Induction of the angiogenic factor VEGF in the uterus by the antiprogestinonapristone

Onapristone (also referred to as ZK 98,299) is an antiprogestin that shares a number of structural similarities to mifepristone (RU-486) and other dru gs in this class. While investigating the actions of antiprogestins on ster oid hormone induced gene expression of angiogenic factors such as vascular endothelial growth factor (VEGF), we noted that onapristone alone induces V EGF transcript levels in the immature, ovariectomized rat uterus. In additi on, onapristone induces expression of c-fos mRNA, which is induced by estro gens 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 b y the antiprogestin RU-486. Both transcripts are very rapidly induced by on apristone, with maximal mRNA levels observed 3-6 h after in vivo administra tion of the drug. This time course is similar to that for induction of thes e 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 in tra peritoneal injection. These results indicate that onapristone rapidly u pregulates several genes normally under estrogenic regulation in the immatu re rat uterus. Importantly, this is the first report of the induction of a major angiogenic factor by an antiprogestin. Since an increase in vasculari ty increases tumor expansion and metastasis, the induction of angiogenesis and its regulatory factors such VEGF may be an important end-point to consi der in the development and use of antiprogestins for the treatment of neopl astic disease. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.