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, Dr. 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 used to treat childhood leukemia. Today, methotrexate continues to be one of the most widely prescribed cancer chemotherapeutic agents.
In the last decade, newer insights and uses of folate metabolism have appeared.
Folate can help prevent congenital neural tube defects, namely spina bifida and anencephaly. As early as the 1950s, scientists observed 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. 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%.
Two qualifications: first, the folate must be taken at the time of conception, which is frequently a period of time women are not yet aware that they are pregnant; second, we're not certain what dose of folate is necessary to convey protection against neural defects. 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.
Folate can help prevent congenital neural tube defects, namely spina bifida and anencephaly.
As of January 1998, all uncooked cereal grain products in the United States were 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.
Vitamins B6 and B12 also play roles in the disposal of homocysteine from our bodies.
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?
Many human studies, as well as studies with animal models, 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.
Many human studies, as well as studies with animal models, indicate that higher levels of dietary folate convey some protection against the development of colorectal cancer.
The dose of folate necessary to convey some protection against cancer is not entirely clear but some study results suggest that as little as four times the basal requirement is enough to convey a significant amount of protection.
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.
Because it is a water-soluble vitamin, if you boil your vegetables in a large volume of water and then discard the water, much of the folate is discarded as well.