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.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/drug therapy , Cytosine/analogs & derivatives , Dioxolanes/therapeutic use , Kidney Neoplasms/drug therapy , Nucleosides/therapeutic use , Animals , Cytosine/therapeutic use , Drug Screening Assays, Antitumor , Female , Humans , Mice , Neoplasm Transplantation , Transplantation, Heterologous , Tumor Cells, CulturedABSTRACT
Resistance to the cytotoxic effects of alkylating agents is a major limitation to their clinical efficacy. Although a number of animal and human tumor cell models have been developed to study this problem, it has proven difficult to achieve very high levels of resistance to alkylating agents in vitro. This is consistent with the recent clinical evidence that alkylator resistance can be overcome by dose escalations of less than 10-fold. A number of mechanisms of alkylator resistance have been described, more than one of which may occur in the same model. This paper describes a human breast cancer cell subline selected for 3-fold resistance to melphalan and cross-resistant to other alkylators in which only one of the previously described mechanisms of resistance, enhanced removal of DNA interstrand cross-linking, is demonstrable. Northern blot analysis using the human incisional repair gene ERCC-1 cDNA demonstrated that this particular gene product is not the altered function in these cells, so the molecular characterization of the observed enhanced repair is pending. Because these cells are also cross-resistant to radiation and to adriamycin and epipodophyllotoxin, they may represent a clinically relevant model in which to examine the role of DNA repair of lesions resulting from alkylators and other cytotoxic agents.