Histological changes in dunning prostate tumors and testes of rats treated with LH‐RH antagonist SB‐75

Abstract

Rats bearing Dunning R-3327 hormone-dependent prostate tumors were treated with LH-RH antagonist SB-75 in the form of microcapsules for sustained delivery administered every 3 weeks and which released 24, 48, 72 micrograms/day respectively. The effects were compared with those of microcapsules of the agonist D-Trp-6-LH-RH releasing 25 micrograms/day. Both types of LH-RH analogs significantly inhibited tumor growth over a period of treatment lasting 8 weeks. The effect of SB-75 was dose-dependent. The total inhibition of spermatogenesis, as well as atrophic signs in the prostate and seminal vesicles, demonstrated a marked suppression of the pituitary-gonadal system by these analogs. The histological signs of tumor regression were analyzed. The vascular content of tumors did not change after the treatments, but an increased amount of connective tissue was found in the treated tumors, especially after administration of SB-75. Both the agonist and the antagonist caused a moderate decrease of the number of mitotic cells and a marked increase of apoptosis in the tumors. The apoptotic index, i.e. the percentage of tumorous glands showing signs of apoptosis, reached 40-50% in treated groups, compared to only 15% in controls. An apoptotic index of 60% was noted in a separate group of rats treated with 200 micrograms SB-75/animal/day for 3 days. The signs of enhanced apoptosis disappeared 1 week after the short-term treatment. The induction of apoptosis by LH-RH analogs seemed to be of greater importance in tumor growth inhibition than their antimitotic effect. These results extend our previous observations on the efficacy of LH-RH antagonists in inhibition of various cancers. This histopathologic evaluation clearly supports our contention that modern antagonists of LH-RH, free of edematogenic effects, inhibit the growth of Dunning prostate tumors. Because of the immediate inhibitory effects, the use of LH-RH antagonists might lead to an improvement in the clinical response in patients with prostate cancer.

Bombesin antagonists inhibit growth of MDA-MB-435 estrogen-independent breast cancers and decrease the expression of the ErbB-2/HER-2 oncoprotein and c- jun and c- fos oncogenes

“…Mitotic and apoptotic cells were counted in 10 standard high-power microscopic fields containing, on the average, 400 cells, and their numbers per 1,000 cells were accepted as the mitotic and apoptotic indices, respectively. For demonstration of the nucleolar organizer region in tumor cell nuclei, the silver nucleolar organizer region method was used (27). The silver-stained black dots in 50 cells of each tumor were counted, and the silver nucleolar organizer region number per cell was calculated.…”

Inhibition of growth of OV-1063 human epithelial ovarian cancer xenografts in nude mice by treatment with luteinizing hormone-releasing hormone antagonist SB-75.

“…Mitotic and apoptotic cells were counted in 10 high-power fields, and their number per 1000 cells was calculated. For the demonstration of the nucleolar organizer region (NOR) in tumor cell nuclei, the argyrophilic NOR (AgNOR) method of Chiu et al (21) was used with little modification (22). The silver-stained black dots in 50 cells of each tumor were counted and the AgNOR number per cell was calculated.…”

“…The extent of necrosis was measured on the slide containing the largest cross section of tumors, and the percentage area of necrosis was calculated by using an ocular net with 100 crossing points. All (16,20,22). …”

Evaluation of orntide microspheres in a rat animal model and correlation to in vitro release profiles

“…Blockade of the pituitary LHRH receptors prevents stimulatory effects of native LHRH and results in rapid inhibition of the pituitary-gonadal axis; thus, testosterone suppression is immediate without the characteristic stimulatory phase for LHRH superagonists (Scheme 3). In addition, it has been reported that LHRH antagonists directly inhibit growth of numerous tumors, including mammary, pancreatic, and prostatic tumors, by binding to receptors localized on tumor cells [18][19][20][21].…”