ANTIVASCULAR APPROACHES TO SOLID TUMOR-THERAPY - EVALUATION OF VINBLASTINE AND FLAVONE ACETIC-ACID

Several agents have now been identified which exert their anti-tumour effects in large part via the tumour vasculature; these include TNF al pha and flavone acetic acid (FAA). More recently, Vincristine and Vinb lastine have also been shown to cause a prolonged and selective decrea se in tumour perfusion. Vinblastine, unlike FAA, causes no increase in plasma TNF alpha levels in mice bearing the CaNT tumour, suggesting 2 distinct mechanisms of anti-vascular activity for these structurally diverse agents. Since FAA and Vinblastine also show quite different no rmal tissue toxicities, which are separately dose-limiting, we have ex amined the strategy of combining these 2 agents. When Vinblastine prec eded FAA by 24 hr or less, tumour growth delay was significantly enhan ced without a concomitant increase in toxicity. The level of enhanceme nt was not significantly reduced by a 5-fold decrease in Vinblastine d ose, though any reduction in the dose of FAA caused a rapid reduction in treatment effectiveness. Investigation of the functional vasculatur e of treated tumours suggested that increased anti-vascular effects ma y contribute to the enhanced growth inhibition of the combined treatme nt. Our results demonstrate the potential benefit of combining 2 diffe rent classes of antivascular agent, using Vinblastine and FAA (or 5,6- MeXAA) as prototype drugs. (C) 1995 Wiley-Liss, Inc.