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Inhibitory effects of the sustained delivery systems (microcapsules and microgranules) of a potent antagonist of luteinizing hormone-releasing hormone N-Ac- on the growth of experimental prostate cancers were investigated. In the first experiment, three doses of a microcapsule preparation releasing 23.8, 47.6, and 71.4 Although androgen deprivation represents standard treatment for prostatic cancer, new approaches are constantly explored to improve the therapy in terms of response rates, duration of response, and increase in survival rate (1, 2). Since the isolation and structural elucidation of hypothalamic luteinizing hormone-releasing hormone (LH-RH), more than 3000 analogs were synthesized in view of their potential medical applications (3,4). The inhibition of the pituitarygonadal axis by chronic administration of LH-RH agonistic analogs, including LH-RH, shown in animals (5) and man (6), led to demonstration of the suppression of growth of prostate tumors in animals (7) and their successful use in the treatment of prostatic cancer in patients (8) as a better alternative to castration or estrogens (1, 3). Although repeated administration of LH-RH agonists is required to inhibit luteinizing hormone (LH) release and reduce the levels of sex steroids, similar effects can be obtained with a single dose of LH-RH antagonists (1, 3, 4). The antagonistic analogs were synthesized initially for use in gynecology as contraceptives (1, 3). However, progress in development and clinichl application of LH-RH antagonists has been slow (1). High-dose requirements, due to low potency of earlier compounds and side effects related to histamine release of analogs with D-arginine in position 6, delayed clinical use of LH-RH antagonists (1,4,9).Modem LH-RH antagonists, free of edematogenic and anaphylactoid reactions, containing neutral hydrophilic D-ureidoalkyl amino acids such as D-citrulline and D-homocitrulline at position 6, were recently synthesized in our laboratory and tested in vitro and in vivo (10-12). Among these analogs,RH; SB-75} was shown to be one of the most powerful antagonists in blocking ovulation and inhibiting LH levels in rats (9,11,12). The use of antagonists in tumor therapy would avoid the transient stimulation that occurs initially in response to LH-RH agonists and prevent the temporary clinical "flareup" of the disease.Further improvement in the convenience and reliability of treatment could be achieved by the use of long-acting delivery systems for controlled release of peptides (1,3,(12)(13)(14)(15) (13,(16)(17)(18) and clinically (1,3,19). Prototypes of microcapsules of somatostatin analog RC-160 and, more recently, of LH-RH antagonist SB-75 were also used in the treatment of experimental breast cancer and pancreatic cancer (20,21). More modern forms of sustained-delivery systems, which consist of microparticles (microgranules) containing pamoate or LH-RH, also have been prepared (9,12,15). Microcapsules are more uniform spherical particles with

Enkephalins, naturally occurring peptides with powerful opiatelike effects, have recently been detected throughout the tissues of the alimentary tract, but their role is unknown. This study was designed to compare the effects of methionine-enkephalin (met-enkephalin) and morphine on the myoelectrical pattern of the small bowel. Five conscious dogs were prepared with electrodes spaced 25 cm apart along the entire small intestine. Spike activity and slow waves were recorded with a Beckman Dynograph. Records were obtained in fasted conditions and following a meat meal or intravenous infusion of caerulein while animals received intravenous infusion of either met-enkephalin or morphine in various doses (range 10-160 microgram/kg . h). Met-enkephalin at a dose of 40 microgram/kg . h caused a significant decrease in spike activity and in the frequency of bursts of the interdigestive myoelectric complexes (IMC), whereas morphine almost doubled the frequency of the IMC. Met-enkephalin in dogs given food or infused with caerulein significantly decreased the fed-type spike activity of the small bowel, whereas morphine did not affect it. The effects of met-enkephalin and morphine on the intestinal myoelectrical pattern can be reversed by naloxone, an opioid antagonist, suggesting that they are mediated by separate opioid receptors.