THE OVERALL OBJECTIVES OF THIS PROPOSAL ARE TO DEVELOP A PANEL OF WELL-CHARACTERIZED, DRUG-RESISTANT HUMAN CANCER CELL LINES WHICH COULD BE USED BY COMMERCIAL AND GOVERNMENT AGENCIES TO IDENTIFY AND DEVELOP NEW ANTICANCER DRUGS TO TREAT PATIENTS WHOSE

THE OVERALL OBJECTIVES OF THIS PROPOSAL ARE TO DEVELOP A PANEL OF WELL-CHARACTERIZED, DRUG-RESISTANT HUMAN CANCER CELL LINES WHICH COULD BE USED BY COMMERCIAL AND GOVERNMENT AGENCIES TO IDENTIFY AND DEVELOP NEW ANTICANCER DRUGS TO TREAT PATIENTS WHOSE TUMORS EXHIBIT MULTIDRUG RESISTANCE. SINCE IT HAS BEEN SHOWN THAT DEVELOPMENT OF RESISTANCE TO ONE ANTINEOPLASTIC DRUG IS OFTEN ASSOCIATED WITH INCREASED RESISTANCE AND/OR ENHANCED SENSITIVITY TO OTHER CHEMOTHERAPEUTIC DRUGS, A NUMBER OF HUMAN TUMOR LINES WILL BE USED TO ISOLATE MUTANTS RESISTANT TO SPECIFIC ANTINEOPLASTIC DRUGS. THESE MUTANTS WILL BE STUDIED FOR THEIR CROSS-RESISTANCE AND ENHANCED SENSITIVITY TO OTHER CHEMOTHERAPEUTIC DRUGS TO DEVELOP A MATRIX SHOWING DEGREES OF CROSS-RESISTANCE AND SENSITIVITY OF THE SELECTED MUTANTS TO A VARIETY OF ANTINEOPLASTIC AGENTS. DURING PHASE I, PROTOCOLS TO TEST CELLS FOR THEIR DRUG RESISTANCE, DRUG CROSS-RESISTANCE, AND ENHANCED DRUG SENSITIVITY WILL BE DEVELOPED FOR USE IN PHASE II. IN ADDITION, A BATTERY OF WELL-CHARACTERIZED CROSS-RESISTANT MUTANTS WILL BE CRYOPRESERVED FOR FUTURE TESTING. THE MUTANT CELL LINES AND THE PROTOCOLS DEVELOPED IN PHASE I WILL BE USED TO STUDY THE DRUG CROSS-RESISTANCE TO MOST OF THE CLINICAL AND EXPERIMENTAL CHEMOTHERAPEUTIC AGENTS TO DETERMINE WHETHER SOME OF THE DRUG-RESISTANT PATTERNS ARE DUE TO A COMMON FACTOR, SUCH AS DECREASED CELL MEMBRANE PERMEABILITY. A LIMITED NUMBER OF STUDIES TO DETERMINE IF IN VITRO DRUG RESISTANCE IS INDICATIVE