FLAVONE ACETIC-ACID STIMULATES NITRIC-OXIDE AND PEROXYNITRITE PRODUCTION IN SUBCUTANEOUS MOUSE-TUMORS

Flavone acetic acid (FAA) has powerful anti-tumor activity against man y types of solid murine tumors, but its biochemical mechanism of actio n is not understood, The present study examined the role of tumor vasc ulature and nitric oxide in mediating the anti-tumor effects of FAA. A thymic nude mice bearing subcutaneous RJ2-14 tumors were treated with a single dose of FAA, 200 mg/kg i.p., and euthanized at various times. Apoptosis within tumors was apparent during the first six hours of FA A treatment, We found that Type III, endothelial nitric oxide synthase (NOS) activity was significantly increased in tumors, but not in othe r tissues, as early as two hours after FAA dosing. FAA also stimulated the formation of the toxic peroxynitrite radical in tumors within two hours of treatment as assessed by immunostaining for nitrotyrosine. S taining was observed in dilated tumor vessels and surrounding tumor ce lls and correlated with the presence of apoptosis, Tumor endothelium m ay therefore be a critical target for FAA activity via stimulation of the nitric oxide pathway. (C) 1997 Academic Press.