THIS PROPOSAL IS FOR EXTENDING THE EVALUATION OF RIBONUCLEOTIDE REDUCTASE INHIBITORS AS ANTITUMOR AGENTS.

THIS PROPOSAL IS FOR EXTENDING THE EVALUATION OF RIBONUCLEOTIDE REDUCTASE INHIBITORS AS ANTITUMOR AGENTS. VICINICAL POLYHYDROXY AND POLYAMINO BENZOIC ACID DERIVATIVES, ESPECIALLY VF147, I.E., 3.4- DIHYDROXYBENZOHYDROXAMIC ACID, HAVE SHOWN GOOD ACTIVITY AGAINST L1210 TUMOR MODEL AND AGAINST SOME OF THE TUMOR MODELS IN THE NATIONAL CANCER INSTITUTE (NCI) TEST PANEL. THE INVESTIGATOR PROPOSES TO EXTEND INVESTIGATIONS TO ASSESS DOSE AND SCHEDULE DEPENDENCE AND INTERACTION AND/OR SYNERGISM WITH DOXORUBICIN AND CYCLOPHOSPHAMIDE IN EARLY ANDADVANCED L1210 AND SOME SOLID TUMOR MODEL SYSTEMS SUCH AS CD8F(1) MAMMARY TUMOR, B16 MELANOMA AND LEWIS LUNG CARCINOMA. SELECTED SECOND GENERATION COMPOUNDS IN THIS CHEMICAL SERIES WILL BE TESTED FOR TOXICITY, ANTITUMOR ACTIVITY, FREE RADICAL SCAVENGING ACTIVITY AND SYNERGISM WITH DOXORUBICIN AND CYCLOPHOSPHAMIDE. THE RATIONALE FOR CARRYING OUT INVESTIGATIONS TO EVALUATE INTERACTION OF THESECOMPOUNDS ARE MOST EFFECTIVE AS FREE RADICAL SCAVENGERS THANAS METAL CHELATORS. SINCE ANTHRAQUINONE ANTICANCER DRUG METABOLISM IN THE BIOLOGICAL SYSTEM IS MEDIATED VIA THE FORMATION OF FREE RADICALS THAT ARE CAPABLE OF CAUSING TISSUE DAMAGE, ESPECIALLY THAT OF THE CARDIAC TISSUE, IT IS HOPED THAT FREE RADICAL SCAVENGERS MAY AMELIORATE THE CARDIOTOXICITY OF THESE AGENTS.