Sa. Hill et al., ANTIVASCULAR APPROACHES TO SOLID TUMOR-THERAPY - EVALUATION OF VINBLASTINE AND FLAVONE ACETIC-ACID, International journal of cancer, 63(1), 1995, pp. 119-123
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.