Inhibition of angiogenesis by interferon-alpha in human transitional cell carcinoma growing orthotopically in nude mice and study of combination therapy with cytoreductive chemotherapy

The purpose of this study was to optimize the anti-angiogenic activity of interferon-alpha (IFN-alpha) and to examine whether combination therapy with IFN-alpha and Paclitaxel inhibits tumor growth in human transitional cell carcinoma (TCC) growing orthotoPically in nude mice. Human TCC 253J B-VR cells, which resist the antiproliferative effects of IFN-alpha, were injected into the bladder wall of athymic nude mice. After the tumors were palpable, therapy was begun with IFN-alpha at different dosing schedules and in combination with Paclitaxel. Daily administrations of low-dose (5,000 or 10,000 units) IFN-alpha produced maximal reduction in the tumor burden and microvessel densities. Combination therapy with paclitaxel and IFN-alpha showed synergistic inhibition of tumor growth and tumor vascularization with decreased mRNA expression of basic fibroblast growth factor and matrix metalloprotease-9, resulting in apoptosis and inhibition of cell proliferation. These data suggest that the frequent administration of the optimal biological dose of IFN-alpha is more efficient with regard to anti-angiogenic activity than that of the maximal tolerable dose, and a combination of the cytoreductive chemotherapeutic agent produces a synergistic effect of treatment.