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Sustained Release Formulations of Luteinizing Hormone-releasing Hormone Antagonist SB-75 Inhibit Proliferation and Enhance Apoptotic Cell Death of Human Prostate Carcinoma (PC-82) in Male Nude Mice¹

Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, and Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70146 [T. W. R., A. V. S., S. R., K. S., S. M.], and Department of Urology, James Buchanan Brady Urological Institute, The Johns Hopkins Hospital, Baltimore, Maryland 21205 [J. T. I.]

The function of the pituitary-gonadal axis in normal (immunocompetent) and nude (immunocompromised) mice, like that of other species, can be suppressed by luteinizing hormone-releasing hormone (LH-RH) agonists and antagonists administered by continuous release systems and, therefore, nude mice provide a valuable model for investigation of the effects of LH-RH analogues on growth of xenografts of human cancers. To extend our findings further, we treated male nude mice bearing xenografts of human prostate adenocarcinoma PC-82, for 42 days, with sustained release formulations (microcapsules or microgranules) of the agonist [D-Trp⁶]LH-RH, the antagonist [Ac-D-Nal(2)¹,D-Phe(4Cl)²,D-Pal(3)³,D-Cit⁶,D-Ala¹⁰]LH-RH (SB-75), or the somatostatin analogue
. At necropsy, in mice given microcapsules releasing 25 µg/day of [D-Trp⁶]-LH-RH, tumor weight and volume were significantly decreased, compared with control mice, and weights of testes, ventral prostate, and seminal vesicles were also reduced in this group. In mice which received microgranules liberating 50 µg/day of antagonist SB-75, there was a greater decrease in tumor weight and volume than that produced by the agonist and a significant reduction in the weight of the testes and accessory sex organs. Histological parameters also demonstrated significant tumor inhibition, with the best results being obtained by treatment with the antagonist SB-75. The tumor inhibition induced by SB-75 was demonstrated to be due to decreased cellular proliferation, with enhanced cellular death (i.e., apoptosis) of the PC-82 cells. Microcapsules releasing 50 µg/day of RC-160 decreased tumor weight and volume by 23% and 28%, respectively, but this reduction was not significant. Serum levels of testosterone were decreased by 90% in mice given the LH-RH agonist and by 94% in response to the antagonist SB-75. Serum levels of prostate-specific antigen were significantly lower in mice treated with LH-RH analogues, with the antagonist SB-75 causing a greater reduction. A ratio of prostate-specific antigen to tumor weight suggests that levels of serum prostate-specific antigen may be correlated with tumor mass. Using sensitive multipoint micromethods, one class of binding sites for LH-RH, with a dissociation constant of 7.8 ± 1.2 nM and a maximal binding capacity of 126.4 ± 23.1 fmol/mg protein, was found in the control tumors. Tumors from mice treated with either LH-RH agonist or antagonist, but not somatostatin analogue RC-160, showed a significant reduction in maximal binding capacity for LH-RH, compared to control tumors. These data clearly demonstrate, for the first time, that the growth of human prostate cancers in nude mice can be inhibited by administration of modern antagonists of LH-RH, like SB-75.

¹ This work was supported by NIH Grant CA 40003 and by the Medical Research Service of the Veterans Affairs (to A. V. S.). The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

² To whom requests for reprints should be addressed, at VA Medical Center, 1601 Perdido Street, New Orleans, LA 70146.

Received 10/18/91. Accepted 2/26/92.

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