INHIBITORY EFFECTS OF THE DOPAMINE AGONISTS QUINAGOLIDE (CV 205-502) AND BROMOCRIPTINE ON PROLACTIN SECRETION AND GROWTH OF SMTTW PITUITARY-TUMORS IN THE RAT

The SMtTW tumor, a spontaneous PRL-secreting transplantable tumor, is the only available animal model sensitive to dopamine agonists. This m odel has been used to compare the long term in vivo effects of CV 205- 502 (CV) and bromocriptine (BR) on PRL secretion and tumor growth. The se two drugs were given for 2 months to female Wistar-Furth rats beari ng either small or large tumors 4 and 6 months after the graft. Untrea ted grafted rats served as control. In all rats treated with 5 or 10 m g/kg.day BR or 0.3 mg/kg.day CV, a normalization of plasma PRL levels was observed whatever the pretreatment levels (plasma PRL of CV or BR- treated rats, <15 ng/ml vs. 28253 ng/ ml in control rats 8 months afte r graft). An inhibition of tumor growth was found for both small and l arge tumors, but the tumors never disappeared completely (mean tumor w eights at autopsy, 440 and 660 mg in BR and CV groups us. 5270 mg in c ontrol group 8 months after graft). Experiments performed with increas ing doses of BR (0.15-5 mg/kg.day) or CV (0.03-0.6 mg/kg.day) indicate d that CV is effective at doses 5-10 times lower than those of BR. A s hrinkage under treatment and a regrowth after drug withdrawal were dem onstrated for large tumors by in vivo ultrasonographic measurements of tumor size. Histological and ultrastructural effects were similar for the two drugs: decrease in hemorrhage, reduction of the cell size and secretory activity, increase in immunoreactive PRL cellular content, and inhibition of exocytosis. There was no difference in the PRL mRNA content of treated and untreated tumors, as assessed by in situ hybrid ization. In conclusion, CV and BR exhibit similar inhibitory effects o n tumor growth and PRL secretion. These effects are rapidly and fully reversible after drug withdrawal. The present results give a complete account of the actions of the two dopamine agonists under conditions c omparable to those used in the treatment of human prolactinomas.