Inhibition of growth of experimental prostate cancer with sustained delivery systems (microcapsules and microgranules) of the luteinizing hormone-releasing hormone antagonist SB-75.

Abstract

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

Recovery of Pituitary-Gonadal Function in Male and Female Rats after Prolonged Administration of a Potent Antagonist of Luteinizing Hormone-Releasing Hormone (SB-75)

“…Subse quently, we and others synthesized new LH-RH antagonists free of edematogenic effects and other anaphylactoid reactions in rats and human beings [6,7,9,[31][32][33][34][35]. Among these analogs, SB-75 proved to be one of the most potent as judged by the inhibition of LH levels in castrated rats in doses as small as 0.625 gg and by a marked suppression of testosterone to castra tion levels in intact rats [9], In oncological studies, SB-75 inhib ited the growth of experimental mammary cancers in mice [36] and rats [35], pancreatic cancer in hamsters [37] and prostate cancers in rats [38][39][40].…”

Evaluation of luteinizing hormone-releasing hormone antagonistic activity in vitro.

“…These analogues may have various practical applications, including treatment of gynecologic disorders and hormone-sensitive tumors such as prostate and breast cancers (1,2,(7)(8)(9). Although chronic administration of LHRH agonists is necessary for inhibition of LH, a single dose of a potent LHRH antagonist is sufficient to evoke the same effect (1, 2, 5-13).…”

“…Some of them proved to be highly potent and free from edematogenic effects. The LHRH antagonists were also very effective in suppressing the growth of experimental mammary cancers and prostate tumors (7,9). To assess the bioactivity of these compounds, the dispersed rat pituitary superfusion system was initially used (5,6).…”

Hecate-CGβ conjugate and gonadotropin suppression shows two distinct mechanisms of action in the treatment of adrenocortical tumors in transgenic mice expressing Simian Virus 40 T antigen under inhibin-α promoter

“…The effectiveness of GnRH-a in cancer treatment, namely in prostate cancer and mammary gland tumors, was first established in animal models already 25 years ago (Redding et al 1982. The first studies with the cetrorelix (used in this study) were performed in the 1990s , Szende et al 1990, Korkut et al 1991. There are also reports showing the effectiveness of GnRH-a in benign prostate hyperplasia treatment (Lepor 2006) and they have been recently clinically tested in the treatment of human prostate cancer (Gittelman et al 2008, Klotz et al 2008, Huhtaniemi et al 2009).…”