Combination of a long-acting delivery system for luteinizing hormone-releasing hormone agonist with Novantrone chemotherapy: increased efficacy in the rat prostate cancer model.

Self Cite

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Somatostatin analogs as adjuncts to agonists of luteinizing hormone-releasing hormone in the treatment of experimental prostate cancer.

Redding¹

1987

Self Cite

“…Serum levels of LH and testosterone were measured by radioimmunoassays as described (17). Statistical analyses were performed by using a computer-assisted program of Duncan's new multiple range test (18).…”

mentioning

confidence: 99%

Suppression of meiosis of male germ cells by an antagonist of luteinizing hormone-releasing hormone.

Szende¹,

Redding²

1990

Self Cite

Male nude mice were implanted with osmotic minipumps releasing 50 pzg of a potent antagonist of luteinizing hormone-releasing hormone (LH-RH) per day {N-Ac-[D-Nal(2)',D-Phe(pCI)2,D-Pal(3)3,D-Cit',D-Ala'0JLH-RH} [Nal(2), 3-(2-naphthyl)alanine; Phe(pCI), 4-chlorophenylalanine; Pal(3), 3-(3-pyridyl)alanine; Cit, citrulline], or they were treated with s.c. injections of SB-75 (25 pug twice a day). Another group of nude mice received an injection of microcapsules of the agonist [D-Trp6]LH-RH liberating 25 pAg/day.One month after the initiation of treatment, the testicular weights were significantly reduced and the blood testosterone values were at castration levels in all treated groups. Histologically, only the testicles of the mice treated with SB-75 released from minipumps showed a significant decrease of meiosis. The most advanced forms ofgerm cells were spermatogonia in 26%, spermatocytes in 17%, and round spermatids in 35% of the seminiferous tubules. Only 22% of the tubules contained elongated spermatids. The suppression of meiotic activity by this modern LH-RH antagonist can possibly be used for the development of methods for male contraception and for the protection of germ cells against the damage caused by cytotoxic drugs and x-radiation.The possible application of analogs of luteinizing hormonereleasing hormone (LH-RH) for development of new contraceptive methods has been investigated for more than a decade (1-4). Potent LH-RH agonists have been developed and used clinically in the areas of cancer and gynecology (2, 3). However, the suitability of LH-RH agonists for male contraception has been questioned because of the induction of impotence when LH-RH agonists alone are used or because of the risks when chronic testosterone supplementation is given to overcome the adverse effects of the LH-RH agonist treatment on libido and potency (2, 3, 5). LH-RH antagonists also exert antifertility effects in female and male rats (6-9) as well as in monkeys (10-12). We showed that pretreatment of rats with one of these antagonists, N--chlorophenylalanine] exerted a protective effect against x-radiation-or chemotherapy-induced testicular damage because of temporary arrest of germ cell proliferation at the time of irradiation or chemotherapy (13,14). However, this class of antagonists with D-Arg in position 6 produced transient edema due to liberation of histamine (15).To eliminate the undesirable edematogenic effects seen with these antagonists, modern antagonists were synthesized In view of the extensive use of the nude mouse model for the investigation of transplanted human cancers, we also demonstrated a strong suppression of the pituitary-gonadal axis in nude mice by continuous administration of LH-RH antagonists. ¶ In this study, we report the effect ofthe LH-RH antagonist SB-75 on the testicular histology in nude mice. MATERIALS AND METHODSAthymic nude (nu/nu) male mice, =6 weeks old on arrival, were obtained from the National Cancer Institute. Mice were housed in sterile plastic cages and were placed in...

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Korkut¹,

Bokser²,

Comaru-Schally³

et al. 1991

Self Cite

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