POTENTIATION OF CYTOTOXIC CANCER THERAPIES BY TNP-470 ALONE AND WITH OTHER ANTI-ANGIOGENIC AGENTS

The ability of TNP-470, a synthetic analog of fumagillin which has been described as an anti-angiogenic agent, to potentiate cytotoxic cancer therapies was investigated in vivo in the murine FSallC fibrosarcoma and the Lewis lung carcinoma. TNP-470 was more toxic toward FSallC tumor cells from tumors treated in vivo than toward bone-marrow CFU-GM from the same animals. TNP-470 had a dose-modifying effect on the toxicity of cyclophosphamide toward FSallC tumor cells which amounted to an 8-fold increase in tumor-cell killing at a cyclophosphamide does of 500 mg/kg. Treatment with TNP-470 and minocycline increased the permeability of the FSall fibrosarcoma in vivo to the fluorescent dye Hoechst 33342 and increased the killing of both the brignt and the dim tumor cells by cyclophophamide. TNP-470, especially in combination with minocycline, formed a highly effective modulator combination for treatment of the Lewis lung carcinoma with cytotoxic cancer therapies against primary and metastatic disease. The combination of TNP-470/minocycyline and cyclophosphamide led to 40 to 50% long-term survivors in Lewis-lung-carcinoma-bearing animals. Our results indicate that the use of anti-angiogenic modulators in cancer therapy is a very promising area for further study. (C) 1994 Wiley-Liss, Inc.