Gonadotropin-releasing hormone (GnRH) agonist exert "in vivo" an inhibitory action on the growth of hormone-dependent canine mammary tumours (Lombardi et al. [1999] J. Vet. Pharmacol Ther. 22(1):56-61). The present experiments have been performed "in vitro" in order to investigate the mechanisms involved in this direct antiproliferative action of GnRH agonists. In particular, the aim was to study whether these compounds might exert their antiproliferative effect by interfering with the stimulatory action of epidermal growth factor (EGF). To this purpose, the effects of GnRH agonist, Goserelin (GnRH-A), on the mitogenic action of EGF, on EGF-activated intracellular signaling mechanisms (intracellular calcium and nitric oxide production) as well as on ATP induced cell proliferation and signalling, and on the binding of EGF receptors have been evaluated in primary culture of canine mammary tumour cells. The results of these "in vitro" studies show that GnRH-A counteracts the mitogenic action of EGF and ATP, decreases the EGF/ATP-induced calcium signalling and reduces EGF binding, probably by means of NO-induced [Ca2+]i downregulation. These data suggest that GnRH agonists may inhibit the proliferation of the tumour cells by interfering with the stimulatory action of EGF.
Copyright 2002 Wiley-Liss, Inc.