Retinoic acid (RA) and its analogs have emerged as dermatological agents and as potential cancer chemopreventive/chemotherapeutic agents. As a class, these compounds tend to share teratogenic potential and the ability to show vitamin A toxicity. However, the O-awl glucuronide metabolite of RA has been suggested to be a less toxic, active product. The synthetic retinoid 4-hydroxyphenylretinamide (4-HPR) shows some uniquely desirable features as a breast cancer chemopreventive agent with reduced toxicity and teratogenicity. Our own studies with 4-HPR-O-glucuronide show it to be even less toxic and more active than 4-HPR as a breast cancer ehemopreentive. However, these glucuronides are unstable toward hydrolysis. We have been synthesizing stable C-linked analogs of 4-HPR-O-glucuronide for evaluation of breast cancer chemopreventive/chemotherapeutic activity (CA49837). A number of these analogs show great promise despite the fact that they do not bind well to any of the known nuclear receptors.
The specific aims of our proposed research program are: 1) synthesis of the C-linked glucuronide analog of 4-HBR (4-HBRCG) and evaluation of its efficacy in chemotherapy of DMBA-indueed mammary tumors relative to 4-HPRCG, the latter of which represents our most effective analog in chemoprevention. If 4-HBRCG proves to be the most active compound in chemotherapy, and if like its parent drug, 4-HBR, it shows reduced liability in reducing blood retinol, then MTD and chemoprevention studies will be performed with 4-HBRCG. if however, 4- HPRCG proves superior, we will focus our attention on studies of this analog, including MTD evaluation; 2) Evaluation of the chemopreventive/chemotherapeutic activity of our most potent analog; 3) evaluate the necessity for RAR activation in the initiation of apoptosis by 4-HPR and its analogs; 4) synthesis of [3H]HPR and its use to determine whether metabolism of 4-HPR is needed for it to act; and identification of the primary target of 4-HPR action in cells and/or in vivo; 5) evaluation of our most potent analog (4-HPRCG or 4- HBRCG) with regard to tissue distribution and teratogenic potential
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