Response of the FSaII fibrosarcoma to antiangiogenic modulators plus cytotoxic agents

The formation of a blood supply (angiogenesis) is critical to the growth of solid tumors. The naturally occurring steroid tetrahydrocortisol, the synthetic cyclodextrin derivative beta-cyclodextrin tetradecasulfate, and the tetracycline derivative minocycline have antiangiogenic activity. Tetrahydrocortisol (125 mg/kg) and beta-cyclodextrin tetradecasulfate (1000 mg/kg) in a 1:1 molar ratio by continuous infusion over 14 days and minocycline (10 mg/kg) administered i.p. daily from day 4 to day 18 postimplantation of the FSaII fibrosarcoma did not alter the growth of the tumor. These antiangiogenic modulators were not cytotoxic toward FSaIIC tumor cells or bone marrow CFU-GM when tumor-bearing animals were treated and cytotoxicity determined by colony formation in culture. The antiangiogenic modulators markedly increased the cytotoxicity of cyclophosphamide toward FSaIIC tumor cells and to a much lesser degree toward bone marrow CFU-GM. The cytotoxicity of CDDP and radiation was enhanced only by administration of the three modulators in combination. In tumor growth delay studies, the three modulator combination increased the effectiveness of CDDP by 1.5-fold, of cyclophosphamide by 1.9-fold and of radiation by 1.4-fold. Although the antiangiogenic therapies alone did not substantially reduce the number of lung metastases compared with the untreated controls, addition of the antiangiogenic agents to treatment with the cytotoxic therapies reduced not only the number of lung metastases formed from the primary tumor but also reduced the number of large metastases. Thus, antiangiogenic therapies can potentiate the efficacy of standard anticancer therapies.