Anti-vascular approaches to solid tumour 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 alpha and flavone acetic acid (FAA). More recently, Vincristine and Vinblastine have also been shown to cause a prolonged and selective decrease 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 normal tissue toxicities, which are separately dose-limiting, we have examined the strategy of combining these 2 agents. When Vinblastine preceded FAA by 24 hr or less, tumour growth delay was significantly enhanced without a concomitant increase in toxicity. The level of enhancement was not significantly reduced by a 5-fold decrease in Vinblastine dose, though any reduction in the dose of FAA caused a rapid reduction in treatment effectiveness. Investigation of the functional vasculature of treated tumours suggested that increased anti-vascular effects may contribute to the enhanced growth inhibition of the combined treatment. Our results demonstrate the potential benefit of combining 2 different classes of anti-vascular agent, using Vinblastine and FAA (or 5,6-MeXAA) as prototype drugs.
Hill
S A
SA
Gray Laboratory Cancer Research Trust, Mount Vernon Hospital, Middlesex, UK.
Sampson
L E
LE
Chaplin
D J
DJ
D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage*; D051379:Mice; D008808:Mice, Inbred CBA; D009374:Neoplasms, Experimental; D012039:Regional Blood Flow / Q000187:drug effects; D014747:Vinblastine / Q000008:administration & dosage*
D000970:Antineoplastic Agents; D005419:Flavonoids; D014747:Vinblastine; C049328:flavone acetic acid