POTENTIAL NEW TOPICAL ANTI-PSORIASIS AGENTS

PSORIASIS AFFECTS APPROXIMATELY 2 PERCENT OF THE U. S. POPULATION AND MOST PRESENT TREATMENTS ARE EITHER POTENTIALLY HARMFUL OR ENTAIL DIFFICULT AND/OR UNPLEASANT PROCEDURES. THEREFORE NEW AGENTS ARE EAGERLY SOUGHT. THE GOAL OF THIS PROJECT IS TO DEVELOP A TOPICAL ANTIPSORIATIC AGENT THAT HAS ANTIPROLIFERATIVE AND ANTI-INFLAMMATORY ACTIVITY COMBINED IN A SINGLE COMPOUND, THUS COMBATING BOTH THE CAUSE AND SYMPTOMS OF THE DISEASE. THE REDUCTION OF RIBONUCLEOTIDES TO DEOXYRIBONUCLEOTIDES, CATALYZED BY RIBONUCLEOTIDE REDUCTASE, IS A CRUCIAL AND RATE LIMITING STEP IN THE PATHWAY LEADING TO DNA SYNTHESIS AND THEREFORE REPRESENTS A FAVORABLE BIOCHEMICAL SITE FOR INHIBITION OF DNA SYNTHESIS AND THEREFORE CELL PROLIFERATION. THIS LABORATORY HAS DEVELOPED A NEW SERIES OF RIBONUCLEOTIDE REDUCTASE INHIBITORS THAT ARE POTENT INHIBITORS OF THE ENZYME AND PRODUCE ANTITUMOR ACTIVITY IN ANIMAL TUMOR MODELS. ONE IS CURRENTLY IN CLINICAL TRIALS. A COMPOUND OF THIS SERIES MAY HAVE THE POTENTIAL TO BE AN EFFECTIVE TOPICAL ANTIPSORIATIC AGENT. SUPPORT FOR THIS THESIS IS PROVIDED BY THE FACT THAT HYDROXYUREA, A WEAK RIBONUCLEOTIDE REDUCTASE INHIBITOR, IS PRESENTLY USED AS BOTH AN ANTICANCER AND AN ANTIPSORIATIC AGENT. THE POTENTIAL OF DIDOX, ONE OF THE BEST ANTICANCER COMPOUNDS IN THIS SERIES, TO AFFECT PSORIASIS WILL BE DETERMINED. THIS WILL BE ACCOMPLISHED BY MEASURING ITS EFFECT ON EPIDERMAL DNA SYNTHESIS IN HAIRLESS MOUSE SKIN AND HUMAN SKIN/NUDE MOUSE MODELS. TO TEST THE ANTI-INFLAMMATORY POTENTIAL OF DIDOX THE MOUSE SKIN EAR INFLAMMATION MODEL WILL BE USED. AN ISOLATED HUMAN/RAT SKIN FLAP MODEL WILL BE USED TO STUDY TRANSDERMAL ABSORPTION AND ASSESS TOXICITY.