POTENT ANTITUMOR-ACTIVITY OF A NOVEL NUCLEOSIDE ANALOG, BCH-4556 (BETA-L-DIOXOLANE-CYTIDINE), IN HUMAN RENAL-CELL CARCINOMA XENOGRAFT TUMOR-MODELS

beta-L-Dioxolane-cytidine (BCH-4556) is a novel anticancer nucleoside analogue with a stereochemically unnatural beta-L configuration. This compound was previously shown to have a potent antitumor activity in h uman prostate and hepatocellular xenograft tumor models (K. L. Grove e t at, Cancer Res., 55: 3008-3011, 1995). Herein, me extended the effic acy validation of BCH-4556 to renal cell carcinoma (RCC) cell lines bo th in vitro and in vivo. In vitro cytotoxicity and proliferation inhib ition determinations in human RCC cell lines CAKI-1, CAKI-2, 786-0, an d A498 produced IC50 concentrations ranging from 15-35 eta M. bl vivo antitumor activity was consistent with the in vitro sensitivity. BCH-4 556 was very effective in human RCC tumor xenograft models, including CAKI-1, A498, RXF-393, and SN12C carcinomas. Very good responses mere observed in animals bearing CAKI-1, A498, and RXF-393 RCC tumors given i.p. doses of 10, 25, and 50 mg/kg twice a day for 5 days, with compl ete regression recorded in most of the animals tested. Curative activi ty mas also observed, with 40-60% of animals remaining tumor free in a ll three RCC models at the: day of study termination. Significant tumo r shrinkage was also evident in the SN12C model. BCH-4556 efficacy eva luation in the orthotopic subrenal capsule tumor models demonstrated a potent tumor growth inhibition against human CAKI-1 xenografts and tu mor stasis against mouse Renca tumors, BCH-4556 was also effective in inhibiting the growth of rebound CAKI-1 tumors after the administratio n of a second treatment cycle. The observed antitumor activity of BCH- 4556 in several RCC human solid tumor xenografts, including the lethal RXF-393 model, warrants further investigation of this novel nucleosid e analogue in clinical trials of RCC.