Effects of vitamin A and its analogs (retinoids) on normal and neoplastic cells

The pharmacology and clinical uses of tamoxifen

Folate, a water-soluble B vitamin, has recently garnered much attention because of its purported role in the pathogenesis of cardiovascular disease, neural tube defects, and cancer of certain organs (reviewed in references 8–12). Although the appreciation of the role of folate in carcinogenesis is a recent development, several previous observations have suggested a possible relationship between folate deficiency and the development of cancer. Cytopathologists in the 1950s and 1960s noticed cytologic similarities between exfoliated macrocytic gastric and cervical epithelial cells in individuals with folate and/or vitamin B12 deficiency and dysplastic cells. Some of these macrocytic epithelial cells persisted even after the correction of folate and/or vitamin B12 deficiency. 13 Because the cytologic appearance of these cells had some features of malignancy, it was postulated that these abnormal cells might be a transitional cell type between normal and neoplastic epithelium. However, a functional similarity between megaloblastic and neoplastic epithelial cells was not fully appreciated until recently. The concept that folate deficiency would predispose epithelial cells to a neoplastic transformation appears somewhat contradictory at first glance. Folate is an important factor for a number of metabolic pathways in the cell that involve the transfer of one-carbon groups. Among such pathways are the biosyntheses of purines and thymidylates. It is in this manner that folate plays a key role in DNA replication and cell division. Consequently, a deficiency of folate in tissues with rapidly replicating cells results in ineffective DNA synthesis, resulting in reduced cell proliferation, impaired cellular physiology, and abnormal cytologic morphology. This biochemical function of folate has been utilized in the area of how folate modulates cell proliferation in the process of carcinogenesis. Intuitively, interruption of folate metabolism in neoplastic cells would be expected to lead to ineffective DNA synthesis, resulting in the inhibition of tumor growth. Indeed, this has been the basis for antitumor therapy utilizing a number of antifolate agents, including methotrexate and 5-fluorouracil. Clinically, it has been observed that folate treatment of children with acute leukemia results in an “acceleration phenomenon” of the cancer. Experimentally, it has been shown that growth of a transplanted cancer is inhibited in folate-deficient rats, that folate deprivation reduces virally induced cancers, and that the time required for developing neoplasms in transgenic mice, which are predisposed to developing nerve sheath tumors similar to human neurofibromatosis, is significantly delayed by restricting the level of folate in the diet. Although it is well established that folic acid deficiency will retard the growth of, and occasionally kill, established cancers, it does not necessarily follow that nonneoplastic folate-deficient tissues are less likely to undergo neoplastic transformation. Conversely, a growing body of epidemiologic and clinical evidence suggests that, regardless of the systemic folate status, folate deficiency in certain epithelial tissues may be a factor that predisposes to the development of neoplasms arising from these tissues. Establishing a cause-and-effect relationship between a dietary factor and cancer is a difficult task. In some cases, correlation studies, which examine the relationship between This project has been supported in part by an operating grant and scholarship from the Medical Research Council of Canada and a Future Leader Award from the International Life Sciences Institute North America. Address correspondence to Dr. Young-In Kim, Department of Medicine, University of Toronto, Room 7258, Medical Sciences Building, 1 King’s College Circle, Toronto, Ontario, M5S 1A8 Canada. Received March 12, 1998; accepted August 13, 1998.

Folate and carcinogenesis: evidence, mechanisms, and implications.

Although baseline requirements for nicotinamide adenine dinucleotide (NAD+) synthesis can be met either with dietary tryptophan or with less than 20 mg of daily niacin, which consists of nicotinic acid and/or nicotinamide, there is growing evidence that substantially greater rates of NAD+ synthesis may be beneficial to protect against neurological degeneration, Candida glabrata infection, and possibly to enhance reverse cholesterol transport. The distinct and tissue-specific biosynthetic and/or ligand activities of tryptophan, nicotinic acid, nicotinamide, and the newly identified NAD+ precursor, nicotinamide riboside, reviewed herein, are responsible for vitamin-specific effects and side effects. Because current data suggest that nicotinamide riboside may be the only vitamin precursor that supports neuronal NAD+ synthesis, we present prospects for human nicotinamide riboside supplementation and propose areas for future research.

Nicotinic Acid, Nicotinamide, and Nicotinamide Riboside: A Molecular Evaluation of NAD+ Precursor Vitamins in Human Nutrition

The roles of synthesis and degradation in the control of rat liver tryptophan pyrrolase.

Glucocorticosteroids and Transaminase Activity I. INCREASED ACTIVITY OF GLUTAMIC-PYRUVIC TRANSAMINASE IN FOUR CONDITIONS ASSOCIATED WITH GLUCONEOGENESIS

http://science.sciencemag.org/content/sci/127/3293/287.3.full.pdf

An enzymatic basis for the gluconeogenic action of hydrocortisone.

The effect of tryptophane on the synthesis of nicotinic acid in the rat

Although actinomycin D has been used to prevent protein synthesis in experiments of several hours' duration, its effects on the synthesis of adaptive enzymes which are induced over a period of several days have received less attention. Treatment of young rats with doses of actinomycin D, which permitted survival for a period of 5 days, resulted in marked increases in the activities of four hepatic enzymes known to be induced by cortisol: alanine transaminase, tyrosine transaminase, serine dehydrase, and tryptophan pyrrolase. Actinomycin D also induced responses of two of these enzymes in adrenalectomized rats.

Fred Rosen

Papers

Glucocorticosteroids and Transaminase Activity I. INCREASED ACTIVITY OF GLUTAMIC-PYRUVIC TRANSAMINASE IN FOUR CONDITIONS ASSOCIATED WITH GLUCONEOGENESIS

An enzymatic basis for the gluconeogenic action of hydrocortisone.

The effect of tryptophane on the synthesis of nicotinic acid in the rat

Induction of several adaptive enzymes by actinomycin d.

Inhibition of glucose uptake in lymphosarcoma P1798 by cortisol and its relationship to the biosynthesis of deoxyribonucleic acid.