COMBINATION VERSUS SINGLE-AGENT THERAPY IN EFFECTING COMPLETE THERAPEUTIC RESPONSE IN HUMAN BLADDER-CANCER - ANALYSIS OF CISPLATIN AND OR 5-FLUOROURACIL IN AN IN-VIVO SURVIVAL MODEL

An in vivo study of cisplatin (CDDP) and 5-fluorouracil (5FU) cytotoxi city was performed using a multidose matrix with a human bladder trans itional cell carcinoma xenograft tumor line (DU4284) tested by subrena l capsule assay in 154 nude mice (NM-SRCA). Statistical analysis of in itial growth inhibition at 20 days and host survival demonstrates ther apeutic, cooperative interaction. Toxic doses of either CDDP or 5FU al one as well as low-dose combinations provided modest or no survival be nefit. The single dose of CDDP (7 mg/kg) and of 5FU (100 mg/kg) was be st (by analysis of efficacy and toxicity) of those tested and caused > 97% initial regression. While 94% of controls incurred tumor deaths by 225 days, 75% treated at this dose were tumor free and likely cured. Our conclusions were: (a) NM-SRCA human xenograft testing is excellent for rapid in vivo screening of promising treatment strategies to eval uate for efficacy at acceptable toxicity, but confirmation of true the rapeutic impact should be sought by correlating initial growth inhibit ion with host survival; (b) enhanced survival seen only when CDDP/5FU are used together (versus either single agent) supports the value of p ursuing histiotype-specific screening of potentially synergistic drug combinations; and (c) of clinical relevance, human transitional cell c arcinoma is now identified as a histiotype in which a therapeutic, coo perative interaction between CDDP/5FU has been demonstrated in vivo.