Lergotrile mesylate (2-chloro-6-methylergoline-8\g=b\-acetonitrile, methanesulphate salt) was shown to be a potent inhibitor of prolactin secretion in vivo and in vitro. The dopamine receptor blocker, pimozide, was able to reverse the inhibitory effect of lergotrile mesylate (LM) on prolactin release from rat pituitaries in vitro. Alpha-adrenergic or beta-adrenergic receptor blockers were unable to antagonize the action of LM on prolactin release. These findings indicate that ergolines such as LM inhibit prolactin release from pituitaries by activating an adenohypophyseal dopamine receptor. LM is currently undergoing clinical trial as a prolactin inhibitor and a dopamine agonist.

The benzothiophene antiestrogen, raloxifene (LY156758), has selective estrogen pharmacological antagonist activity in rats. The PAIII rat prostatic adenocarcinoma model was used to evaluate the effects of this agent on the lymphatic and pulmonary metastasis and survival in tumor-bearing male Lobund-Wistar (LW) rats. Raloxifene was inactive against colony formation of PAIII cells in vitro. Similarly, following subcutaneous (s.c.) implantation of 10(6) PAIII cells in the tail, s.c. administration of raloxifene (2.0, 10.0, or 20.0 mg/kg/day) for 30 days failed to demonstrate cytoreductive activity against primary tumor growth in the tail. However, in these same animals, raloxifene administration produced significant (P < 0.05) inhibition of PAIII metastasis from the primary tumor in the tail to the gluteal and iliac lymph nodes (maximal responses = 89% and 81% from control values, respectively). PAIII metastasis to the lungs was significantly inhibited by raloxifene treatment. Numbers of pulmonary foci in PAIII-bearing rats were significantly (P < 0.05) reduced by raloxifene administration in a dose-related manner (maximal reduction = 97% from control values). In these animals, maximal regression of 20% for ventral prostate and 21% for seminal vesicle were also seen after raloxifene administration (P < 0.05 for both). Coadministration of E2B and raloxifene had no consistent antagonistic effect upon the antitumor responses produced by raloxifene. Raloxifene (40.0 mg/kg/day for 28 days) produced marked decreases in PAIII metastasis in the lymphatic and pulmonary components. Continued administration of the compound produced significant (P < 0.05) extension of survival of PAIII-bearing rats. Further studies are needed to define the maximal antitumor efficacy and the mechanism of action of raloxifene in urogenital solid tumor animal models. These data support the contention that raloxifene represents a class of active antimetastatic agents with potential efficacy in the treatment of hormone-insensitive human prostatic cancer.

Serum prolactin was determined by radioimmunoassay 4 hours after administration of several psychoactive drugs. Pimozide, an agent that blocks the dopamine-receptor interaction, and chlorpromazine, an agent that blocks both dopamine and norepinephrine-receptor interaction, stimulated prolactin secretion in male and intact and ovariectomized female rats. Reserpine and Oi-methyl-para-tyrosine also stimulated prolactin secretion. All drugs that stimulated prolactin secretion demonstrated a considerably greater ability to do so in intact female rats. Pretreatment for 10 days of ovariectomized rats with 50 ng of estradiol benzoate did not change baseline serum prolactin levels, but it greatIy augmented the rise in serum prolactin observed after treatment with pimozide. Progesterone pretreatment of ovariectomized rats did not alter the amount of prolactin released after pimozide administration. This study demonstrates the irnportance of dopamine involvement in the inhibition of prolactin secretion, and it also shows that the reaetion to psychoaetive drugs ean be modified by the endocrine status of the experimental subjeets.