STUDIES ON MECHANISMS OF CISPLATINUM-RESISTANCE IN URINARY TUMORS AND DRUG SCREENING FOR REVERSAL OF THE RESISTANCE.

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We have isolated cisplatinum (CDDP) -resistant cell lines, P/CDP4 and P/CDP5, from human PC-3 prostatic cancer cells after a stepwise exposure to CDDP to elucidate mechanisms of cisplatinum-resistance in urinary tumors.P/CDP4 and P/CDP5 showed 11-fold and 23-fold higher resistance to CDDP than did PC-3.P/CDP5 was cross-resistant to carboplatin, mitomycin C,etoposide, m-AMSA,bleomycin and UV irradiation.Alkaline elution of DNA showed an increased amount of DNA interstrand cross-links in PC-3 but not in P/CDP5 when PC-3 and P/CDP5 were cultured with CDDP.Flameless atomic absorption spectrophotometry revealed that intracellular accumulation of CDDP in P/CDP4 and P/CDP5 was decreased to 18% to 34% and 9% to 18% of that PC-3, respectively, when PC-3 and its CDDP-resistant counterparts were incubated with 5 and 10 mug/ml of CDDP for 24 hrs.These data suggest that decreased drug accumulation is involved in the development of CDDP-resistance in the PC-3 cell line.