Inhibitory effects of the sustained delivery systems (
microcapsules and microgranules) of a potent antagonist of
luteinizing hormone-releasing hormone N-Ac-[3-(2-naphthyl)-D-alanine1, 4-chloro-D-phenylalanine2, 3-(3-pyridyl)-D-alanine3, D-citrulline6, D-alanine10]
LH-RH (SB-75) 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 micrograms of antagonist
SB-75 per day were compared with
microcapsules of agonist [D-Trp6]
LH-RH liberating 25 micrograms/day in rats bearing Dunning R3327H transplantable prostate
carcinoma. During 8 weeks of treatment,
tumor growth was decreased by [D-Trp6]
LH-RH and all three doses of
SB-75 as compared to untreated controls. The highest dose of
SB-75 (71.4 micrograms/day) caused a greater inhibition of
prostate cancer growth than [D-Trp6]
LH-RH as based on measurement of
tumor volume and percentage change in
tumor volume. Doses of 23.8 and 47.6 micrograms of
SB-75 per day induced a partial and submaximal decrease, respectively, in
tumor weight and volume.
Tumor doubling time was the longest (50 days) with the high dose of
SB-75 vs. 15 days for controls. The
body weights were unchanged. The weights of testes, seminal vesicles, and ventral prostate were greatly reduced in all three groups that received
SB-75, and
testosterone levels were decreased to nondetectable values in the case of the two higher doses of
SB-75. LH levels were also diminished. Similar results were obtained in the second experiment, in which the animals were treated for a period of 8 weeks with microgranules of
SB-75.
Therapy with microgranules of
SB-75 significantly decreased
tumor growth as measured by the final
tumor volume, the percentage change from the initial
tumor volume, and the reduction in
tumor weight. The results indicate that antagonist
SB-75, released from sustained delivery systems, can produce a state of chemical
castration and effectively inhibit the growth of experimental
prostate cancers. The efficacy of the antagonist
SB-75 in inhibiting
androgen-dependent Dunning prostatic
carcinoma and the absence of side effects suggest its possible usefulness for the treatment of
hormone-sensitive
tumors.