Potent antitumor activity of a novel nucleoside analogue, BCH-4556 (beta-L-dioxolane-cytidine), in human renal cell carcinoma xenograft tumor models.

Abstract

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 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 determinations in human RCC cell lines CAKI-1, CAKI-2, 786-0, and A498 produced IC50 concentrations ranging from 15-35 nM. 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.

• Authors: S A Kadhim, T L Bowlin, W R Waud, E G Angers, L Bibeau, J M DeMuys, K Bednarski, A Cimpoia, G Attardo
• Journal: Cancer research (Cancer Res) Vol. 57 Issue 21 Pg. 4803-10 (Nov 01 1997) ISSN: 0008-5472 [Print] United States
• PMID: 9354442 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Dioxolanes
• Nucleosides
• troxacitabine
• Cytosine

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Carcinoma, Renal Cell (drug therapy)
• Cytosine (analogs & derivatives, therapeutic use)
• Dioxolanes (therapeutic use)
• Drug Screening Assays, Antitumor
• Female
• Humans
• Kidney Neoplasms (drug therapy)
• Mice
• Neoplasm Transplantation
• Nucleosides (therapeutic use)
• Transplantation, Heterologous
• Tumor Cells, Cultured