Induction of the angiogenic factor VEGF in the uterus by the antiprogestin onapristone

Onapristone (also referred to as ZK 98,299) is an antiprogestin that shares a number of structural similarities to mifepristone (RU-486) and other drugs in this class. While investigating the actions of antiprogestins on steroid hormone induced gene expression of angiogenic factors such as vascular endothelial growth factor (VEGF), we noted that onapristone alone induces VEGF transcript levels in the immature, ovariectomized rat uterus. In addition, onapristone induces expression of c-fos mRNA, which is induced by estrogens but not progestins in this target tissue. This induction of VEGF and c-fos by onapristone is inhibited by the antiestrogen ICI 182,780, but not by the antiprogestin RU-486. Both transcripts are very rapidly induced by onapristone, with maximal mRNA levels observed 3-6 h after in vivo administration of the drug. This time course is similar to that for induction of these genes by estrogenic hormones. Dose-response studies show that both these genes are maximally induced by a 2.5 mg/kg dose of onapristone following intra peritoneal injection. These results indicate that onapristone rapidly upregulates several genes normally under estrogenic regulation in the immature rat uterus. Importantly, this is the first report of the induction of a major angiogenic factor by an antiprogestin. Since an increase in vascularity increases tumor expansion and metastasis, the induction of angiogenesis and its regulatory factors such VEGF may be an important end-point to consider in the development and use of antiprogestins for the treatment of neoplastic disease.