A major objective of this program project is the discovery and characterization of novel cancer chemopreventive agents from natural sources. Test substances are evaluated in test systems designed to monitor the potential of inhibiting carcinogenesis at the stages of initiation, promotion or progression. Our battery of assays is currently comprised of the following test systems: inhibition of dimethylbenz(a)enthracene (DMBA-induced mutagenicity with Salmonella typhimurium strain TM677; induction of quinone reductase with cultured Hepa 1c1c7 cells; antagonism of phorbol ester or staurosporine binding to receptor, or inhibition of protein kinase C activity; inhibition of phorbol ester-induced ornithine decarboxylase activity with cultured mouse epidermal 308 cells; inhibition of cyclooxygenase activity; induction of HL-60 cell differentiation; antagonism of estrogen-estrogen receptor interaction; inhibition of aromatase activity. The approach we have developed primarily involves evaluation of test materials in this battery of in vitro assays followed by evaluation of active leads for potential to inhibit DMBA-induced preneoplastic lesions in mammary organ culture. Substances found active in these test systems are then subjected to bioassay-directed fractionation utilizing the in vitro test system wherein activity was originally demonstrated. Resulting active principles of defined structure are then re-tested in the mammary organ culture test system to verify procurement of the correct active principle and, based on these data, the compounds are considered as candidates for chemical synthesis, structural modification or for more advanced in vivo testing. By means of this collaborative approach, we have assured that the activity being monitored by the short-term tests systems is consistent with cancer chemoprevention. In addition, these test systems are generally of value in providing some mechanistic insight which is of critical importance in considering the overall relevance of new chemopreventive agents. Thus, an additional objective of this project, is to perform preliminary mechanistic evaluations. Overall, this profile of activity should be of sufficient magnitude to make an enlighten decision as to whether the agents are worthy of more detailed mechanistic evaluations or more advanced testing. These types of continuation studies are beyond the scope of the project but are conducted in conjunction with outside collaborators. Since agents previously discovered in this program project have fallen into this category, we are confident that this experimental approach is appropriate for the discovery and characterization of novel chemopreventive agents that can be entered into a pathway that is ultimately directed toward human intervention trials.
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