The role of diet and nutrition in cancer has received widespread study. Whereas the importance of dietary carcinogens and lipids has been studied extensively, other dietary constituents such as protein amount and composition has only begun to be investigated. We wish to take a new and innovative approach concerning the potential involvement and interrelationships of several amino acids in the development of cancer in two animal models. These specific amino acids are ornithine, arginine, and lysine. Recent studies in this laboratory have implicated arginine and ornithine as potential regulators of polyamine biosynthesis. Ornithine is decarboxylated by the enzyme ornithine decarboxylase to form putrescine, which in turn is converted to spermidine and spermine. The polyamines (putrescine, spermidine, and spermine) have for many years been known to be required for both normal and neoplastic cell growth. Our hypothesis is that by limiting substrate ornithine which is available for polyamine biosynthesis through dietary means, cancer-cell growth can be retarded without harmful effects upon the animal. Ornithine is not used for protein biosynthesis and is not a major constituent of mammalian diet. However, the bulk of animal ornithine is synthesized from arginine. Arginine is obtained from dietary sources but can be synthesized to some extent since it is not considered an essential amino acid in adult animals. Lysine is capable of directly inhibiting ornithine synthesis from arginine, as well as inhibiting the uptake of ornithine into all tissues. Thus, lysine supplementation to normal diets accompanied with arginine limitation, may have profound effects upon ornithine pools and subsequently limit cancer cell growth through a direct effect upon polyamine biosynthesis. Our previous studies indicate that a reduction in ornithine will result in decreased polyamine biosynthesis and tumor cell growth. Hence, by controlling or limiting ornithine pools through appropriate diet the general population might be able to substantially reduce the risk of cancer through prevention. The overall objective of this proposal is to arrive at the appropriate conditions of dietary manipulations of animal arginine/ornithine sufficient to retard the growth of the L1210 leukemia tumor in mice, and to inhibit significantly and reproducibly the production of papillomas and/or carcinomas in the mouse two-stage model of epidermal carcinogenesis. Our previous animal studies indicate that such dietary restraints apparently have no obervable deletorious effect upon the overall health of the animal and did lead to a significant reduction in tumor yield in the mouse epidermal model. In a carefully controlled manner, we intend to ascertain the effect of these dietary manipulations upon specific biochemical alterations in the appropriate tissue which have been implicated in the process of tumor promotion and growth; including: ornithine decarboxylase activity, polyamine accumulation, and DNA synthesis.
| Hawel 3rd, L; Tjandrawinata, R R; Byus, C V (1994) Selective putrescine export is regulated by insulin and ornithine in Reuber H35 hepatoma cells. Biochim Biophys Acta 1222:15-26 |
| Gonzalez, G G; Byus, C V (1991) Effect of dietary arginine restriction upon ornithine and polyamine metabolism during two-stage epidermal carcinogenesis in the mouse. Cancer Res 51:2932-9 |
| Byus, C V; Wu, V S (1991) The level of substrate ornithine can alter polyamine-dependent DNA synthesis following phorbolester stimulation of cultured hepatoma cells. J Cell Physiol 149:9-17 |
| Gilbert, R S; Gonzalez, G G; Hawel 3rd, L et al. (1991) An ion-exchange chromatography procedure for the isolation and concentration of basic amino acids and polyamines from complex biological samples prior to high-performance liquid chromatography. Anal Biochem 199:86-92 |
