Higher Antitumor Activity of Vinflunine than Vinorelbine against on orthotopic murine model of transitional cell carcinoma of the bladder.

BONFIL, RD, RUSSO, DM, BINDA, MM, DELGADO, FM Y VINCENTI, M.

New Orleans, Los Angeles, USA.

Congreso; 92nd Annual Meeting of the American Association for Cancer Research.; 2001

American Association for Cancer Research

#1987 Higher Antitumor Activity of Vinflunine than Vinorelbine against an orthotopic murine model of transitional cell carcinoma of the bladder. Bonfil, R.D., Russo, D.M., Binda, M.M., Delgado F. M and Vicenti M. Lab. Fundación de Investigación del Cáncer at CEFYBO,  Buenos Aires, Argentina and Pierre Fabre Oncologie, Boulogne, France. Vinorelbine (VRL) proved to be useful for intravesical treatment of MB-49, a murine model of superficial transitional cell carcinoma (TCC) of the bladder. Vinflunine (VFL) is a novel semi-synthetic Vinca-alkaloid obtained through superacid chemistry by the selective introduction of two fluorine atoms at the 20` position of the VNR, a part of the molecule previously inaccessible by classic methods. VFL showed higher in vivo antitumor activity than VRL when administrated by intraperitoneal (ip) route in different tumor models. Based on these data, the aim of this study was to investigate the feasibility of systemic ip treatment of superficial TCC of the bladder with VFL and to compare its activity in respect to VRL when administrated by the sale route. The in vitro chemosensitivity of MB-49 cells to both drugs was first assessed by the MTT colorimetric viability assay. Exposure to the drugs for 3h followed by a 48 h recovery in drug-free medium resulted in a higher sensitivity of MB-49 cells to VRL than to VFL (IC 50 values of 60nM and 400nM, respectively). The effect of non-cytotoxic drug concentrations on in vitro invasiveness was also assayed, evaluating the ability of MB-49 cells to migrate across Matrigel-coated porous filters. Inhibition of control invasiveness of 40 to 70% (1-25 ng/ml VRL) and 22 to 80% (1-100 ng/ml VFL) was observed (variation between groups p<0.0001 ANOVA). The ip administration of the drugs twice a week for 4 weeks in C57/Bl6J female mice revealed that VFL was very well tolerated, with a 8-fold increased in the maximum tolerated dose (MTD)in respect to VRL (40 mg/kg and 4.8 mg/kg , respectively).The administration schedule was evaluated in C57/Bl6J female mice that were transurethrally inoculated with MB-49 cells (5x 10 4 )  immediately after bladder electrocauterization. Intravesical tumor incidence on day 21 was 0% and 17% in mice treated ip with 20 and 10 mg/kg VFL respectively (p=0, 0017 and p=0, 0001, Fisher´s Exact Test) contrasting with 75-83 % obtained in all VRL-treated groups and controls. Experiments in which survival was analyzed, revealed significant differences among groups (p<0.0001 ANOVA). All mice treated with 20 mg/kg VFL were still alive 60 days after intravesical MB-49 tumor implantation, as well as 50% of those treated with  10 mg/kg VFL, while most of the remaining  mice(control and VRL-treated) died before  day 32. These results strongly support VFL as a promising agent to systemic use in the treatment of TCC of the bladder.