The primary goal of this project is to evaluate the chemopreventive efficacy of novel selenium compounds and to study their mechanism of action using the dimethylbenz[a]anthracene (DMBA)-induced mammary tumor model in rats.
AIM 1 is a continuation of our research with aliphatic selenium compounds. Based on our previous observation that they are effective blocking agents in the DMBA model by interfering with DNA adduct formation, the proposed experiments will be focused on the modulation of phase I and phase II metabolizing enzymes that are relevant to the activation and detoxification of polycyclic hydrocarbons. Currently, there is little known about the chemopreventive activity of the long chain aliphatic selenium compounds under chronic feeding condition. Their efficacy in the post-initiation phase of DMBA carcinogenesis therefore requires further investigation.
AIM 2 will examine the pharmacology of triphenylselenonium chloride and the effect of this compound on proliferative activity of the mammary gland. The pharmacokinetics experiments are driven by our observation that tripheylselenonium is very well tolerated by animals and that there is minimal accumulation of tissue selenium even at the chemopreventive dose range. We also have preliminary evidence suggesting that an effect of triphenylselenonium might be targeted on early events associated with clonal expansion of the transformed cells. Since mammary tumors in the DMBA model originate from terminal end buds and not from alveolar buds, our research is aimed at determining whether tripheylselenonium has a differential effect on the size of the proliferative fraction in the terminal end bud compartment versus the alveolar bud compartment of the mammary gland.
AIM 3 will occupy a major effort in the renewal by evaluating the anticarcinogenic activity of new selenium compounds supplied by Drs. Ganther and Block. Our priority is to start with the triphenylselenonium- related compounds and to phase in the garlic selenium compounds in the later years. The objectives of this aim are (a) to establish tolerance data and chemopreventive dose range of new compounds, (b) to study the structure-activity relationship, (c) to provide feedback information for the synthesis of more active analogs, and (d) to identify desirable compounds for further pharmacology and mechanism studies.
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