Increased vascularization associated with tumor progression may either involve up-regulation of angiogenic stimulators or down-regulation of angiogenic inhibitors, or both. New blood vessels are necessary for tumor growth and they also serve as a route for metastatic cells into the systemic circulation. Current work focuses on the vascular endothelial growth factor (VEGF) and its tyrosine kinase receptors, flt-1 and KDR. VEGF expression is significantly increased in human breast carcinomas, whereas other known angiogenic stimulators, including basic fibroblast growth factor and transforming growth factors alpha and beta, are not differentially expressed in malignant and the adjacent non-neoplastic breast tissues. In the same breast samples, expression of the two known VEGF receptors, flt-1 and KDR, is not coordinately increased with the VEGF in the carcinomas. Tumor vasculature presents a potential target for anticancer therapy. Flavone acetic acid (FAA) causes hemorrhagic necrosis in a wide spectrum of transplanted rodent tumors which has been associated with effects on the tumor vasculature. FAA is used in this study as a model compound to search for unique properties of tumor vasculature which can serve as therapeutic targets. FAA treatment of mice with transplanted subcutaneous tumors results in increased tumor cell apoptosis, which is first observed after one hour and occupies 95% of the tumor by 24 hours. There is an indication that the antitumor effects of FAA involve increased nitric oxide (NO) synthesis. Nitric oxide synthase (NOS) activity in the tumors is increased two hours after FAA treatment with a simultaneous increase in the formation of toxic peroxinitrite radical. These findings suggest that the apoptotic pathway is triggered by NO-mediated mechanism. In vitro studies show that FAA stimulates endothelial specific NOS activity and causes G2/M cell cycle arrest in microvascular endothelial cells in a dose-dependent manner. FAA also blocks angiogenesis in the chorioallantoic membrane (CAM) assay and endothelial tube formation in Matrigel. The cytostatic and anti-angiogenic effects of FAA may contribute to its tumoricidal activity.
| Buck, T B; Hall, A L; Sinha, C C et al. (2000) cis-hydroxyproline stimulates the growth of rat mammary carcinoma cells. In Vivo 14:11-Jul |
| Schoeffner, D J; Thorgeirsson, U P (2000) Susceptibility of nonhuman primates to carcinogens of human relevance. In Vivo 14:149-56 |
| Harris, S R; Panaro, N J; Thorgeirsson, U P (2000) Oxidative stress contributes to the anti-proliferative effects of flavone acetic acid on endothelial cells. Anticancer Res 20:2249-54 |
| Panaro, N J; Popescu, N C; Harris, S R et al. (1999) Flavone acetic acid induces a G2/M cell cycle arrest in mammary carcinoma cells. Br J Cancer 80:1905-11 |
