Introduction and Objectives:
Apaziquone is a novel bioreductive alkylating agent in development for intravesical therapy of nonmuscle invasive bladder cancer. The standard dose of apaziquone in all ongoing clinical studies is 4 mg/ 40 mL (0.1mg/mL). The objective of this study was to test the efficacy of varying concentrations of apaziquone versus placebo in an animal model of bladder cancer.
A total of 1x105 MB49 cells were instilled into the bladder of C57BL/6 mice after electrocauterization to establish the tumor model. Mice bearing orthotopic tumors were administered varying concentrations of apaziquone (0.05, 0.1, 0.4, and 0.8 mg/mL) or placebo (0.85% saline) via intravesical instillation (0.1 mL) one week after tumor implantation. Instillations were continued once a week for 4 weeks. Tumor incidence, overall and median survival is reported.
At the end of the observation period (80 days), all animals in the control (0.85% saline) and 0.05 mg/mL groups had died (fig. 1). The median survival of mice receiving apaziquone at concentrations of 0.1 mg/mL (42.5 days); 0.4 mg/mL (40.5 days) and 0.8 mg/mL (49 days) was longer than that of mice treated with 0.05 mg/mL (30 days) and 0.85% saline (27 days). Statistically significant differences in survival were observed in control vs apaziquone-treated groups [0.1 mg/ml(P < 0.05); 0.4 mg/mL(P < 0.01); 0.8 mg/mL (P < 0.01)], and in the low concentration (0.05 mg/mL) vs 0.1 mg/mL (P < 0.05), 0.4 mg/mL (P < 0.01) and 0.8 mg/mL (P < 0.01), respectively.
The median survival of the 0.1, 0.4 and 0.8 mg/mL treated groups did not differ, but 33.3% in the 0.1 mg/mL cohort, and 14.3% in the 0.4 mg/mL cohort were long-term survivors (>80 days). All other animals (n = 37) had died of cancer by the end of the observation period. Three mice did not survive anesthesia. At necropsy all mice had advanced local disease with deep invasion of the muscularis propria, and usually with multiple lung metastases.
Apaziquone at the 0.1 mg/mL concentration demonstrates excellent antitumor activity compared to placebo or 0.05 mg/mL solutions. In this model there was no significant difference in the median survival between 0.1 mg/mL and higher concentrations of apaziquone (0.4 and 0.8 mg/mL) supporting continued development with the current clinical dose (0.1mg/mL).