Potent antitumor activity of a novel nucleoside analogue, 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 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.
Kadhim
S A
SA
Biochem Therapeutic Inc., Laval, Quebec, Canada.
Bowlin
T L
TL
Waud
W R
WR
Angers
E G
EG
Bibeau
L
L
DeMuys
J M
JM
Bednarski
K
K
Cimpoia
A
A
Attardo
G
G
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D003596:Cytosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004148:Dioxolanes / Q000627:therapeutic use*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy*; D051379:Mice; D009368:Neoplasm Transplantation; D009705:Nucleosides / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004148:Dioxolanes; D009705:Nucleosides; C074908:troxacitabine; D003596:Cytosine