MULTIDRUG-RESISTANCE PATTERSN IN HUMAN TUMOR CELLS

NEW ANTITUMOR COMPOUNDS IDENTIFIED IN SCREENING PROGRAMS AREFREQUENTLY INEFFECTIVE AGAINST METASTATIC HUMAN TUMORS THAT EXHIBIT MULTIPLE-DRUG RESISTANCE. TO ENHANCE THE EFFICIENCYOF SCREENING FOR AGENTS LIKELY TO BE EFFECTIVE IN THE TREATMENT OF SUCH TUMORS, INTEGRATED GENETICS, INC. PROPOSESTO DEVELOP A DIAGNOSTIC PRODUCT CONSISTING OF A PANEL OF WELL-CHARACTERIZED, MULTIDRUG-RESISTANT DERIVATIVES OF HUMANTUMOR CELL LINES, FOLLOWING SELECTIONS FOR RESISTANCE TO ACTINOMYCIN D, ADRIAMYCIN, COLCHICINE, DAUNORUBICIN, VINBLASTINE, OR VINCRISTINE. THE PANEL WILL BE USEFUL AS A DIRECT, INITIAL SCREEN FOR COMPOUNDS ACTIVE AGAINST TUMORS HAVING DIFFERENT SPECTRA OF DE NOVO OR ACQUIRED RESISTANCE TO THESE COMMONLY USED CHEMOTHERAPEUTIC AGENTS. DURING PHASE I, AN ESTABLISHED, MALIGNANT, MELANOMA CELL LINE WILL BE PROPAGATED WITH STEP-WISE SELECTION FOR INCREASINGLY HIGHER LEVELS OF RESISTANCE TO EACH DRUG LISTEDABOVE. EACH OF THE SIX SUBLINES WILL THEN BE TESTED FOR THEIR RELATIVE LEVELS OF RESISTANCE TO ALL SIX DRUGS. PRELIMINARY MOLECULAR CHARACTERIZATION OF THESE MULTIDRUG-RESISTANT SUBLINES WILL BE RESTRICTED TO A DETERMINATION OF THE PRESENCE OR ABSENCE OF COMMON AMPLIFIEDDNA OR RNA SEQUENCES BY HYBRIDIZATION TO A DEFINED CDNA PROBE (HOMOLOGOUS TO A COMMON, AMPLIFIED GENE FROM CHINESE HAMSTER CELLS). DURING PHASE II, MULTIDRUG-RESISTANT SUBLINES OF OTHER HUMAN TUMOR CELL LINES FROM DIFFERENT NEOPLASTIC TISSUES (E.G., CARCINOMAS OF SMALL LUNG CELLS, BREAST, COLON, KIDNEY, ETC.) WILL BE SELECTED AND TESTED FOR COMMON AMPLIFIED DNA SEQUENCES.