Selenium supplementation has been widely reported to suppress tumorigenesis in many animal models. Despite the achievement of significant progress in the design of novel selenium compounds in recent years, there has been a vacuum of knowledge regarding the anticancer efficacy of selenium in foods. The reason is due to the fact that most common foods have very low selenium and are therefore not suitable for experimental use. One of our goals in selenium chemoprevention research is to find ways of providing sufficient quantities of selenium safely in a food system. Plants are known to convert inorganic selenium in soil to organoseleniuin analogs of naturally occurring sulfur compounds. Vegetables with a rich source of sulfur might, therefore, be expected to concentrate selenium if they are so fertilized. This idea was tested with garlic, which is abundant in a variety of sulfur compounds. Additionally, the allylic sulfides present in garlic are known to have potent anticarcinogenic activity. Our intention was to let nature produce more powerful anticancer agents by substituting sulfur with selenium in plants. The hypothesis is supported by our previous research with structurally related selenium and sulfur analogs in which we showed that, molecule for molecule, selenium is much more active than sulfur in cancer prevention. We recently reported that garlic cultivated with selenite fertilization is indeed superior to either regular garlic or selenite in the suppression of mammary tumors in an animal model. Furthermore, this selenium-enriched garlic is capable of maintaining full activity of functional selenoenzymes such as glutathione peroxidase and Type I 5'-deiodinase at nutritional levels of selenium intake. Since garlic and onion belong to the same allium family, we are interested in finding out whether the experience with garlic could be similarly extended to onion. Preliminary data suggested that rats have a higher tolerance to selenium from these vegetables compared to selenium from selenite or selenomethionine.
Aim 1 will test the hypothesis that the increased tolerance is due to lower tissue selenium accumulation as a result of a more rapid elimination mechanism via the respiratory and/or urinary route. In order to elucidate the utility of these high selenium vegetables for cancer prevention purposes, further studies will be carried out using the (DMBA)-induced mammary tumor model in rats.
Aim 2 is therefore designed to investigate whether the anticarcinogenic potency of the high selenium-vegetables is dependent on the level of selenium enrichment, and to evaluate the inhibitory effect on initiation versus post-initiation stage of carcinogenesis.
Aim 3 will be focused on delineating the mechanism of tumor suppression in the DMBA model by examining the modulation of mammary cell DMBA-DNA adducts, DMBA urinary excretion, as well as phase I and phase II enzymes that are involved in the activation and detoxification of DMBA.
Aim 4 will extend the in vivo mammary cancer prevention study to the NMU model because of the opportunity of using ras mutation as a sensitive marker for monitoring clonal expansion or intervention of NMU-transformed cells. The objective is to assess whether inhibition of this molecular endpoint can be used as a signal of selenium chemoprevention in the early stage of mammary gland carcinogenesis.
Aim 5 will examine the stability of selenium compounds in garlic and onion at conditions which simulate cooking temperatures. Experiments will be carried out to determine whether heat treatment will affect the nutritional and anticarcinogenic activities of these high selenium vegetables.
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