Vinblastine and hyperthermia target the neovasculature in BT(4)An rat gliomas: Therapeutic implications of the vascular phenotype

Purpose: The antivascular and antitumor activity of vinblastine and hyperth ermia at different tumor volumes were examined in the subcutaneous (s.c.) B T(4)An rat glioma model. Methods and Materials: The influence of vinblastine (3 mg/kg) and hyperther mia (44 degreesC/60 min) on tumor growth was assessed in small (100 mm(3)) and large (200 mm(3)) BT(4)An tumors. To disclose how vinblastine and hyper thermia interacted in the neoplasms, tumor blood flow and the extent of vas cular damage, hypoxia, cell proliferation, and apoptosis were assessed afte r treatment. The content of smooth muscle cells/pericytes in the tumor vasc ulature was examined in small and large tumors to assess how the vascular p henotype changed during tumor growth. Results: In the large tumors, vinblastine reduced the blood flow, but the t umor growth was not affected. The combination of drug and local heating yie lded massive vascular damage and a significant tumor response. The small ne oplasms had a higher content of smooth muscle cells/pericytes in the vessel walls (host vasculature), and the tumor vasculature displayed a higher res istance to vascular damage than the large neoplasms. Yet, vinblastine alone exhibited a potent antiproliferative activity and induced massive apoptosi s in the small tumors, and the drug significantly inhibited tumor growth. T he addition of hyperthermia yielded no additional growth delay in the small tumors. Conclusion: The antivascular properties of vinblastine and hyperthermia can be exploited to facilitate vascular damage in BT(4)An solid tumors with a low content of host vasculature. (C) 2001 Elsevier Science Inc.