Retinoic acid (RA) and its metabolite 13-cis-retinoic acid have emerged as agents for the treatment of dermatological conditions. These agents and their analogues (retinoids) have also generated considerable interest because of their potential utility as cancer chemopreventive or chemotherapeutic agents. Although a promising class of compounds, their usefulness has been hampered by the relatively narrow therapeutic indices of most of these materials. The natural retinoids, as well as their analogues, are rapidly and extensively metabolized. Few of these metabolites retain useful biological activity with the exception of 13-cis-RA and the O-acyl glucuronide of RA, retinoyl-beta-glucuronide. THis glucuronide in particular has been suggested to be a less toxic, active metabolite of RA. Interestingly, preliminary studies suggest the O-glucuronide of the important synthetic retinoid 4-hydroxyphenylretinamide (4-HPR) also may represent a less toxic, effective metabolite of the parent molecule. However, it has yet to be shown whether these O-glucuronides are active metabolites or whether they are hydrolyzed back to the parent molecule at an appropriate rate to show useful properties.
The specific aims of this chemical program are: 1) the synthesis of substantial quantities of the O-glucuronides of RA and 4-HPR for detailed evaluations as well as their preparation in radiolabelled form to evaluate their uptake and fate, 2) the preparation of stable analogues of the above glucuronides to evaluate whether the intact forms of the glucuronides are uniquely effective metabolites, and 3) determine the stability and/or inhibitory activity of the analogues toward beta-glucuronidase.
The specific aims of the biological studies will be a comprehensive evaluation of the ability of these glucuronides and analogues to: 1) influence the growth of MCF-7 human breast cancer cells in vitro, 2) prevent DMBA induced mammary gland transformation in rats, and 3) be absorbed and metabolized by both the cells and experimental animals. Should any of these compounds show useful activities in these models for breast cancer, future goals would include further development of any compounds that appear to be promising.
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