Vinblastine and hyperthermia target the neovasculature in BT₄AN rat gliomas: Therapeutic implications of the vascular phenotype

Purpose: The antivascular and antitumor activity of vinblastine and hyperthermia at different tumor volumes were examined in the subcutaneous (s.c.) BT₄An rat glioma model. Methods and Materials: The influence of vinblastine (3 mg/kg) and hyperthermia (44°C/60 min) on tumor growth was assessed in small (100 mm³) and large (200 mm³) BT₄An tumors. To disclose how vinblastine and hyperthermia interacted in the neoplasms, tumor blood flow and the extent of vascular damage, hypoxia, cell proliferation, and apoptosis were assessed after treatment. The content of smooth muscle cells/pericytes in the tumor vasculature was examined in small and large tumors to assess how the vascular phenotype changed during tumor growth. Results: In the large tumors, vinblastine reduced the blood flow, but the tumor growth was not affected. The combination of drug and local heating yielded massive vascular damage and a significant tumor response. The small neoplasms had a higher content of smooth muscle cells/pericytes in the vessel walls (host vasculature), and the tumor vasculature displayed a higher resistance to vascular damage than the large neoplasms. Yet, vinblastine alone exhibited a potent antiproliferative activity and induced massive apoptosis in the small tumors, and the drug significantly inhibited tumor growth. The 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 BT₄An solid tumors with a low content of host vasculature.