter bones, the BMI will mistakenly classify some of them as underweight.
I should also mention here that in 1998 the U.S. lowered its cutoff for the lower limit of overweight from a BMI of 27.8 to 25.0, in accordance with the WHO standards, thereby immediately reclassifying millions of Americans as overweight who the day before the change had "normal" weight. In addition, doctors in the US do not agree on the healthy lower limit of the BMI  for adult women, and the WHO does not have the classification of "underweight". And the 0.5 to 1.0 inches in height that you lose with age increases your BMI without you actually gaining any weight.

     The consensus in the US is that a BMI of 18.5 to 25 is normal weight, 25 to 30 is overweight, and greater than 30 is obese. Using these definitions, there have already been two published studies, one of diabetic patients and one of patients with ASCVD, and both demonstrated that overweight patients had a lower death rate than both normal weight and obese patients. No one has an explanation for these results, nor have I even seen theories that attempt to explain them. The JAMA study looked at 97 studies of all-cause mortality, encompassing 270,000 deaths and over 2,800,000 subjects, so it is fairly comprehensive.
We are left with the paradox that being overweight by BMI standards statistically increases your risk for high blood pressure, diabetes, ASCVD, stroke and some cancers, yet overall it is protective of mortality.

     In a previous blog I listed the 11 countries in order of longevity. I will repeat the list here adding the mean BMI of each country. Except for Japan, #1 and with the lowest BMI, there is no clear pattern:
Japan---22, Switzerland---25, Australia---26, Italy 23.5, Israel---25, Iceland---26, Spain---24.5, France---23.5, Canada---25.5, Singapore---22, and New Zealand---26.6.

     So once again we are left with "a beautiful theory ruined by an ugly fact" to quote a Nobel scientist. Perhaps we should re-normalize the BMI values and re-define normal weight. Or perhaps we should have a separate classification of "healthy BMI" and "unhealthy BMI". Or, more likely, there is a confounding fact of which we are unaware which would explain the results, but so far there are no candidates. It does make me feel better with my BMI of 27 because at 6'2" I doubt that I could get down to 185 pounds, even if I wanted to. I think we underestimate the genetic effects on us of our parents' diseases, especially parents of the same sex.