BIOFLAVONOID METABOLITES AND TUMOR CELL INHIBITION

THE OBJECTIVE OF THIS PROJECT IS TO SYNTHESIZE COMPOUNDS (CHALCONES AND THEIR ANALOGS) RELATED TO A NATURAL PRODUCT (METHYL P-HYDROXYPHENYLLACTATE OR MEHPLA) THAT MAY BE USEFUL AS ANTITUMOR AGENTS. STUDIES HAVE DEMONSTRATED THAT NORMAL AND MALIGNANT CELLS CONTAIN HIGH-AFFINITY BINDING SITES FOR ESTRADIOL (ESTROGEN RECEPTOR) AND A SECOND CLASS OF BINDING SITE (TYPE II) WHOSE AFFINITY FOR ((3)H) ESTRADIOL (KD 20 NM) SUGGESTS THAT BINDING OF THE STEROID TO TYPE II SITES IN VIVO IS UNLIKELY TO OCCUR. A BIOFLAVONOID AND/OR TYROSINE METABOLITE (MEHPLA) HAS BEEN IDENTIFIED AS THE NATURAL LIGAND FOR NUCLEAR TYPE II BINDINGSITES. MEHPLA INHIBITS ESTROGEN STIMULATION OF UTERINE CELLULAR HYPERPLASIA AND DNA SYNTHESIS IN THE RAT AND MCF-7 HUMAN BREAST CANCER CELL PROLIFERATION IN TISSUE CULTURE. CHALCONE AND RELATED ENONE ANALOGS OF MEHPLA WILL INHIBIT MOUSE MAMMARY TUMOR GROWTH IN VIVO IT IS PLANNED TO SYNTHESIZE CHALCONE AND CORRESPONDING ENONE ANALOGS AND ASSESS THEIR ANTITUMOR ACTIVITY. COMPOUNDS WILL BE PRELIMINARILY SCREENED FOR BINDING AFFINITY FOR NUCLEAR TYPE II SITES, ANTI-UTEROTROPIC ACTIVITY IN THE ADULT OVARIECTOMIED RAT, AND INHIBITION OF MCF-7 CELL PROLIFERATION IN VITRO. THE LEAD COMPOUNDS WILL BE ADMINISTERED TO MICE BEARING TRANSPLANTABLE MAMMARY TUMORS AND ATHYMIC NUDE MICE BEARING MCF-7 HUMAN BREAST CANCER CELL TUMORS TO ASSESS THEIR EFFECTS ON TUMOR GROWTH IN VIVO. THE PHASE I STUDIES WILL DETERMINE WHETHER SYNTHETIC ANALOGS OF THIS TYPE OF COMPOUND HAVE POTENTIAL FOR FURTHER DEVELOPMENT AS ANTITUMOR AGENTS IN PHASE II STUDIES.