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Development of various somatostatin analogs for the treatment and diagnosis of tumors utilizing somatostatin receptor genes

Research Project

Project/Area Number 04557131
Research Category

Grant-in-Aid for Developmental Scientific Research (B)

Allocation TypeSingle-year Grants
Research Field 内分泌・代謝学
Research InstitutionChiba University

Principal Investigator

SEINO Susumu  Chiba University, School of Medicine, Professor, 医学部, 教授 (80236067)

Co-Investigator(Kenkyū-buntansha) HAYASHI Shigehiro  Sandoz Pharmaceuticals Ltd.Tsukuba Research Institute Head, Department of Pharma, つくば総合研究所・薬理研究部, 部長
KUROMI Hiroshi  Chiba University, School of Medicine, Assistant Professor, 医学部, 講師 (30009633)
Project Period (FY) 1992 – 1993
Project Status Completed (Fiscal Year 1993)
Budget Amount *help
¥11,700,000 (Direct Cost: ¥11,700,000)
Fiscal Year 1993: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 1992: ¥7,700,000 (Direct Cost: ¥7,700,000)
KeywordsSomatostatin Receptors / G-protein / Tumors / Somatostatin Analogs / Receptor-imaging
Research Abstract

Somatostatin exerts its effect through its specific high affinity receptors. We have previously reported cloning, functional characterization, and tissue distribution of two subtypes of human and mouse somatostatin receptors (SSTR1, SSTR2). In the present study, we have cloned three additional human somatostatin receptors (SSTR1, SSTR2, SSTR3). Human SSTR1, SSTR2, and SSTR3 are proteins of 418, 388, and 364 amino acids, respectively, RNA blotting studies have revealed that SSTR3 mRNA was detected in human brain and SSTR4 mRNA was present in human pancreatic cancer cell line, MIA PaCa2, while SSTR5 mRNA was not detected in the human tissues examined. The SSTR3 mRNA was expressed at high levels in rat pancreatic islets as well. The human SSTR3, SSTR4, and SSTR5 exhibit specfic binding to somatostatin-14 with IC50 values 1.7, 1.6 and 0.16nM, respectively. We also have characterized the binding affinity of various somatostatin analogs to the SSTR3, 4, and 5. The rank of the potency of the analogs are : somatostatin 28 (SS-28) = CGP 23996>somatostatin-14 (SS-14)>SMS201-995 for hSSTR3 ; SS-14=SS-28>>RC-160>>SMS201-995 for hSSTR4 and SS-28>SS-14>>RC-160>SMS201-995 for hSSTR5. We have determined somatostatin receptor subtypes expressed human endocrine tumors. In two cases of glucagonomas, all the SSTR subtype mRNAs except for SSTR5 mRNA were expressed. In 4 cases of insulinoma, there was a heterogeneous expression hSSTRs. In a carcinoid, SSTR1 and SSTR4 mRNA were detected. Since somatostatin analog, SMS201-995 which has been approved for the treatment of endocrine tumors, was effective in the treatment of a patient with glucagonoma in which SSTR2 mRNA was present, whereas it had no effect in a patient with carcinoid in which SSTR2 mRNA was not detected, these results suggest that the efficacy of SMS201-995 may depend, at least in part, on the expression of SSTR2 in tumors. Cloning of five human somatostatin receptor subtypes facilitates the development of various somatosta

Report

(3 results)
  • 1993 Annual Research Report   Final Research Report Summary
  • 1992 Annual Research Report
  • Research Products

    (20 results)

All Other

All Publications (20 results)

  • [Publications] Yamada,Y: "Somatostatin receptors,an expanding gene family:Cloning and functional characterization of human SSTR3,a protein coupled to adenylyl cyclase" Mol.Endocrinol.6. 2136-2142 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Breder,C.D.: "Differential expression of somatostatin receptor subtypes in brain." J.Neurosci.12. 3920-3934 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Rens-Domiano: "Pharmacological properties of two cloned somatostatin receptors." Mol.Pharm.42. 28-34 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Yamada,Y: "Cloning,functional expression and pharmacological characterization of a fourth(hSSTR4)and a fifth(hSSTR5)human somatostatin receptor subtype." Biochem.Biophys.Res.Commun.195. 844-852 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Yamada,Y.: "Human somatostatin receptor genes:Localization to human chromosomes 14,17 and 22,and identification of simple tandem repeat polymorphisms." Genomics. 15. 449-452 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Kubota,A.: "Identification of somatostatin receptor subtypes and an implication for the efficacy of somatostatin analog SMS 201-995 in treatment of human endocrine tumors." J.Clin.Invest.(in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Yamada, Y.: "Somatostatin receptors, an expanding gene family : Cloning and functional characterization of human SSTR3, a protein coupled to adenylyl cyclase." Mol.Endocrinol.6. 2136-2142 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Breder, C.D.: "Differential expression of somatostatin receptor subtypes in brain." J.Neurosci.12. 3920-3934 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Rens-Domiano, S.: "Pharmacological properties of two cloned somatostatin receptors." Mol.Pharm.42. 28-34 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Yamada, Y.: "Cloning, functional expression and pharmacological characterization of a fourth (hSSTR4) and a fifth (hSSTR5) human somatostatin receptor subtype." Biochem.Biophys.Res.Commun.195. 844-852 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Yamada, Y.: "Human somatostatin receptor genes : Localization to human chromosomes 14, 17 and 22, and identification of simple tandem repeat polymorphisms." Genomics. 15. 449-452 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Kubota, A.: "Identification of somatostatin receptor subtypes and an implication for the efficacy of somatostatin analog SMS 201-995 in treatment of human endocrine tumors." J.Clin.Invest.(in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Yamada,Y: "Cloning,functional expression and pharmacological characterization of a fourth(hSSTR4)and a fifth(hSSTR5)human somatostatin receptor subtype." Biochem.Biophys.Res.Commun.195. 844-852 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Yamada,Y.: "Human somatostatin receptor genes:Localization to human chromosomes 14,17 and 22,and identification of simple tandem repeat polymorphisms." Genomics. 15. 449-452 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Kubota,A.: "Identification of somatostatin receptor subtypes and an implication for the efficacy of somatostatin analog SMS 201-995 in treatment of human endocrine tumors." J.Clin.Invest.(in press).

    • Related Report
      1993 Annual Research Report
  • [Publications] Rens-Domiano,S.: "Pharmacological properties of two cloned somatostatin receptors." Mol.Pharm.42. 28-34 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Breder,C.D.: "Differential expression of somatostatin receptor subtypes in brain." J.Neurosci.12. 3920-3934 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Yamada,Y.: "Somatostatin receptors.an expanding gene family:Cloning and functional characterization of human SSTR3,a protein coupled to adenylyl cyclase." Mol.Endocrinol.6. 2136-2142 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] 伊原 千尋: "ソマトスタチン受容体蛋白に対するポリクローナル抗体の作製とその応用について" 日本内分泌学会雑誌. 68. -321 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] 笠井 馨美: "正常副腎および褐色細胞腫におけるソマトスタチン受容体蛋白について" 日本内分泌学会雑誌. 68. -321 (1992)

    • Related Report
      1992 Annual Research Report

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Published: 1992-04-01   Modified: 2016-04-21  

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