Determinants of anti-vascular action by combretastatin A-4 phosphate: role of nitric oxide.

摘要: The anti-vascular action of the tubulin binding agent combretastatin A-4 phosphate (CA-4-P) has been quantified in two types murine tumour, breast adenocarcinoma CaNT and round cell sarcoma SaS. functional vascular volume, assessed using a fluorescent carbocyanine dye, was significantly reduced at 18 h after CA-4-P treatment both tumour types, although degree reduction very different tumours. SaS which higher nitric oxide synthase (NOS) activity than showed ~10-fold greater resistance to damage by CA-4-P. This is consistent with our previous findings, that NO exerts protective against this drug. Simultaneous administration NOS inhibitor, Nω-nitro-L-arginine (L-NNA), resulted enhanced cytotoxicity types. Administration diethylamine NO, an donor, conferred protection damaging effects. Following CA-4-P, neutrophil infiltration into tumours, measured myeloperoxidase (MPO) activity, increased. Levels MPO also correlated levels injury Neutrophilic generates free radicals may therefore contribute associated treatment. increased presence L-NNA, suggesting effect CA-4-P-induced be, least partially, mediated limiting infiltration. data are hypothesis contributes generation acts protect vasculature CA4-P-induced injury. probably anti-neutrophil action. © 2000 Cancer Research Campaign