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Biochem Therapeutic Inc., Laval, Quebec, H7V 4A7 Canada [S. A. K., T. L. B., E. G. A., L. B., J-M. D., K. B., A. C., G. A.], and Southern Research Institute, Birmingham, Alabama 35255-5305 [W. R. W.]
ß-L-Dioxolane-cytidine (BCH-4556) is a novel anticancer nucleoside analogue with a stereochemically unnatural ß-L configuration. This compound was previously shown to have a potent antitumor activity in human prostate and hepatocellular xenograft tumor models (K. L. Grove et al., Cancer Res., 55: 3008–3011, 1995). Herein, we extended the efficacy validation of BCH-4556 to renal cell carcinoma (RCC) cell lines both in vitro and in vivo. In vitro cytotoxicity and proliferation inhibition deter-minations in human RCC cell lines CAKI-1, CAKI-2, 786-0, and A498 produced IC50 concentrations ranging from 15–35 
M. In vivo antitumor activity was consistent with the in vitro sensitivity. BCH-4556 was very effective in human RCC tumor xenograft models, including CAKI-1, A498, RXF-393, and SN12C carcinomas. Very good responses were 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 complete regression recorded in most of the animals tested. Curative activity was also observed, with 40–60% of animals remaining tumor free in all three RCC models at the day of study termination. Significant tumor shrinkage was also evident in the SN12C model. BCH-4556 efficacy evaluation in the orthotopic subrenal capsule tumor models demonstrated a potent tumor growth inhibition against human CAKI-1 xenografts and tumor stasis against mouse Renca tumors. BCH-4556 was also effective in inhibiting the growth of rebound CAKI-1 tumors after the administration 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 nucleoside analogue in clinical trials of RCC.
1 To whom requests for reprints should be addressed, at Biochem Therapeutic Inc., 275 Armand-Frappier Boulevard, Laval, Quebec, H7V 4A7 Canada.
Received 4/11/97. Accepted 8/25/97.
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