Effect of E7010 on liver metastasis and life span of syngeneic C57BL/6 mice bearing orthotopically transplanted murine Colon 38 tumor

Abstract.

Purpose: E7010 is an orally active sulfonamide antitumor agent showing good activity against various subcutaneously inoculated rodent tumors and human tumor xenografts. The purpose of this study was to evaluate the effect of E7010 on liver metastasis and life span of mice bearing orthotopically transplanted murine Colon 38 tumor. Methods: Orthotopic transplantation of murine Colon 38 tumor as intact tissue yielded hepatic metastasis with a high incidence in about 1 month in C57BL/6 mice, and the mice died in about 2 months with cachexia. In this model, the maximum tolerated dose of E7010 (100 mg/kg per day) was administered orally on various schedules, including for 14 days or daily until death, starting at 14 days after transplantation, or for 8 days from 21 days after transplantation. Results: E7010 showed tumor growth inhibition (T/C=40%) at the orthotopic site similar to that at the subcutaneous site (T/C=32%) when administered from 14 days after transplantation. When E7010 was started from 21 days after transplantation, it significantly decreased the number of hepatic metastases (control 17.1±20.8, E7010 2.6±5.3), although inhibition of tumor growth at the orthotopic site was only moderate (T/C=60%). The administration of E7010 until death produced a significant increase in life span (control 49.8±8.9 days, E7010 62.5±6.1 days). Although the tumor weight of the E7010-treated group on the day of death was similar to that of the untreated group (control 1.166±0.507 g, E7010 1.211±0.632 g), there were significantly fewer liver metastases in the E7010-treated group (control 41.3±31.1, E7010 2.0±2.0). Conclusion: E7010 suppressed tumor growth at both primary and metastatic sites and increased life span in an orthotopic transplantation model of murine Colon 38 tumor in syngeneic C57BL/6 mice. Hepatic metastasis was inhibited more effectively than the growth of the primary tumor.