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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 Model¹

Department of Surgery/Urology [T. E. K., J. R. G., K. S. W., S. H. P., P J. W.] and Pathology [P. J. W.], and Division of Biometry & Medical Informatics [G. R.], Duke University School of Medicine; Duke University Comprehensive Cancer Center [K. S. W., P. J. W.]; and Research Service, Durham Veterans Administration Medical Center [P. J. W.], Durham, North Carolina

³ To whom requests for reprints should be addressed, at P.O. Box 3314, Duke University Medical Center, Durham, NC 27710.

An in vivo study of cisplatin (CDDP) and 5-fluorouracil (5FU) cytotoxicity was performed using a multidose matrix with a human bladder transitional cell carcinoma xenograft tumor line (DU4284) tested by subrenal capsule assay in 154 nude mice (NM-SRCA). Statistical analysis of initial growth inhibition at 20 days and host survival demonstrates therapeutic, cooperative interaction. Toxic doses of either CDDP or 5FU alone as well as low-dose combinations provided modest or no survival benefit. The single dose of CDDP (7 mg/kg) and of 5FU (100 mg/kg) was best (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 evaluate for efficacy at acceptable toxicity, but confirmation of true therapeutic impact should be sought by correlating initial growth inhibition with host survival; (b) enhanced survival seen only when CDDP/5FU are used together (versus either single agent) supports the value of pursuing histiotype-specific screening of potentially synergistic drug combinations; and (c) of clinical relevance, human transitional cell carcinoma is now identified as a histio-type in which a therapeutic, cooperative interaction between CDDP/5FU has been demonstrated in vivo.

¹ Supported in part by a VA Merit Review grant and the CURED Foundation, Duke University.

² Present address: Division of Urology, Emory U. School of Medicine, Atlanta, GA 30322.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 7/ 2/93. Accepted 11/12/93.