Course Authors
Robert M. Russell, M.D., and Joel Mason, M.D.
In the last three years, Dr. Russell has received grant/research support from BASF and Roche Vitamins. Dr. Russell has also served as a consultant for Whitehall Robbins-Quaker; Dr. Mason has received grant/research support from Mead-Johnson Nutritional and also served as a consultant for Mead-Johnson Nutritional.
Estimated course time: 1 hour(s).
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Upon completion of this Cyberounds®, you should be able to:
RMR
The B vitamin, folate, has certainly come a long way in the 50 years since it was first identified and synthesized in the 1940s. Initially, it was merely thought to serve a hemopoietic function, that is, it was a micronutrient which was necessary for adequate production of blood cells and blood elements. However, today it is being used to prevent certain birth defects and its efficiency in preventing particular cancers and cardiovascular diseases is being explored. In this Cyberounds® Nutrition conference, Joel and I will discuss the well-known and not-so-well-known virtues of this nutrient.
Background
Even in the decade after it was first identified, this hemopoietic function of folate was exploited for the development of the initial chemotherapeutic cancer agents. In 1949, Sidney Farber of Boston reported that a chemical compound that was nearly identical to folate (differing only by two atoms) was a potent antagonist of the vitamin and, thereby, could profoundly inhibit activity of the bone marrow.
This compound, which we now call methotrexate, proved to be the first effective cancer chemotherapeutic agent and was shown by Farber to be effective in treating childhood leukemia. Today, methotrexate continues to be one of the most widely used cancer chemotherapeutic agents. Despite this widespread use, people frequently forget that methotrexate is merely the 4-amino, 10- methyl derivative of folic acid.
In the 1950s, Heidelberger and his associates decided that they would construct a new cancer therapeutic agent which would block a different folate-dependent biochemical reaction, synthesis of the nucleotide, thymidine. They decided to create a compound called 5-fluorouracil which inhibits the synthesis of thymidine, thereby inhibiting the rapid proliferation of cancer cells. 5- fluorouracil, like methotrexate, continues to be a widely used cancer chemotherapeutic agent.
JM
Early on folate metabolism was also exploited to get rid of another unwanted type of cell, namely, pathogenic bacteria. The original antibiotics, the sulfonamides, are entirely based on their ability to inhibit folate synthesis in bacteria. Their efficacy was first identified in the 1930s before folate had been isolated: a Nobel Prize was awarded in 1939 for the discovery of sulfonamide antibiotics. It was not until the 1940s that scientists recognized that the means by which sulfonamide drugs kill undesirable bacteria is by inhibiting a condensation reaction which occurs only in bacteria by which folate is synthesized.
Rob, I think that many of our Cyberounds® colleagues are probably aware of these two traditional exploitations of folate metabolism: cancer chemotherapeutic agents and antibiotics. What they may not be aware of are the newer insights and uses of folate metabolism that have appeared only in the last six to eight years.
Folate and Birth Defects
Folate can help prevent congenital neural tube defects, namely spina bifida and anencephaly. As early as the 1950s, Smithells and colleagues had already made the seminal observation that women delivering babies with these neural tube defects had lower than usual dietary intakes of certain vitamins as well as depressed vitamin levels in their blood. In the mid-1970s, several case control and cohort studies determined that women giving birth to infants with such defects either had lower intakes of dietary folate or lower blood levels of the vitamin than control women. The compelling evidence really came, Rob, when the results from four prospective intervention trials emerged over the past several years, each of which demonstrated, in a very compelling fashion, that higher intakes of folate during the first six weeks of pregnancy could lower the incidence of this birth defect by approximately 80%. I should mention that two of these four prospective intervention trials are, in addition, placebo-controlled and randomized.
Let me qualify this compelling body of evidence with two statements. First, it has become quite clear that the increased intake of folate that provides protection against neural tube defects must be taken at the time of conception, which is frequently a period of time women are not yet aware that they are pregnant. The public health implication of this is that women who potentially become pregnant are the ones who need to be taking increased amounts of this vitamin. The second qualification I would like to make is that it is not entirely clear yet what the optimal dose of folate necessary to convey protection against neural defects is. Nevertheless, observational studies suggest that 400 ug/day is sufficient to see some benefit. Now, this level is important because the present RDA for women in the United States is only a 180 ug and the mean dietary intake of folate by women in the United States approximates the lower value as opposed to the desirable value.
Starting in January of 1998, all uncooked cereal grain products in the United States will be fortified at a concentration of 140 ug of folate per 100 g of grain as a result of this compelling body of studies. It is estimated that this will increase the daily intake of folate by women who habitually ingest low amounts of dietary folate by about 100 ug a day.
RMR
Joel, is there any evidence of information yet as to how folate prevents these neural tube defects?
JM
Rob, I think it is fair to say that we really do not understand how folate is conveying this very strong protective effect. However, there are some recent observations in a chick embryo model of neural tube defects, emerging from our laboratory, which indicate that elevation of homocysteine levels (a result of diminished folate status) can directly induce neural tube defects. Rob, speaking of homocysteine, perhaps you could begin to discuss the issue of folate status and elevated blood levels of homocysteine as it pertains to cardiovascular disease. (Readers may also wish to refer to a previous Hematology/Oncology conference on homocysteine.)
Folate and Cardiovascular Disease
RMR
Joel, it has been known for several decades that children born with a very rare inborn error of metabolism called congenital homocysteinuria develop very high levels of homocysteine in the blood and, typically, die of either thrombotic or embolic disease in the second, third or fourth decade of life. The reason to discuss this in regard to folate metabolism is because the folate status of an individual is a very important determinant of what blood homocysteine levels are. Homocysteine is disposed of by the cells of the body by a folate-dependent pathway. Therefore, diminished levels of folate will cause a build up of the precursor molecule, namely, homocysteine.
The other important piece of information that was recognized in the past decade is that one does not need a 50- or 100-fold increase in blood homocysteine levels to convey an increased risk for thrombotic and embolic disorders such as what is seen with the congenital homocysteinuria individuals. It is now well accepted that a very modest elevation of homocysteine, namely a 20 to 30% increase over normal, is associated with a very substantial rise in cardiovascular disease. There is now a huge body of literature, based on very large epidemiologic studies, which indicates that modest elevations of homocysteine blood are associated with increased risk of myocardial infarctions, cerebral vascular disease and peripheral vascular disease. Furthermore, analyses of large populations such as the Framingham Heart Study indicate that one of the major determinants of blood homocysteine levels in ambulatory, otherwise healthy individuals is the folate level in those individuals.
Just by way of example: in the elderly Framingham cohort, approximately 30% of elderly individuals have low enough levels of dietary folate intake to cause significant elevations in blood homocysteine. Although we do not know whether this observation applies to other populations in the United States yet, it implies that a very large proportion of the otherwise healthy U.S. population has dietary levels of folate that are insufficient to optimize homocysteine levels.
Joel, there are plenty of studies which indicate that one can lower blood homocysteine levels by taking increased intake of folate. Nevertheless, I would like to point out that what this field really lacks is an intervention trial demonstrating that lowering homocysteine in this manner can reduce the incidence of cardiovascular events. Several such trials are presently underway, and the results of these trials will probably be forthcoming in the next three to five years. Despite the current lack of data from intervention trials, I would like to say that there is a very strong consensus among investigators in this field that elevations in blood homocysteine related to diminished intake of folate play an important role in cardiovascular disease.
Parenthetically, I would like to mention that vitamins B6 and B12 also play roles in the disposal of homocysteine in our bodies and many studies utilize supplements not only with folate but also with B12 and B6 to optimize the decrease in blood homocysteine levels.
JM
Rob, I continue to be somewhat confused by what the definition of an elevated blood homocysteine is. Could you elaborate on this?
RMR
Joel, the reason you find this somewhat confusing is because we really do not yet have a precise definition for an elevated blood homocysteine level. Most investigators presently suggest that a level over 14 micromol/L serum is a level above which significant increases in cardiovascular risk are observed. Nevertheless, this is highly analogous to the situation of when scientists first identified that elevated blood cholesterol was a risk factor for cardiovascular disease. Initially, a normal blood cholesterol level was considered to be up to approximately 250 mg/dl because this level represents the upper limits of the normative range for the U.S. population.
Nevertheless, subsequent studies revealed that even at levels in this range, there was a significant risk of cardiovascular disease and we now realize that to substantially decrease the risk of cardiovascular disease related to high cholesterol levels, one should aim for a level closer to 200 mg/dl. So, it may be that we need a level considerably lower than 14 micromol/L.
Joel, the last of the new clinical implications of folate metabolism is one in which you have a particular research interest: the issue of folate and its potential role as a cancer hemopreventive agent. Could you discuss this topic for us?
Ongoing Studies of Folate and Cancer Prevention
JM
Under the microscope, a folate deficient cell (a so-called amegaloblastic cell) and a pre-cancerous cell (a so-called dysplastic cell) look very similar. This cytologic similarity between these two abnormal cells types was merely thought to be a coincidence until the 1980s when several investigators asked the question whether there might be some functional relationship between these two cell types.
There are now more than 12 large epidemiologic studies, the consensus of which indicate an inverse relationship between the risk of colorectal neoplasia (i.e., adenomatous polyps and/or cancer) and the dietary intake of folate. These observations have been consistently found not only in populations at high risk, such as those individuals with ulcerative colitis, but also in the general population. Furthermore, there are animal models of colorectal cancer which also indicate that higher levels of dietary folate convey some protection against the development of colorectal cancer. The latter observation is highly suggestive of a true cause and effect relationship between dietary folate and the risk of colorectal cancer.
Dietary folate has also been related to other epithelial cancers such as those of the uterine cervix, stomach, esophagus and lung. Nevertheless, the data are clearly most compelling for the colorectum.
Although folate as a chemopreventive agent in cancer is clearly the most speculative of all the new clinical insights into folate metabolism, the data are very provocative and have stimulated the institution of several large prospective randomized trials in individuals who have a predilection for developing colorectal polyps. My laboratory group is conducting one of these large trials and we all look forward with excitement for the results of both our trial and the other trials that are presently being conducted. The dose of folate that is necessary to convey some protection against cancer is not entirely clear but the epidemiologic data, as well as the animal models, suggest that as little as four times the basal requirement is enough to convey a significant amount of protection. If one defines the basal requirement of folate in the adult human as somewhere between 200 and 400 ug per day, as little as 1 mg of folate a day might one day in the future be demonstrated to be a protective dose of folate.
Nevertheless Rob, I would like to indicate to our Cyberounds® colleagues that this is a field that is still evolving and we are by no means suggesting that people start taking this vitamin as a preventive agent yet. Such a recommendation will first require knowledge of the results of the intervention trials that are presently underway. I want to add that one has to be extremely cautious in giving large doses of folate to individuals who potentially have a colorectal neoplasm already existing. Cancer cells are rapidly proliferating and, as such, they have high requirements for folate. Giving large doses of folate to individuals who have existing cancers can actually accelerate the growth of those cancers. One must be extremely circumspect about who receives these large doses of folate.
RMR
Joel, again, let me ask you whether there is any insight yet as to how folate mediates this protective effect against cancer?
JM
Unfortunately we do not know definitively the means by which folate modulates the risk of colorectal cancer. Nevertheless, my laboratory as well as others have demonstrated that altering the dietary intake of folate has a very strong affect on the integrity of certain critical tumor suppressor genes that are involved in the development of colorectal cancer. This is a field of very active research and, hopefully, we will have some more clear answers in the near future.
Briefly, I would like to report some of the foods in the American diet that are rich in folate content: fortified breakfast cereals, leafy green vegetables, orange juice and organ meats such as liver and kidney are all rich soures. Folate is a heat-liable vitamin, so overcooking can destroy its activity.
Rob, this is a very exciting time for this vitamin, folate. It has rapidly transformed itself from a vitamin which we formerly thought of just in terms of prevention of anemia into a compound which has major implications in regard to some of the most important public health problems that exist in Western society, namely congenital birth defects, cardiovascular disease and cancer. I hope our Cyberounds(TM) colleagues will continue to follow the developments of this field in the periodic literature and post their own findings and observations here.