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
D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 (RC-160). At necropsy, in mice given
microcapsules releasing 25 micrograms/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 micrograms/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 micrograms/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.(ABSTRACT TRUNCATED AT 400 WORDS)