Receptors for Luteinizing Hormone-Releasing Hormone (LHRH) in dunning R3327 prostate cancers and rat anterior pituitaries after treatment with a sustained delivery system of LHRH antagonist SB-75

G. Srkalovic, L. Bokser, S. Radulovic, E. Korkut, Andrew V Schally

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Membrane receptors for LHRH were evaluated in Dunning R3327 prostate cancers and rat anterior pituitaries. The receptors were characterized both in untreated animals and after the in vivo treatment with microcapsules of the agonist D-Trp6-LHRH and a sustained delivery system releasing different doses (23.8, 47.6, 71.4 μg/day) of LHRH antagonist [Ac-D-Nal(2)1-D-Phe(4Cl)2-D-Pal(3)3,D-Cit 6, D-Ala10]-LHRH (SB-75). The therapy, which lasted 8 weeks, strongly inhibited tumor growth. A group of normal Sprague-Dawley male rats was also treated for 6 weeks with microcapsules of SB-75 releasing 25 μg/ day. In the Dunning tumors from the control group, ligand [125I, D-Trp6]-LHRH was bound to two classes of binding sites [dissociation constant, class a (Kda) = 1.01 ± 0.30 × 10-9 M; Kdb, = 1.71 ± 0.41 × 10-6 M; maximal binding capacity of receptors, class a (Bmaxa) = 48.66 ± 22.13 fmol/mg of protein; Bmaxb = 92.10 ± 29.40 pmol/mg of protein] in both kinetic and equilibrium studies. Treatment with D-Trp6-LHRH produced down-regulation of membrane receptors for LHRH in Dunning tumors. Microcapsules of SB-75 resulted in dose-dependent up-regulation of binding sites for LHRH in Dunning tumors. Analysis of the binding data showed that interaction of labeled D-Trp6-LHRH with binding sites in anterior pituitaries was consistent with the presence of a single class of noncooperative receptors (Kd = 43.75 × 10-9 M; Bmax = 5.25 pmol/mg membrane proteins). Prolonged treatment with microcapsules of D-Trp6-LHRH reduced both Bmax and Kd. Lower doses of SB-75 (23.8 and 47.6 μg/day) produced up-regulation, whereas the highest dose (71.4 μg/day) resulted in down-regulation of binding sites for LHRH in rat pituitaries. In normal Sprague-Dawley rats, treatment with microcapsules of SB-75 (25 μg/day) for 6 weeks produced a slight increase in the number of available binding sites (Bmax = 2.35 ± 0.82 pmol/mg membrane protein) and a moderate decrease in affinity (Kd = 35.10 ± 15.19 × 10-9 M) of pituitary membrane receptors for LHRH. The findings provide additional support for the view that LHRH analogs exert direct effects on tumor cells. Our findings indicate that prolonged treatment with high doses of modern LHRH antagonists produces down-regulation of pituitary receptors. Our work in tumors also implies that some differences may exist between LHRH receptors, even in the same tissue, leading to the concept of subclassification of LHRH receptors.

Original languageEnglish
Pages (from-to)3052-3060
Number of pages9
JournalEndocrinology
Volume127
Issue number6
StatePublished - Dec 1 1990
Externally publishedYes

Fingerprint

LHRH Receptors
Hormone Antagonists
Gonadotropin-Releasing Hormone
Prostatic Neoplasms
Capsules
Binding Sites
Neoplasms
Down-Regulation
Membranes
Sprague Dawley Rats
Membrane Proteins
cetrorelix
Up-Regulation
Proteins

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Receptors for Luteinizing Hormone-Releasing Hormone (LHRH) in dunning R3327 prostate cancers and rat anterior pituitaries after treatment with a sustained delivery system of LHRH antagonist SB-75. / Srkalovic, G.; Bokser, L.; Radulovic, S.; Korkut, E.; Schally, Andrew V.

In: Endocrinology, Vol. 127, No. 6, 01.12.1990, p. 3052-3060.

Research output: Contribution to journalArticle

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abstract = "Membrane receptors for LHRH were evaluated in Dunning R3327 prostate cancers and rat anterior pituitaries. The receptors were characterized both in untreated animals and after the in vivo treatment with microcapsules of the agonist D-Trp6-LHRH and a sustained delivery system releasing different doses (23.8, 47.6, 71.4 μg/day) of LHRH antagonist [Ac-D-Nal(2)1-D-Phe(4Cl)2-D-Pal(3)3,D-Cit 6, D-Ala10]-LHRH (SB-75). The therapy, which lasted 8 weeks, strongly inhibited tumor growth. A group of normal Sprague-Dawley male rats was also treated for 6 weeks with microcapsules of SB-75 releasing 25 μg/ day. In the Dunning tumors from the control group, ligand [125I, D-Trp6]-LHRH was bound to two classes of binding sites [dissociation constant, class a (Kda) = 1.01 ± 0.30 × 10-9 M; Kdb, = 1.71 ± 0.41 × 10-6 M; maximal binding capacity of receptors, class a (Bmaxa) = 48.66 ± 22.13 fmol/mg of protein; Bmaxb = 92.10 ± 29.40 pmol/mg of protein] in both kinetic and equilibrium studies. Treatment with D-Trp6-LHRH produced down-regulation of membrane receptors for LHRH in Dunning tumors. Microcapsules of SB-75 resulted in dose-dependent up-regulation of binding sites for LHRH in Dunning tumors. Analysis of the binding data showed that interaction of labeled D-Trp6-LHRH with binding sites in anterior pituitaries was consistent with the presence of a single class of noncooperative receptors (Kd = 43.75 × 10-9 M; Bmax = 5.25 pmol/mg membrane proteins). Prolonged treatment with microcapsules of D-Trp6-LHRH reduced both Bmax and Kd. Lower doses of SB-75 (23.8 and 47.6 μg/day) produced up-regulation, whereas the highest dose (71.4 μg/day) resulted in down-regulation of binding sites for LHRH in rat pituitaries. In normal Sprague-Dawley rats, treatment with microcapsules of SB-75 (25 μg/day) for 6 weeks produced a slight increase in the number of available binding sites (Bmax = 2.35 ± 0.82 pmol/mg membrane protein) and a moderate decrease in affinity (Kd = 35.10 ± 15.19 × 10-9 M) of pituitary membrane receptors for LHRH. The findings provide additional support for the view that LHRH analogs exert direct effects on tumor cells. Our findings indicate that prolonged treatment with high doses of modern LHRH antagonists produces down-regulation of pituitary receptors. Our work in tumors also implies that some differences may exist between LHRH receptors, even in the same tissue, leading to the concept of subclassification of LHRH receptors.",
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N2 - Membrane receptors for LHRH were evaluated in Dunning R3327 prostate cancers and rat anterior pituitaries. The receptors were characterized both in untreated animals and after the in vivo treatment with microcapsules of the agonist D-Trp6-LHRH and a sustained delivery system releasing different doses (23.8, 47.6, 71.4 μg/day) of LHRH antagonist [Ac-D-Nal(2)1-D-Phe(4Cl)2-D-Pal(3)3,D-Cit 6, D-Ala10]-LHRH (SB-75). The therapy, which lasted 8 weeks, strongly inhibited tumor growth. A group of normal Sprague-Dawley male rats was also treated for 6 weeks with microcapsules of SB-75 releasing 25 μg/ day. In the Dunning tumors from the control group, ligand [125I, D-Trp6]-LHRH was bound to two classes of binding sites [dissociation constant, class a (Kda) = 1.01 ± 0.30 × 10-9 M; Kdb, = 1.71 ± 0.41 × 10-6 M; maximal binding capacity of receptors, class a (Bmaxa) = 48.66 ± 22.13 fmol/mg of protein; Bmaxb = 92.10 ± 29.40 pmol/mg of protein] in both kinetic and equilibrium studies. Treatment with D-Trp6-LHRH produced down-regulation of membrane receptors for LHRH in Dunning tumors. Microcapsules of SB-75 resulted in dose-dependent up-regulation of binding sites for LHRH in Dunning tumors. Analysis of the binding data showed that interaction of labeled D-Trp6-LHRH with binding sites in anterior pituitaries was consistent with the presence of a single class of noncooperative receptors (Kd = 43.75 × 10-9 M; Bmax = 5.25 pmol/mg membrane proteins). Prolonged treatment with microcapsules of D-Trp6-LHRH reduced both Bmax and Kd. Lower doses of SB-75 (23.8 and 47.6 μg/day) produced up-regulation, whereas the highest dose (71.4 μg/day) resulted in down-regulation of binding sites for LHRH in rat pituitaries. In normal Sprague-Dawley rats, treatment with microcapsules of SB-75 (25 μg/day) for 6 weeks produced a slight increase in the number of available binding sites (Bmax = 2.35 ± 0.82 pmol/mg membrane protein) and a moderate decrease in affinity (Kd = 35.10 ± 15.19 × 10-9 M) of pituitary membrane receptors for LHRH. The findings provide additional support for the view that LHRH analogs exert direct effects on tumor cells. Our findings indicate that prolonged treatment with high doses of modern LHRH antagonists produces down-regulation of pituitary receptors. Our work in tumors also implies that some differences may exist between LHRH receptors, even in the same tissue, leading to the concept of subclassification of LHRH receptors.

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