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Kasprzak A, Geltz A. The State-of-the-Art Mechanisms and Antitumor Effects of Somatostatin in Colorectal Cancer: A Review. Biomedicines 2024; 12:578. [PMID: 38540191 PMCID: PMC10968376 DOI: 10.3390/biomedicines12030578] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 03/02/2024] [Accepted: 03/03/2024] [Indexed: 01/03/2025] Open
Abstract
Somatostatin, a somatotropin release inhibiting factor (SST, SRIF), is a widely distributed multifunctional cyclic peptide and acts through a transmembrane G protein-coupled receptor (SST1-SST5). Over the past decades, research has begun to reveal the molecular mechanisms underlying the anticancer activity of this hormonal peptide. Among gastrointestinal tract (GIT) tumors, direct and indirect antitumor effects of SST have been documented best in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and less well in non-endocrine cancers, including sporadic colorectal cancer (CRC). In the latter, the signaling pathways involved in the antitumor function of SST are primarily MAPK/ERK/AKT and Wnt/β-catenin. Direct (involving the MAPK pathway) and indirect (VEGF production) antiangiogenic effects of SST in CRC have also been described. The anti-inflammatory role of SST in CRC is emphasized, but detailed molecular mechanisms are still being explored. The role of SST in tumor genome/tumor microenvironment (TME)/host's gut microbiome interactions is only partially known. The results of SST analogues (SSAs)' treatment of sporadic CRC in monotherapy in vivo are not spectacular. The current review aims to present the state-of-the-art mechanisms and antitumor activity of endogenous SST and its synthetic analogues in CRC, with particular emphasis on sporadic CRC.
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Affiliation(s)
- Aldona Kasprzak
- Department of Histology and Embryology, University of Medical Sciences, Swiecicki Street 6, 60-781 Poznań, Poland;
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Sáez-Martínez P, Jiménez-Vacas JM, León-González AJ, Herrero-Aguayo V, Montero Hidalgo AJ, Gómez-Gómez E, Sánchez-Sánchez R, Requena-Tapia MJ, Castaño JP, Gahete MD, Luque RM. Unleashing the Diagnostic, Prognostic and Therapeutic Potential of the Neuronostatin/GPR107 System in Prostate Cancer. J Clin Med 2020; 9:E1703. [PMID: 32498336 PMCID: PMC7355908 DOI: 10.3390/jcm9061703] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 05/22/2020] [Accepted: 05/26/2020] [Indexed: 01/22/2023] Open
Abstract
Certain components of the somatostatin-system play relevant roles in Prostate Cancer (PCa), whose most aggressive phenotype (Castration-Resistant-PCa (CRPC)) remains lethal nowadays. However, neuronostatin and the G protein-coupled receptor 107 (GPR107), two novel members of the somatostatin-system, have not been explored yet in PCa. Consequently, we investigated the pathophysiological role of NST/GPR107-system in PCa. GPR107 expression was analyzed in well-characterized PCa patient's cohorts, and functional/mechanistic assays were performed in response to GPR107-silencing and NST-treatment in PCa cells (androgen-dependent (AD: LNCaP) and androgen-independent (AI: 22Rv1/PC-3), which are cell models of hormone-sensitive and CRPC, respectively), and normal prostate cells (RWPE-1 cell-line). GPR107 was overexpressed in PCa and associated with key clinical parameters (e.g., advance stage of PCa, presence of vascular invasion and metastasis). Furthermore, GPR107-silencing inhibited proliferation/migration rates in AI-PCa-cells and altered key genes and oncogenic signaling-pathways involved in PCa aggressiveness (i.e., KI67/CDKN2D/MMP9/PRPF40A, SST5TMD4/AR-v7/In1-ghrelin/EZH2 splicing-variants and AKT-signaling). Interestingly, NST treatment inhibited proliferation/migration only in AI-PCa cells and evoked an identical molecular response than GPR107-silencing. Finally, NST decreased GPR107 expression exclusively in AI-PCa-cells, suggesting that part of the specific antitumor effects of NST could be mediated through a GPR107-downregulation. Altogether, NST/GPR107-system could represent a valuable diagnostic and prognostic tool and a promising novel therapeutic target for PCa and CRPC.
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Affiliation(s)
- Prudencio Sáez-Martínez
- Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), 14004 Cordoba, Spain; (P.S.-M.); (J.M.J.-V.); (A.J.L.-G.); (V.H.-A.); (A.J.M.H.); (E.G.-G.); (R.S.-S.); (M.J.R.-T.); (J.P.C.); (M.D.G.)
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, 14071 Cordoba, Spain
- Hospital Universitario Reina Sofía (HURS), 14004 Cordoba, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), 14004 Cordoba, Spain
| | - Juan M. Jiménez-Vacas
- Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), 14004 Cordoba, Spain; (P.S.-M.); (J.M.J.-V.); (A.J.L.-G.); (V.H.-A.); (A.J.M.H.); (E.G.-G.); (R.S.-S.); (M.J.R.-T.); (J.P.C.); (M.D.G.)
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, 14071 Cordoba, Spain
- Hospital Universitario Reina Sofía (HURS), 14004 Cordoba, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), 14004 Cordoba, Spain
| | - Antonio J. León-González
- Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), 14004 Cordoba, Spain; (P.S.-M.); (J.M.J.-V.); (A.J.L.-G.); (V.H.-A.); (A.J.M.H.); (E.G.-G.); (R.S.-S.); (M.J.R.-T.); (J.P.C.); (M.D.G.)
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, 14071 Cordoba, Spain
- Hospital Universitario Reina Sofía (HURS), 14004 Cordoba, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), 14004 Cordoba, Spain
| | - Vicente Herrero-Aguayo
- Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), 14004 Cordoba, Spain; (P.S.-M.); (J.M.J.-V.); (A.J.L.-G.); (V.H.-A.); (A.J.M.H.); (E.G.-G.); (R.S.-S.); (M.J.R.-T.); (J.P.C.); (M.D.G.)
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, 14071 Cordoba, Spain
- Hospital Universitario Reina Sofía (HURS), 14004 Cordoba, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), 14004 Cordoba, Spain
| | - Antonio J. Montero Hidalgo
- Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), 14004 Cordoba, Spain; (P.S.-M.); (J.M.J.-V.); (A.J.L.-G.); (V.H.-A.); (A.J.M.H.); (E.G.-G.); (R.S.-S.); (M.J.R.-T.); (J.P.C.); (M.D.G.)
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, 14071 Cordoba, Spain
- Hospital Universitario Reina Sofía (HURS), 14004 Cordoba, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), 14004 Cordoba, Spain
| | - Enrique Gómez-Gómez
- Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), 14004 Cordoba, Spain; (P.S.-M.); (J.M.J.-V.); (A.J.L.-G.); (V.H.-A.); (A.J.M.H.); (E.G.-G.); (R.S.-S.); (M.J.R.-T.); (J.P.C.); (M.D.G.)
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, 14071 Cordoba, Spain
- Hospital Universitario Reina Sofía (HURS), 14004 Cordoba, Spain
- Urology Service, HURS/IMIBIC, 14004 Cordoba, Spain
| | - Rafael Sánchez-Sánchez
- Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), 14004 Cordoba, Spain; (P.S.-M.); (J.M.J.-V.); (A.J.L.-G.); (V.H.-A.); (A.J.M.H.); (E.G.-G.); (R.S.-S.); (M.J.R.-T.); (J.P.C.); (M.D.G.)
- Hospital Universitario Reina Sofía (HURS), 14004 Cordoba, Spain
- Anatomical Pathology Service, HURS, 14004 Cordoba, Spain
| | - María J. Requena-Tapia
- Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), 14004 Cordoba, Spain; (P.S.-M.); (J.M.J.-V.); (A.J.L.-G.); (V.H.-A.); (A.J.M.H.); (E.G.-G.); (R.S.-S.); (M.J.R.-T.); (J.P.C.); (M.D.G.)
- Hospital Universitario Reina Sofía (HURS), 14004 Cordoba, Spain
- Urology Service, HURS/IMIBIC, 14004 Cordoba, Spain
| | - Justo P. Castaño
- Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), 14004 Cordoba, Spain; (P.S.-M.); (J.M.J.-V.); (A.J.L.-G.); (V.H.-A.); (A.J.M.H.); (E.G.-G.); (R.S.-S.); (M.J.R.-T.); (J.P.C.); (M.D.G.)
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, 14071 Cordoba, Spain
- Hospital Universitario Reina Sofía (HURS), 14004 Cordoba, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), 14004 Cordoba, Spain
| | - Manuel D. Gahete
- Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), 14004 Cordoba, Spain; (P.S.-M.); (J.M.J.-V.); (A.J.L.-G.); (V.H.-A.); (A.J.M.H.); (E.G.-G.); (R.S.-S.); (M.J.R.-T.); (J.P.C.); (M.D.G.)
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, 14071 Cordoba, Spain
- Hospital Universitario Reina Sofía (HURS), 14004 Cordoba, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), 14004 Cordoba, Spain
| | - Raúl M. Luque
- Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), 14004 Cordoba, Spain; (P.S.-M.); (J.M.J.-V.); (A.J.L.-G.); (V.H.-A.); (A.J.M.H.); (E.G.-G.); (R.S.-S.); (M.J.R.-T.); (J.P.C.); (M.D.G.)
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, 14071 Cordoba, Spain
- Hospital Universitario Reina Sofía (HURS), 14004 Cordoba, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), 14004 Cordoba, Spain
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Gomes-Porras M, Cárdenas-Salas J, Álvarez-Escolá C. Somatostatin Analogs in Clinical Practice: a Review. Int J Mol Sci 2020; 21:ijms21051682. [PMID: 32121432 PMCID: PMC7084228 DOI: 10.3390/ijms21051682] [Citation(s) in RCA: 138] [Impact Index Per Article: 27.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 02/22/2020] [Accepted: 02/25/2020] [Indexed: 12/14/2022] Open
Abstract
Somatostatin analogs are an invaluable therapeutic option in the diagnosis and treatment of somatotropinomas, thyrotropinomas, and functioning and non-functioning gastroenteropancreatic neuroendocrine tumors. They should also be considered an effective and safe therapeutic alternative to corticotropinomas, gonadotropinomas, and prolactinomas resistant to dopamine agonists. Somatostatin analogs have also shown to be useful in the treatment of other endocrine diseases (congenital hyperinsulinism, Graves’ orbitopathy, diabetic retinopathy, diabetic macular edema), non-endocrine tumors (breast, colon, prostate, lung, and hepatocellular), and digestive diseases (chronic refractory diarrhea, hepatorenal polycystosis, gastrointestinal hemorrhage, dumping syndrome, and intestinal fistula).
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Affiliation(s)
- Mariana Gomes-Porras
- Department of Endocrinology, “La Paz” University Hospital. Paseo de la Castellana, 261, 28046 Madrid, Spain;
| | - Jersy Cárdenas-Salas
- Department of Endocrinology, “Fundación Jiménez-Diaz” University Hospital. Av. de los Reyes Católicos, 2, 28040 Madrid, Spain;
| | - Cristina Álvarez-Escolá
- Department of Endocrinology, “La Paz” University Hospital. Paseo de la Castellana, 261, 28046 Madrid, Spain;
- Correspondence: ; Tel.: +34-917-277-209
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Di Lorenzo G, Autorino R, De Laurentiis M, Bianco R, Lauria R, Giordano A, De Sio M, D'Armiento M, Bianco AR, De Placido S. Is There a Standard Chemotherapeutic Regimen for Hormone-Refractory Prostate Cancer? Present and Future Approaches in the Management of the Disease. TUMORI JOURNAL 2018; 89:349-60. [PMID: 14606635 DOI: 10.1177/030089160308900402] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Prostate cancer that no longer responds to hormonal manipulation can be defined as hormone-refractory prostate cancer. Until recently, there has been no standard chemotherapeutic approach for hormone-refractory prostate cancer. The major benefits of chemotherapy in the treatment of the disease are palliative in nature, in terms of reduction of pain and use of analgesics and improvement of performance status, as followed in the most recent trials. Phase III studies are necessary to better evaluate the efficacy of the different regimens, because several old studies suffer for methodological deficits. There is a promising activity of new drug combinations, such as vinca alkaloids and taxanes. Phase I and II trial are testing combinations of classic chemotherapeutic agents and biologic drugs, and the first results appear interesting. In this article, recent advances in the treatment of hormone-refractory prostate cancer using chemotherapeutic regimens are critically reviewed.
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Hormaechea-Agulla D, Jiménez-Vacas JM, Gómez-Gómez E, L-López F, Carrasco-Valiente J, Valero-Rosa J, Moreno MM, Sánchez-Sánchez R, Ortega-Salas R, Gracia-Navarro F, Culler MD, Ibáñez-Costa A, Gahete MD, Requena MJ, Castaño JP, Luque RM. The oncogenic role of the spliced somatostatin receptor sst5TMD4 variant in prostate cancer. FASEB J 2017; 31:4682-4696. [PMID: 28705809 DOI: 10.1096/fj.201601264rrr] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 06/27/2017] [Indexed: 12/17/2022]
Abstract
sst5TMD4, a splice variant of the sst5 gene, is overexpressed and associated with aggressiveness in various endocrine-related tumors, but its presence, functional role, and mechanisms of actions in prostate cancer (PCa)-the most common cancer type in males-is completely unexplored. In this study, formalin-fixed, paraffin-embedded prostate pieces from patients with localized PCa, which included tumoral and nontumoral adjacent regions (n = 45), fresh biopsies from patients with high-risk PCa (n = 52), and healthy fresh prostates from cystoprostatectomies (n = 14) were examined. In addition, PCa cell lines and xenograft models were used to determine the presence and functional role of sst5TMD4. Results demonstrated that sst5TMD4 is overexpressed (mRNA/protein) in PCa samples, and this is especially drastic in metastatic and/or high Gleason score tumor samples. Remarkably, sst5TMD4 expression was associated with an altered frequency of 2 single-nucleotide polymorphisms: rs197055 and rs12599155. In addition, PCa cell lines and xenograft models were used to demonstrate that sst5TMD4 overexpression increases cell proliferation and migration in PCa cells and induces larger tumors in nude mice, whereas its silencing decreased proliferation and migration. Remarkably, sst5TMD4 overexpression activated multiple intracellular pathways (ERK/JNK, MYC/MAX, WNT, retinoblastoma), altered oncogenes and tumor suppressor gene expression, and disrupted the normal response to somatostatin analogs in PCa cells. Altogether, we demonstrate that sst5TMD4 is overexpressed in PCa, especially in those patients with a worse prognosis, and plays an important pathophysiologic role in PCa, which suggesting its potential as a biomarker and/or therapeutic target.-Hormaechea-Agulla, D., Jiménez-Vacas, J. M., Gómez-Gómez, E., L.-López, F., Carrasco-Valiente, J., Valero-Rosa, J., Moreno, M. M., Sánchez-Sánchez, R., Ortega-Salas, R., Gracia-Navarro, F., Culler, M. D., Ibáñez-Costa, A., Gahete, M. D., Requena, M. J., Castaño, J. P., Luque, R. M. The oncogenic role of the spliced somatostatin receptor sst5TMD4 variant in prostate cancer.
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Affiliation(s)
- Daniel Hormaechea-Agulla
- Maimonides Institute of Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain.,Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain.,Hospital Universitario Reina Sofia (HURS), Cordoba, Spain.,Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain.,Campus de Excelencia Internacional Agroalimentario (CEIA3), Cordoba, Spain
| | - Juan M Jiménez-Vacas
- Maimonides Institute of Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain.,Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain.,Hospital Universitario Reina Sofia (HURS), Cordoba, Spain.,Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain.,Campus de Excelencia Internacional Agroalimentario (CEIA3), Cordoba, Spain
| | - Enrique Gómez-Gómez
- Maimonides Institute of Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain.,Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain.,Hospital Universitario Reina Sofia (HURS), Cordoba, Spain.,Urology Service, Hospital Universitario Reina Sofia (HURS)/Maimonides Institute of Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain
| | - Fernando L-López
- Maimonides Institute of Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain.,Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain.,Hospital Universitario Reina Sofia (HURS), Cordoba, Spain.,Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain.,Campus de Excelencia Internacional Agroalimentario (CEIA3), Cordoba, Spain
| | - Julia Carrasco-Valiente
- Maimonides Institute of Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain.,Hospital Universitario Reina Sofia (HURS), Cordoba, Spain.,Urology Service, Hospital Universitario Reina Sofia (HURS)/Maimonides Institute of Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain
| | - José Valero-Rosa
- Maimonides Institute of Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain.,Hospital Universitario Reina Sofia (HURS), Cordoba, Spain.,Urology Service, Hospital Universitario Reina Sofia (HURS)/Maimonides Institute of Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain
| | - María M Moreno
- Maimonides Institute of Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain.,Hospital Universitario Reina Sofia (HURS), Cordoba, Spain.,Anatomical Pathology Service, Hospital Universitario Reina Sofia (HURS), Cordoba, Spain
| | - Rafael Sánchez-Sánchez
- Maimonides Institute of Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain.,Hospital Universitario Reina Sofia (HURS), Cordoba, Spain.,Anatomical Pathology Service, Hospital Universitario Reina Sofia (HURS), Cordoba, Spain
| | - Rosa Ortega-Salas
- Maimonides Institute of Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain.,Hospital Universitario Reina Sofia (HURS), Cordoba, Spain.,Anatomical Pathology Service, Hospital Universitario Reina Sofia (HURS), Cordoba, Spain
| | - Francisco Gracia-Navarro
- Maimonides Institute of Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain.,Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain.,Hospital Universitario Reina Sofia (HURS), Cordoba, Spain.,Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain.,Campus de Excelencia Internacional Agroalimentario (CEIA3), Cordoba, Spain
| | | | - Alejandro Ibáñez-Costa
- Maimonides Institute of Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain.,Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain.,Hospital Universitario Reina Sofia (HURS), Cordoba, Spain.,Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain.,Campus de Excelencia Internacional Agroalimentario (CEIA3), Cordoba, Spain
| | - Manuel D Gahete
- Maimonides Institute of Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain.,Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain.,Hospital Universitario Reina Sofia (HURS), Cordoba, Spain.,Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain.,Campus de Excelencia Internacional Agroalimentario (CEIA3), Cordoba, Spain
| | - María J Requena
- Maimonides Institute of Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain.,Hospital Universitario Reina Sofia (HURS), Cordoba, Spain.,Urology Service, Hospital Universitario Reina Sofia (HURS)/Maimonides Institute of Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain
| | - Justo P Castaño
- Maimonides Institute of Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain; .,Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain.,Hospital Universitario Reina Sofia (HURS), Cordoba, Spain.,Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain.,Campus de Excelencia Internacional Agroalimentario (CEIA3), Cordoba, Spain
| | - Raúl M Luque
- Maimonides Institute of Biomedical Research of Córdoba (IMIBIC), Cordoba, Spain; .,Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain.,Hospital Universitario Reina Sofia (HURS), Cordoba, Spain.,Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain.,Campus de Excelencia Internacional Agroalimentario (CEIA3), Cordoba, Spain
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Popovics P, Schally AV, Block NL, Rick FG. Preclinical therapy of benign prostatic hyperplasia with neuropeptide hormone antagonists. World J Clin Urol 2014; 3:184-194. [DOI: 10.5410/wjcu.v3.i3.184] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Revised: 06/26/2014] [Accepted: 07/29/2014] [Indexed: 02/06/2023] Open
Abstract
Benign prostatic hyperplasia (BPH) is a pathologic condition of the prostate described as a substantial increase in its number of epithelial and stromal cells. BPH may significantly reduce the quality of life due to the initiation of bladder outlet obstruction and lower urinary tract syndromes. Current medical therapies mostly consist of inhibitors of 5α-reductase or α1-adrenergic blockers; their efficacy is often insufficient. Antagonistic analogs of neuropeptide hormones are novel candidates for the management of BPH. At first, antagonists of luteinizing hormone-releasing hormone (LHRH) have been introduced to the therapy aimed to reduce serum testosterone levels. However, they have also been found to produce an inhibitory activity on local LHRH receptors in the prostate as well as impotence and other related side effects. Since then, several preclinical and clinical studies reported the favorable effects of LHRH antagonists in BPH. In contrast, antagonists of growth hormone-releasing hormone (GHRH) and gastrin-releasing peptide (GRP) have been tested only in preclinical settings and produce significant reduction in prostate size in experimental models of BPH. They act at least in part, by blocking the action of respective ligands produced locally on prostates through their respective receptors in the prostate, and by inhibition of autocrine insulin-like growth factors-I/II and epidermal growth factor production. GHRH and LHRH antagonists were also tested in combination resulting in a cumulative effect that was greater than that of each alone. This article will review the numerous studies that demonstrate the beneficial effects of antagonistic analogs of LHRH, GHRH and GRP in BPH, as well as suggesting a potential role for somatostatin analogs in experimental therapies.
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Ruscica M, Magni P, Steffani L, Gatto F, Albertelli M, Rametta R, Valenti L, Ameri P, Magnaghi V, Culler MD, Minuto F, Ferone D, Arvigo M. Characterization and sub-cellular localization of SS1R, SS2R, and SS5R in human late-stage prostate cancer cells: effect of mono- and bi-specific somatostatin analogs on cell growth. Mol Cell Endocrinol 2014; 382:860-70. [PMID: 24211300 DOI: 10.1016/j.mce.2013.10.027] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2013] [Revised: 10/24/2013] [Accepted: 10/24/2013] [Indexed: 01/10/2023]
Abstract
Somatostatin (SST) and SST receptors (SS1R, SS2R, SS3R, SS4R and SS5R) appear to play a significant role in the progression of human prostate cancer (PCa), which is associated with heterogeneity of SSRs expression and specific cell localization as we already demonstrated in the LNCaP cell line, an in vitro model of human androgen-dependent PCa. In this study, PC-3 and DU-145 human castration-resistant PCa cells were found to express all SSRs, while LNCaP expressed all but SS4R. A 48-h treatment with BIM-23244 (SS2R/SS5R) or BIM-23926 (SS1R) SST analogs was more effective in inhibiting cell proliferation, compared to BIM-23120 (SS2R), BIM-23206 (SS5R) and BIM-23704 (SS1R/SS2R). BIM-23926 (SS1R) treatment increased the amount of p21 and decreased phosphorylated (p) ERK1/2. BIM-23244 (SS2R/SS5R) led to p21 increment only in PC-3 cells, and to pERK1/2 reduction in both cell lines. SS1R/SS2R and SS2R/SS5R receptor dimers were natively present on cell membrane and their amount was increased by BIM-23704 (SS1R/SS2R) or BIM-23244 (SS2R/SS5R) treatment, respectively. SS1R, SS2R and SS5R were differently distributed among nuclear, lysosomal and microsomal compartment, according to their different recycling dynamics. These results show that, in PC-3, DU-145 and LNCaP cells, activation of SS1R and SS2R/SS5R leads to relevant antiproliferative effects.
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Affiliation(s)
- M Ruscica
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - P Magni
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - L Steffani
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - F Gatto
- Department of Internal Medicine and Medical Specialities & Center of Excellence for Biomedical Research, IRCCS AOU San Martino-IST, Università di Genova, Italy
| | - M Albertelli
- Department of Internal Medicine and Medical Specialities & Center of Excellence for Biomedical Research, IRCCS AOU San Martino-IST, Università di Genova, Italy
| | - R Rametta
- Pathophysiology and Transplantation, Università degli Studi di Milano, UO Medicina Interna 1B, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Italy
| | - L Valenti
- Pathophysiology and Transplantation, Università degli Studi di Milano, UO Medicina Interna 1B, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Italy
| | - P Ameri
- Department of Internal Medicine and Medical Specialities & Center of Excellence for Biomedical Research, IRCCS AOU San Martino-IST, Università di Genova, Italy
| | - V Magnaghi
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - M D Culler
- Biomeasure Incorporated/IPSEN, Milford, MA, USA
| | - F Minuto
- Department of Internal Medicine and Medical Specialities & Center of Excellence for Biomedical Research, IRCCS AOU San Martino-IST, Università di Genova, Italy
| | - D Ferone
- Department of Internal Medicine and Medical Specialities & Center of Excellence for Biomedical Research, IRCCS AOU San Martino-IST, Università di Genova, Italy.
| | - M Arvigo
- Department of Internal Medicine and Medical Specialities & Center of Excellence for Biomedical Research, IRCCS AOU San Martino-IST, Università di Genova, Italy
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8
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Xu Y, Jiang Y, Wu B. New Agonist- and Antagonist-Based Treatment Approaches for Advanced Prostate Cancer. J Int Med Res 2012; 40:1217-26. [PMID: 22971474 DOI: 10.1177/147323001204000401] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Increased understanding of prostate cancer biology has led to new treatment strategies and promising new agents for treating prostate cancer, in particular peptide-based agonists and antagonists. In this review article, new therapy modalities and potential approaches for the treatment of advanced prostate cancer are discussed, including agonists and antagonists of luteinizing hormone-releasing hormone, antagonists of bombesin/gastrin-releasing peptide, and growth hormone-releasing hormone and somatostatin analogues. Though the prognosis of patients with prostate cancer is much improved by some of these treatment approaches, including combination treatment methods, extensive side-effects are still reported. These include sexual dysfunction, functional lesions of the liver and renal system, osteoporosis, anaemia and diarrhoea. Future studies should focus on new treatment agents and treatment approaches that can eliminate side-effects and improve quality of life in patients with prostate cancer on the basis of potent treatment efficacy.
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Affiliation(s)
- Y Xu
- Department of Urology, The Affiliated Jiangyin Hospital of Nantong University, Jiangyin, Jiangsu, China
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yf Jiang
- Department of Urology, The Affiliated Jiangyin Hospital of Nantong University, Jiangyin, Jiangsu, China
| | - B Wu
- Department of Urology, The Affiliated Jiangyin Hospital of Nantong University, Jiangyin, Jiangsu, China
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9
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Effect of the somatostatin analog octreotide acetate on circulating insulin-like growth factor-1 and related peptides in patients with non-metastatic castration-resistant prostate cancer: Results of a phase II study. Urol Oncol 2012; 30:408-14. [DOI: 10.1016/j.urolonc.2010.06.014] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2010] [Revised: 06/23/2010] [Accepted: 06/24/2010] [Indexed: 11/22/2022]
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10
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Bellmunt J, Oh WK. Castration-resistant prostate cancer: new science and therapeutic prospects. Ther Adv Med Oncol 2011; 2:189-207. [PMID: 21789134 DOI: 10.1177/1758834009359769] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
There is a growing number of new therapies targeting different pathways that will revolutionize patient management strategies in castration-resistant prostate cancer (CRPC) patients. Today there are more clinical trial options for CRPC treatment than ever before, and there are many promising agents in late-stage clinical testing. The hypothesis that CRPC frequently remains driven by a ligand-activated androgen receptor (AR) and that CRPC tissues exhibit substantial residual androgen levels despite gonadotropin-releasing hormone therapy, has led to the evaluation of new oral compounds such as abiraterone and MDV 3100. Their results, coupled with promising recent findings in immunotherapy (eg sipuleucel-T) and with agents targeting angiogenesis (while awaiting the final results of the CALGB trial 90401) will most probably impact the management of patients with CRPC in the near future. Other new promising agents need further development. With our increased understanding of the biology of this disease, further trial design should incorporate improved patient selection so that patient populations are those who may be most likely to benefit from treatment.
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Affiliation(s)
- Joaquim Bellmunt
- University Hospital del Mar-IMIM Barcelona, Paseo Maritimo 25-29 Barcelona 08003, Spain
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11
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Hasskarl J, Kaufmann M, Schmid HA. Somatostatin receptors in non-neuroendocrine malignancies: the potential role of somatostatin analogs in solid tumors. Future Oncol 2011; 7:895-913. [PMID: 21732759 DOI: 10.2217/fon.11.66] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Somatostatin receptors (sstrs) are G-protein-coupled receptors that mediate various physiological effects when activated by the neuropeptide somatostatin or its synthetic analogs. In addition to the well-documented antisecretory effects of sstr2-preferential somatostatin analogs octreotide and lanreotide, ligand binding to sstr initiates an inhibitory action on tumor growth. This effect may result from both indirect actions (suppression of growth factors and growth-promoting hormones [e.g., GH/IGF-1 axis] and inhibition of angiogenesis) and direct actions (activation of antigrowth activities [e.g., apoptosis]). As solid tumor cells express multiple sstrs, there is a rationale to evaluate the potential antitumor effects of pasireotide (SOM230), a multireceptor-targeted somatostatin analog with high binding affinity for sstr1–3 and sstr5. Pasireotide reduces systemic IGF-1 levels more potently than currently available somatostatin analogs and has been well tolerated in clinical trials.
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Affiliation(s)
| | - Martina Kaufmann
- Novartis Pharma AG, Forum 1, Novartis Campus, CH-4056 Basel, Switzerland
| | - Herbert A Schmid
- Novartis Pharma AG, Forum 1, Novartis Campus, CH-4056 Basel, Switzerland
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12
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Berruti A, Vignani F, Russo L, Bertaglia V, Tullio M, Tucci M, Poggio M, Dogliotti L. Prognostic role of neuroendocrine differentiation in prostate cancer, putting together the pieces of the puzzle. Res Rep Urol 2010; 2:109-24. [PMID: 24198620 PMCID: PMC3818883 DOI: 10.2147/rru.s6573] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Neuroendocrine (NE) differentiation is a common feature in prostate cancer (PC). The clinical significance of this phenomenon is controversial; however preclinical and clinical data are in favor of an association with poor prognosis and early onset of a castrate resistant status. NE PC cells do not proliferate, but they can stimulate the proliferation of the exocrine component through the production of paracrine growth factors. The same paracrine signals may favor the outgrowth of castrate adapted tumors through androgen receptor dependent or independent mechanisms. Noteworthy, NE differentiation in PC is not a stable phenotype, being stimulated by several agents including androgen deprivation therapy, radiation therapy, and chemotherapy. The proportion of NE positive PC, therefore, is destined to increase during the natural history of the disease. This may complicate the assessment of the prognostic significance of this phenomenon. The majority of clinical studies have shown a significant correlation between NE differentiation and disease prognosis, confirming the preclinical rationale. In conclusion the NE phenotype is a prognostic parameter in PC. Whether this phenomenon is a pure prognostic factor or whether it can influence the prognosis by favoring the onset of a castrate resistance status is a matter of future research.
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Affiliation(s)
- Alfredo Berruti
- Oncologia Medica, Università di Torino, Azienda Ospedaliero Universitaria San Luigi, Orbassano, Italy
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13
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Ruscica M, Arvigo M, Gatto F, Dozio E, Feltrin D, Culler MD, Minuto F, Motta M, Ferone D, Magni P. Regulation of prostate cancer cell proliferation by somatostatin receptor activation. Mol Cell Endocrinol 2010; 315:254-62. [PMID: 19932151 DOI: 10.1016/j.mce.2009.11.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2009] [Revised: 11/05/2009] [Accepted: 11/15/2009] [Indexed: 01/24/2023]
Abstract
Although some evidence supports the antitumoral effects of somatostatin (SRIF) and related agonists, the available data in prostate cancer (PCa) model systems and clinical studies are few, conflicting and not conclusive. This study investigated the effects of lanreotide and new mono- and bi-specific SRIF agonists on proliferation, ligand-driven SRIF receptor (sst) dimerization and secretory pattern of the IGF system in LNCaP cells, a model of androgen-dependent PCa. LNCaP expressed all sst(s), but sst(4). Among them, sst(1) and sst(3) were inversely regulated by serum concentration. sst(1)/sst(2) and sst(2)/sst(5) dimers were constitutively present and further stabilized by treatment with BIM-23704 (sst(1)/sst(2)) and BIM-23244 (sst(2)/sst(5)), respectively. Dose-response studies showed that lanreotide and BIM-23244 were significantly more potent in inhibiting LNCaP cell proliferation than BIM-23120 (sst(2)) and BIM-23206 (sst(5)) alone or in combination. Treatment with BIM-23926 [corrected] (sst(1)) markedly reduced cell proliferation, whereas exposure to BIM-23704 resulted in a lower cell growth inhibition. The antiproliferative effects of BIM-23244, lanreotide and BIM-23704 were unchanged, reduced and abolished by the sst(2) antagonist BIM-23627, respectively. All SRIF analogs caused a significant induction in p27(KipI) and p21 and down-regulation of protein expression of cyclin E, as well as reduced IGF-I and IGF-II secretion. In particular, the administration of exogenous IGF-I, at variance to IGF-II, counteracted the inhibitory effect on cell proliferation of these compounds. Moreover, SRIF agonists reduced endogenous IGFBP-3 proteolysis. These results show that, in LNCaP cells, activation of sst(1) and sst(2)/sst(5) results in relevant antiproliferative/antisecretive actions.
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Affiliation(s)
- Massimiliano Ruscica
- Department of Endocrinology, Pathophysiology and Applied Biology, Università degli Studi di Milano, via G. Balzaretti 9, 20133 Milano, Italy
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14
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Mitsogiannis IC, Skolarikos A, Deliveliotis C. Somatostatin analog lanreotide in the treatment of castration-resistant prostate cancer (CRPC). Expert Opin Pharmacother 2009; 10:493-501. [PMID: 19191684 DOI: 10.1517/14656560802694689] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Prostate cancer is a common disease affecting males. Despite initial sensitivity to hormone treatment, prostate cancer eventually progresses to a castration-resistant stage (CRPC), which carries an ominous prognosis. Lanreotide is a long-acting somatostatin analog with the same properties with the native peptide. It has been shown to be highly efficacious in treating various hypersecretoty disorders and tumors. Lanreotide has been administered to patients with CRPC within a novel treatment concept, with the aim of targeting not only cancer cells but also various factors secreted in the tumor cell milieu that confer protection from apoptosis. Within this concept, lanreotide has been administered as part of the "antisurvival factor therapy" in combination with dexamethasone and a gonadotropin releasing hormone (GnRH) analog. It has also been given combined with oestrogens in patients with CRPC. The so far published series have documented a clinical response in many patients treated along with significant improvement in parameters related to quality of life. In view of these promising results, large-scale, randomized, controlled trials are warranted to clearly define the exact role of lanreotide and other somatostatin analogs in the treatment of patients with CRPC.
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Affiliation(s)
- Iraklis C Mitsogiannis
- University of Athens, School of Medicine, 2nd Department of Urology, 5 Proussis Street, 14232 Nea Ionia, Athens, Greece.
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15
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Komiya A, Suzuki H, Imamoto T, Kamiya N, Nihei N, Naya Y, Ichikawa T, Fuse H. Neuroendocrine differentiation in the progression of prostate cancer. Int J Urol 2009; 16:37-44. [PMID: 19120524 DOI: 10.1111/j.1442-2042.2008.02175.x] [Citation(s) in RCA: 91] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Neuroendocrine (NE) cells originally exist in the normal prostate acini and duct, regulating prostatic growth, differentiation and secretion. Clusters of malignant NE cells are found in most prostate cancer (PCa) cases. NE differentiation (NED) is the basic character of the prostate, either benign or malignant. NE cells hold certain peptide hormones or pro-hormones, which affect the target cells by endocrine, paracrine, autocrine and neuroendocrine transmission in an androgen-independent fashion due to the lack of androgen receptor. NED is accessed by immunohistochemical staining or measurement of serum levels of NE markers. The extent of NED is associated with progression and prognosis of PCa. Chromogranin A (CGA) is the most important NE marker. In metastatic PCa, pretreatment serum CGA levels can be a predictor for progression and survival after endocrine therapy. It is recommended to measure longitudinal change in serum CGA. The NE pathway can also be a therapeutic target.
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Affiliation(s)
- Akira Komiya
- Department of Urology, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama, Japan.
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16
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Somatostatin-Analoga in der Therapie des fortgeschrittenen hormonrefraktären Prostatakarzinoms. Urologe A 2008; 47:1334-8. [DOI: 10.1007/s00120-008-1781-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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17
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Koutsilieris M, Bogdanos J, Milathianakis C, Dimopoulos P, Dimopoulos T, Karamanolakis D, Halapas A, Tenta R, Katopodis H, Papageorgiou E, Pitulis N, Pissimissis N, Lembessis P, Sourla A. Combination therapy using LHRH and somatostatin analogues plus dexamethasone in androgen ablation refractory prostate cancer patients with bone involvement: a bench to bedside approach. Expert Opin Investig Drugs 2006; 15:795-804. [PMID: 16787142 DOI: 10.1517/13543784.15.7.795] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
The development of resistance to anticancer therapies is a major hurdle in preventing long-lasting clinical responses to conventional therapies in hormone-refractory prostate cancer. Herein, the molecular evidence documenting that bone metastasis microenvironment survival factors (mainly the paracrine growth hormone-independent, urokinase-type plasminogen activator-mediated increase of IGF-1 and the endocrine production of growth hormone-dependent IGF-1, mainly liver-derived IGF-1 production) produce an epigenetic form of prostate cancer cells that are resistant to proapoptotic therapies is reviewed. Consequently, the authors present the conceptual framework of a novel antibone microenvironment survival factor, mainly an anti-IGF-1 hormonal manipulation for androgen ablation refractory prostate cancer (a combination of conventional androgen ablation therapy [luteinising hormone-releasing hormone agonist-A or orchiectomy]) with dexamethasone plus somatostatin analogue, which yielded durable objective responses and major improvement of bone pain and performance status in stage D3 prostate cancer patients.
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MESH Headings
- Adenocarcinoma/drug therapy
- Adenocarcinoma/secondary
- Adenocarcinoma/surgery
- Androgen Antagonists/therapeutic use
- Androgens/metabolism
- Antineoplastic Agents, Hormonal/pharmacology
- Antineoplastic Agents, Hormonal/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/pharmacology
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Apoptosis
- Bone Neoplasms/drug therapy
- Bone Neoplasms/metabolism
- Bone Neoplasms/secondary
- Clinical Trials, Phase II as Topic
- Combined Modality Therapy
- Dexamethasone/administration & dosage
- Dexamethasone/pharmacology
- Drug Resistance, Neoplasm
- Estramustine/administration & dosage
- Etoposide/administration & dosage
- Gonadotropin-Releasing Hormone/analogs & derivatives
- Gonadotropin-Releasing Hormone/therapeutic use
- Growth Substances/metabolism
- Humans
- Leuprolide/administration & dosage
- Male
- Neoplasm Proteins/metabolism
- Neoplasms, Hormone-Dependent/drug therapy
- Neoplasms, Hormone-Dependent/metabolism
- Neoplasms, Hormone-Dependent/secondary
- Neoplasms, Hormone-Dependent/surgery
- Orchiectomy
- Osteoblasts/metabolism
- Osteoclasts/metabolism
- Paracrine Communication
- Peptides, Cyclic/administration & dosage
- Prospective Studies
- Prostatic Neoplasms/drug therapy
- Prostatic Neoplasms/surgery
- Randomized Controlled Trials as Topic
- Receptors, Androgen/drug effects
- Receptors, Androgen/metabolism
- Salvage Therapy
- Somatostatin/administration & dosage
- Somatostatin/analogs & derivatives
- Survival Analysis
- Triptorelin Pamoate/administration & dosage
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Affiliation(s)
- Michael Koutsilieris
- University of Athens, Department of Basic Sciences, Medical School, 75 Micras Asias, Goudi-Athens 11527, Greece.
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18
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Kalkner KM, Acosta S, Thorsson O, Frederiksen H, Nilsson A, Gustavsson B, Elingsbo M, Stridsberg M, Abrahamsson PA. Octreotide scintigraphy and Chromogranin A do not predict clinical response in patients with octreotide acetate-treated hormone-refractory prostate cancer. Prostate Cancer Prostatic Dis 2005; 9:92-8. [PMID: 16231013 DOI: 10.1038/sj.pcan.4500843] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
In this pilot study, the predictive value of Octreotide scintigraphy (Octreoscan) and/or Chromogranin-A (CgA) was investigated in patients with hormone-refractory prostate cancer treated with Octreotide acetate. In total, 20 patients with progressive disease and bone metastases entered the trial. At baseline Octreoscan, CgA, PSA, alkaline phosphates (ALP) and two self-administered questionnaires (EORTC QLQ C-30 (v3) and brief pain index) were performed and a diary of the pharmaceutical was started. The treatment consisted of Octreotide (Sandostatin LAR) acetate 30 mg intramuscular injection every month. The blood samples and questionnaires were repeated every month until 3 months. Clinical responder was defined as a patient with increased global health score more than 10 units and stable or decreased pain score without an increase in analgesic. In all, 17 patients were treated per protocol, and four were assessed as clinical responders. Six patients developed a reduction in ALP (median -26%, range -5 to -78%). All patients increased in PSA. At baseline, three patients had a negative Octreoscan and the patients with positive lesions, demonstrated uptake of low intensity. At baseline the CgA was elevated above the normal range in 15 of the patients, and during treatment five patients decreased their CgA to the normal range. Neither baseline Octreoscan nor CgA could identify the clinical reponders. A minority of patients improves their health-related quality of life. The decrease and normalization of CgA levels in five patients during therapy indicates therapeutic activity but Octreoscan and CgA could not identify clinical responders.
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Affiliation(s)
- K M Kalkner
- Department of Oncology and Pathology, Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden.
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19
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Sciarra A, Bosman C, Monti G, Gentile V, Autran Gomez AM, Ciccariello M, Pastore A, Salvatori G, Fattore F, Di Silverio F. SOMATOSTATIN ANALOGUES AND ESTROGENS IN THE TREATMENT OF ANDROGEN ABLATION REFRACTORY PROSTATE ADENOCARCINOMA. J Urol 2004; 172:1775-83. [PMID: 15540720 DOI: 10.1097/01.ju.0000140875.07255.f5] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
PURPOSE Prostate cancer progression to androgen ablation refractory stage D3 corresponds to cancer cell escape from androgen withdrawal induced apoptosis. Of note, salvage chemotherapy can extend the median survival of approximately 10 months in patients with stage D3. Therefore, novel therapeutic strategies that target the molecular basis of androgen resistance are required. MATERIALS AND METHODS The MEDLINE and Current Content databases were used to find studies of the use of estrogens and somatostatin analogues for D3 prostate adenocarcinoma. We also analyzed the rationale and clinical results of our combination therapy using lanreotide and ethinylestradiol. RESULTS Negative experiences have been reported with somatostatin analogues as monotherapy. On the other hand, the median progression-free survival reported in our experience using lanreotide acetate plus ethinylestradiol clearly surpassed the 10-month survival historically described in stage D3 cases. CONCLUSIONS The use of somatostatin analogues in combination therapy for D3 prostate cancer sustains the novel concept in cancer treatment in which therapies may target not only cancer cells, but also the microenvironment in combination, which can confer protection from apoptosis.
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20
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Zapata PD, Colas B, López-Ruiz P, Ropero RM, Martín RM, Rodríguez FJ, González FJ, López JI, Angulo JC. [Phosphotyrosine phosphatase SHP-1, somatostatin and prostate cancer]. Actas Urol Esp 2004; 28:269-85. [PMID: 15248398 DOI: 10.1016/s0210-4806(04)73075-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
We review the mechanisms involved in prostatic growth based on androgens and product of neuroendocrine secretion, with special reference to the role of somatostatin (SS) in the inhibition of neoplastic growth. Our contributions in the field confirm the antiproliferative effect of SS on the prostate is mediated by phosphotyrosine phosphatase SHP-1, that is present in human prostate. This enzyme plays a role in the control of prostatic cell proliferation and in the progression of prostate cancer. Besides, we consider its presence may determine the therapeutic potential of SS in the control of prostate cancer.
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Affiliation(s)
- P D Zapata
- Departamento de Bioquímica, Universidad de Alcalá, Servicio de Urología, Hospital Príncipe de Asturias, Alcalá de Henares, Madrid
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21
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Koutsilieris M, Mitsiades CS, Bogdanos J, Dimopoulos T, Karamanolakis D, Milathianakis C, Tsintavis A. Combination of Somatostatin Analog, Dexamethasone, and Standard Androgen Ablation Therapy in Stage D3 Prostate Cancer Patients with Bone Metastases. Clin Cancer Res 2004; 10:4398-405. [PMID: 15240528 DOI: 10.1158/1078-0432.ccr-04-0077] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Androgen ablation-refractory prostate cancer patients (stage D3) develop painful bone metastases and limited responsiveness to conventional therapies, hence the lack of universally accepted "gold standard" treatment for this poor prognosis clinical setting. We tested the safety and efficacy in stage D3 patients of the combination hormonal therapy, which combines administration of somatostatin analog and dexamethasone with standard androgen ablation monotherapy (luteinizing-hormone releasing-hormone analog or orchiectomy). EXPERIMENTAL DESIGN Thirty eight patients with stage D3 prostate cancer (mean age 71.8 +/- 5.9 years) continued receiving androgen ablation therapy in combination with oral dexamethasone (4 mg daily for the 1st month of treatment, tapered down to 1 mg daily by the 4th month, with 1 mg daily maintenance dose thereafter) and somatostatin analog (20 mg octreotide i.m. injections every 28 days). RESULTS Twenty-three of 38 patients (60.5%) receiving this combination regimen had partial responses [PR, >/=50% prostate-specific antigen (PSA) decline], 9 (21.1%) had stable disease, and 7 (18.4%) had progressive disease. In 47.7% (18 of 38) of patients, their serum PSA levels decreased with treatment but did not return to their respective baselines until the end of follow-up (or death from non-prostate cancer-related causes). The median time-to-return to baseline PSA was 12 months (95% CI, 7-17 months), median progression-free survival was 7 months (95% CI, 4.5-9.5 months), median overall survival was 14 months (95% CI, 10.7-17.4 months), and median prostate cancer-specific overall survival (defined as time from onset of combination therapy until prostate cancer-related death) was 16.0 months (95% CI, 11.9-20.1 months). All patients reported significant and durable improvement of bone pain and performance status (for a median duration of 14 months; 95% CI, 9-19 months), without major treatment-related side effects. We observed a statistically significant (P < 0.01) reduction in serum insulin-like growth factor-1 levels at response to the combination therapy. T levels remained suppressed within castration levels at baseline and throughout therapy, including relapse. CONCLUSION The combination therapy of dexamethasone plus somatostatin analog and standard androgen ablation manipulation produces objective clinical responses and symptomatic improvement in androgen ablation-refractory refractory prostate cancer patients.
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Affiliation(s)
- Michael Koutsilieris
- Department of Experimental Physiology, Medical School, University of Athens, Goudi-Athens, Greece.
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Dimopoulos MA, Kiamouris C, Gika D, Deliveliotis C, Giannopoulos A, Zervas A, Alamanis C, Constantinidis C, Koutsilieris M. Combination of LHRH analog with somatostatin analog and dexamethasone versus chemotherapy in hormone-refractory prostate cancer: a randomized phase II study. Urology 2004; 63:120-5. [PMID: 14751362 DOI: 10.1016/j.urology.2003.08.041] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
OBJECTIVES To evaluate prospectively the combination of a luteinizing hormone-releasing hormone analog with a somatostatin analog and dexamethasone in patients with hormone-refractory prostate cancer (HRPC) in a randomized Phase II study. HRPC presents a challenging therapeutic problem. Salvage chemotherapy is the usual approach at this stage of the disease. The combination of a luteinizing hormone-releasing hormone analog with a somatostatin analog and dexamethasone has produced objective clinical responses in HRPC. METHODS Forty patients with HRPC were randomized to receive one of two treatments. Group 1 underwent chemotherapy (estramustine 140 mg three times daily and etoposide 100 mg orally for 21 days) and group 2 the combination of a somatostatin analog (lanreotide 30 mg intramuscularly every 14 days) and dexamethasone (4 mg tapered to 1 mg), in addition to androgen ablation by orchiectomy or a luteinizing hormone-releasing hormone analog (triptorelin 3.75 mg intramuscularly every 28 days). The clinical and prostate-specific antigen (PSA) response, overall survival, time to progression, and toxicity were compared between the two groups. RESULTS The data of 20 patients in group 1 and 18 in group 2 were analyzed. The demographic and clinical data were similar in the two groups at study entry. A PSA response (decrease of greater than 50%) was observed in 45% of group 1 and 44% of group 2. The difference was not statistically significant. A partial clinical response was observed in 29% and 30% of groups 1 and 2, respectively. Again, the difference was not statistically significant. Changes in performance status and pain score during treatment were not significantly different in the two groups. Hematologic toxicity was more frequent in group 1 (80% of patients), and mild diabetes was more frequent in group 2 (22% of patients). The overall survival was 18.8 months in group 1 and 18 months in group 2 (not statistically significant). The time to progression was 6 versus 4 months and, in the PSA responder subgroup, it was 8 versus 7.7 months in groups 1 and 2, respectively (neither difference was statistically significant). CONCLUSIONS The results of our randomized Phase II study indicated that the new combination treatment (luteinizing hormone-releasing hormone analog, somatostatin analog, and dexamethasone) may be equally effective as salvage chemotherapy in patients with HRPC in terms of the clinical and PSA response, overall survival, and time to progression. A larger prospective Phase III trial is required to confirm our observations.
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Affiliation(s)
- Meletios A Dimopoulos
- Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece
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Mosca A, Dogliotti L, Berruti A, Lamberts SWJ, Hofland LJ. Somatostatin receptors: from basic science to clinical approach. Unlabeled somatostatin analogues-1: Prostate cancer. Dig Liver Dis 2004; 36 Suppl 1:S60-7. [PMID: 15077913 DOI: 10.1016/j.dld.2003.11.021] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Neuroendocrine cells have been found in all the stages of prostate cancer, but their clinical significance is not completely understood. Neuroendocrine cells are androgen receptor- and prostate-specific antigen-negative, do not proliferate, and secrete many neuropeptides, such as chromogranin A. Neuroendocrine differentiation of prostate cancer correlates with an advancing tumour stage, poor prognosis and tumour progression after androgen deprivation. Furthermore, neuroendocrine phenotype is associated with the increased expression of neo-angiogenesis and vascular endothelial growth factor and with an over-expression of survivin, a new anti-apoptosis protein. Chromogranin A is the quantitatively major secretory protein of the vesicles inside neuroendocrine prostate cells and it is the marker most frequently used to detect neuroendocrine features, both in tissues and in general circulation. Tumours displaying neuroendocrine phenotype tend to be more aggressive and resistant to hormone-therapy. Neuroendocrine differentiation seems to be a dynamic phenomenon: in vitro and in vivo data suggest that it can be induced by androgen suppression. Moreover, the differences in the expression of somatostatin receptors between primary and hormone-refractory prostate cancer are likely to be related to the changes in neuroendocrine phenotype during androgen deprivation. Circulating chromogranin A levels seem to be scarcely affected by endocrine- and chemotherapy, while they significantly decreased after treatment with somatostatin analogs.
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Affiliation(s)
- A Mosca
- Department of Biological and Clinical Sciences, University of Turin, Medical Oncology, San Luigi Hospital, Regione Gonzole 10, 10043 Orbassano, TO, Italy
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Hansson J, Bjartell A, Gadaleanu V, Dizeyi N, Abrahamsson PA. Expression of somatostatin receptor subtypes 2 and 4 in human benign prostatic hyperplasia and prostatic cancer. Prostate 2002; 53:50-9. [PMID: 12210479 DOI: 10.1002/pros.10121] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
BACKGROUND The presence of receptor subtypes for the inhibitory peptide somatostatin in prostatic tissue has been a controversial issue with conflicting reports. To elucidate whether prostatic epithelial cells express mRNA for somatostatin receptor (SSTR) subtype 2 and 4, we have investigated the localization of SSTR2 and SSTR4 transcripts in prostatic tissues by in situ hybridization. METHODS Nonradioactive in situ hybridization was performed with specific fluorescein-labeled SSTR2 and SSTR4 riboprobes on consecutive sections of benign prostatic hyperplasia (BPH) and prostate cancer tissues. RESULTS We report, for the first time, tissue localization of SSTR2 and SSTR4 mRNA in BPH and malignant cells of human prostate. Hybridization signals for SSTR4 mRNA transcripts were confined to the prostatic epithelium (12 of 16 BPH cases, and in 12 of 13 carcinoma cases), whereas SSTR2 transcripts were predominantly localized in the stromal compartment but also were detectable in epithelial cells in a significant number of specimens (11 of 17 BPH cases, and in 12 of 14 carcinoma cases). Furthermore, the staining intensity for SSTR2 and SSTR4 transcripts is stronger in malignant cells compared with adjacent BPH epithelium. CONCLUSION The data presented suggest that the expression of SSTR2 and SSTR4 transcripts is up-regulated in malignant cells and that not only SSTR2 agonists, but also compounds targeting the SSTR4 subtype may have a potential role in the treatment of prostate cancer.
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Affiliation(s)
- Jens Hansson
- Department of Urology, Lund University, Malmö University Hospital, Malmö, Sweden.
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Hejna M, Schmidinger M, Raderer M. The clinical role of somatostatin analogues as antineoplastic agents: much ado about nothing? Ann Oncol 2002; 13:653-68. [PMID: 12075733 DOI: 10.1093/annonc/mdf142] [Citation(s) in RCA: 88] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Somatostatin (SST) analogues represent a novel approach for the treatment of certain cancers. The objective of this article is to summarise the current knowledge on SST analogues in the treatment of cancer patients. METHODS Computerised (Medline) and manual searches were performed to identify publications on clinical trials published in the English-speaking literature between 1966 and 2000. Information abstracted included patients' pre-treatment status, histology, SST receptor (SSTR) evaluation, type of SST analogue, application schedule and dose, duration of treatment, side-effects, response criteria applied (i.e. WHO response criteria, biochemical criteria or symptomatic investigations) and survival. RESULTS Our search disclosed 22 case reports, five phase 1 and 47 phase II trials, and eight randomised clinical trials using SST analogues (octreotide, lanreotide and vapreotide) as antineoplastic agents. With regard to the phase II trials, conflicting results have been demonstrated in almost all tumour entities investigated. The few randomised studies published so far have shown an impact on survival in patients with hepatocellular cancer, while the effect attributed to treatment in patients with gastrointestinal adenocarcinomas might well have been due to an exceptionally short survival in the control group. There appears to be evidence that SST analogues are able to enhance the therapeutic effects of hormonal intervention in patients with breast cancer, prostate cancer and probably pancreatic cancer. Interpretation of the findings, however, is complicated by the fact that patients were heavily pre-treated in some studies and response criteria have not been uniformly applied. In addition, most studies have not been designed to distinguish between receptor-mediated (direct) and indirect effects of SST analogues in tumour patients. CONCLUSIONS According to the results obtained so far, there can be no doubt about the wide therapeutic index and the high efficacy of SST analogues in the symptomatic management of neuroendocrine tumours. Apart from these indications, the data do not justify recommendation of SST analogues as antineoplastic agents outside of clinical trials, as the optimal dose and schedule of application for antineoplastic activity has not been defined for currently used agents. Carefully designed clinical trials including investigation of SSTR status before treatment, evaluation of an indirect mechanism of SST analogues, and assessment of optimal combination of hormone therapy and chemotherapy with SST analogues are clearly needed in the near future.
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Affiliation(s)
- M Hejna
- Department of Internal Medicine I, University Hospital of Vienna, Austria.
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26
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Abstract
PURPOSE Small-cell carcinoma is very aggressive, metastasizes early and often, and does not respond to most chemotherapy regimens. In approximately 50% of cases of prostate cancer, tumors are a combination of small-cell carcinoma and androgen-sensitive adenocarcinoma. It is widely believed that no successful treatment exists for androgen-independent prostate cancer. METHODS A 67-year-old man had undergone androgen ablation therapy and radical prostatectomy for prostate cancer followed by bilateral orchiectomy, limited radiation therapy, and unsuccessful chemotherapy for pain-causing metastatic bone disease. Biopsy and immunohistochemical analysis revealed neuroendocrine differentiation of the cancer. The full extent of metastatic disease was assessed successfully using In-111, a somatostatin derivative. Octreotide acetate was used to treat the tumors. RESULTS In-111 OctreoScan scintigraphy was more sensitive in the diagnostic demonstration of metastatic foci than was bone scanning. Therapy with the cold somatostatin derivative resulted in a rapid and significant relief of pain with significant tumor shrinkage. The patient remained in remission for at least 10 weeks, when he was lost to follow-up. CONCLUSIONS Somatostatin analogs and their radionuclide and cytotoxic derivatives are recommended as adjuvant treatments for prostate carcinoma, especially in those patients who are at high risk for carcinoma recurrence after radical prostatectomy and who have advanced prostate carcinoma at the time of relapse. Because small-cell carcinomas of the prostate and lung are identical, these analogs may be useful in the detection and treatment of these tumors as well.
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Affiliation(s)
- Michael E Spieth
- Department of Radiology, Marshfield Clinic, Wisconsin 54449, USA.
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Berruti A, Dogliotti L, Mosca A, Tarabuzzi R, Torta M, Mari M, Gorzegno G, Fontana D, Angeli A. Effects of the somatostatin analog lanreotide on the circulating levels of chromogranin-A, prostate-specific antigen, and insulin-like growth factor-1 in advanced prostate cancer patients. Prostate 2001; 47:205-11. [PMID: 11351350 DOI: 10.1002/pros.1064] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND The concept that neuroendocrine cells detected within prostate adenocarcinoma produce paracrine factors, that may exert a proliferative effect on exocrine prostate tumor cells, provides a rationale for the use of somatostatin analogs with the aim to counteract or delay the tumor progression. This study was designed to provide preliminary information on the effect of the administration of a long-acting somatostatin analog, lanreotide, on plasma levels of chromogranin A (CgA). Secondary aims were the evaluation of changes in circulating prostate-specific antigen (PSA) and insulin-like growth factor-1 (IGF-1). METHODS Lanreotide (Ipstyl 30 mg; Ipsen, Milan, Italy) was administered intramuscularly every 14 days for 2 months to nine heavily pretreated prostate cancer patients with hormone refractory disease. All patients had, at baseline conditions, CgA values above the normal range. Androgen deprivation was maintained during the study period, while other concomitant antineoplastic treatments were not allowed. Serum PSA levels and plasma CgA and IGF-1 values were measured every week. RESULTS Lanreotide treatment was very well tolerated and no patient experienced major toxicity. Plasma CgA values at baseline: mean 109 U/liter, standard deviation +/- 85 decreased significantly after treatment as follows: 42 U/liter, +/- 17.8; 27.2 U/liter +/- 13.6; 31.4 U/liter, +/- 17.8 and 27.6 U/liter, +/- 17.0; after 7, 14, 21, and 28 days, respectively (P < 0.01, Friedman ANOVA). Serum PSA did not change. Baseline IGF-1 was found to be above the detection limit in four cases, all of them showing a decrease after lanreotide. CONCLUSIONS Lanreotide administration to prostate cancer patients induces a decrease in plasma CgA and IGF-1 levels, without any influence on serum PSA values. Prostate 47:205-211, 2001.
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Affiliation(s)
- A Berruti
- Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Oncologia Medica, Azienda Ospedaliera San Luigi, Orbassano (Torino), Italy
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Khandwala HM, McCutcheon IE, Flyvbjerg A, Friend KE. The effects of insulin-like growth factors on tumorigenesis and neoplastic growth. Endocr Rev 2000; 21:215-44. [PMID: 10857553 DOI: 10.1210/edrv.21.3.0399] [Citation(s) in RCA: 483] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Several decades of basic and clinical research have demonstrated that there is an association between the insulin-like growth factors (IGFs) and neoplasia. We begin with a brief discussion of the function and regulation of expression of the IGFs, their receptors and the IGF-binding proteins (IGFBPs). A number of investigational interventional strategies targeting the GH or IGFs are then reviewed. Finally, we have assembled the available scientific knowledge about this relationship for each of the major tumor types. The tumors have been grouped together by organ system and for each of the major tumors, various key elements of the relationship between IGFs and tumor growth are discussed. Specifically these include the presence or absence of autocrine IGF-I and IGF-II production; presence or absence of IGF-I and IGF-II receptor expression; the expression and functions of the IGFBPs; in vitro and in vivo experiments involving therapeutic interventions; and available results from clinical trials evaluating the effect of GH/IGF axis down-regulation in various malignancies.
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Affiliation(s)
- H M Khandwala
- Section of Endocrine Neoplasia & Hormonal Disorders, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA
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29
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Insulin-like Growth Factor I and Urokinase-type Plasminogen Activator Bioregulation System as a Survival Mechanism of Prostate Cancer Cells in Osteoblastic Metastases: Development of Anti-Survival Factor Therapy for Hormone-Refractory Prostate Cancer. Mol Med 2000. [DOI: 10.1007/bf03401935] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022] Open
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Baou N, Bouras M, Droz JP, Benahmed M, Krantic S. Evidence for a selective loss of somatostatin receptor subtype expression in male germ cell tumors of seminoma type. Carcinogenesis 2000; 21:805-10. [PMID: 10753219 DOI: 10.1093/carcin/21.4.805] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Somatostatin (SRIF) is a potent antiproliferative signal for both normal and tumoral mammalian cells and an alteration in the SRIF receptor expression pattern has been associated with carcinogenesis. In the present study, the relevance of SRIF signaling to human male germ cell tumors was assessed at the receptor level. The expression of five SRIF receptor (sst1-sst5) mRNAs was estimated by RT-PCR and compared between normal and tumoral testes. All 12 normal testicular tissues studied contained sst3 and sst5 receptor transcripts whereas sst4 was present in almost all (11 of 12). sst1 transcripts were consistently absent while the majority (11/12) of normal samples studied did not contain sst2 mRNA. Parallel assessment of SRIF receptor mRNAs in 10 seminoma testicular germ cell tumors showed expression of a single receptor type, sst5, in all samples analyzed. All seminoma samples were depleted in transcripts corresponding to sst1 and sst2 receptors while either sst3 or sst4 mRNAs were absent in almost all (9 of 10) tumoral samples studied. The comparison of SRIF receptor expression between normal tissue and seminoma tumors thus points to a selective loss of sst3 and sst4 mRNA expression in seminomas. Altogether these data indicate that: (i) normal human testes are putative SRIF targets; (ii) loss of sst3 and sst4 SRIF receptor expression might be associated with seminoma carcinogenesis.
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Affiliation(s)
- N Baou
- Laboratoire de Communication cellulaire en Biologie de la reproduction, INSERM 407, Faculté de Médecine Lyon Sud, BP 12, F-69921 Oullins Cedex, France
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Culler M. Lanreotide and beyond: extending the therapeutic horizons. HOSPITAL MEDICINE (LONDON, ENGLAND : 1998) 1999; 60:714-7. [PMID: 10656063 DOI: 10.12968/hosp.1999.60.10.1214] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Thirty years after the growth hormone inhibiting effects of somatostatin were first described, greater understanding of its activities is opening the door to potential treatments for diabetes, cancer and other disorders. Recent identification of five somatostatin receptor subtypes is allowing treatment to be carefully targeted in order to maximize efficacy, and minimize unwanted effects.
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Su JL, Stimpson S, Edwards C, Van Arnold J, Burgess S, Lin P. Neutralizing IGF-1 monoclonal antibody with cross-species reactivity. Hybridoma (Larchmt) 1997; 16:513-8. [PMID: 9455703 DOI: 10.1089/hyb.1997.16.513] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
We report the generation of a murine IGF-1 monoclonal antibody designated 35I17, which exhibits unique cross-species reactivity. The antibody recognizes recombinant human and rat IGF-1 in ELISA, Western blots, and in an 125I-recombinant human IGF-1 Scintillation Proximity Assay. In addition, 35I17 blocks cell proliferation induced by recombinant human and rat IGF-1, and inhibits cell proliferation induced by sera from human, rat, calf, dog, goat, or mouse. The antibody inhibits rat IGF-1 binding to IGF-1 receptors, and prevents IGF-1-stimulated receptor and IRS-1 phosphorylation in LISN C4 cells, an IGF-1 receptor-transfected cell line. The cross-species and neutralizing properties of 35I17 may be useful in in vitro and in vivo animal studies for elucidating the role of IGF-1 in cancer, rheumatoid arthritis, and other diseases.
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Affiliation(s)
- J L Su
- Department of Molecular Sciences, Glaxo Wellcome Research and Development, Research Triangle Park, NC 27709, USA
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Galbraith SM, Duchesne GM. Androgens and prostate cancer: biology, pathology and hormonal therapy. Eur J Cancer 1997; 33:545-54. [PMID: 9274433 DOI: 10.1016/s0959-8049(96)00444-3] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Affiliation(s)
- S M Galbraith
- Department of Oncology, UCL Medical School, Middlesex Hospital, London, U.K
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Abstract
The potential role of somatostatin (SRIF) in the diagnosis and treatment of nonendocrine human cancers is reviewed. There have been many reports of the growth-inhibitory activity of SRIF on normal and transformed cells in vitro. Many processes involved in malignant tumor growth depend on autocrine growth mechanisms, and somatostatin receptors (ssts) are present on many human cancers. It is possible that mutations in ssts result in a loss of check on proliferation in cancer cells. SRIF analogs may have a number of roles in clinical oncology. Use of radiolabeled tracers enables imaging of tumors bearing ssts; newer agents may enable positron emission tomography (PET) analyses or may be used to deliver lethal radiation doses to cells bearing a unique subset of sst. Although the ability of SRIF and its analogs to inhibit cellular proliferation has been shown in vitro, it has yet to be demonstrated in humans with cancer. Clinical improvements seen with SRIF or its analogs in cancer patients may be related to indirect effects, such as pain relief, reduction of gastrointestinal side effects of chemotherapeutic agents, effects on local production of growth factors, and inhibition of tumoral angiogenesis. Thus, with regard to their potential therapeutic role, SRIF analogs are likely to be used only in conjunction with other approaches, such as radiation, immunotherapy, chemotherapy, and growth factor modulation. Further research into the fundamental functions of each of the ssts and the intracellular actions of SRIF analogs will be needed to assess the potential usefulness of the latter in slowing the progression of human cancers.
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Affiliation(s)
- R J Robbins
- Department of Endocrinology and Metabolism, Cornell University Medical College, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA
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Maulard-Durdux C, Dufour B, Hennequin C, Chrétien Y, Delanian S, Housset M. Phase II study of the oral cyclophosphamide and oral etoposide combination in hormone-refractory prostate carcinoma patients. Cancer 1996; 77:1144-8. [PMID: 8635136 DOI: 10.1002/(sici)1097-0142(19960315)77:6<1144::aid-cncr21>3.0.co;2-0] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND Hormonotherapy temporarily controls symptoms in 80% of patients with metastatic prostate carcinoma. Once progression occurs, no consensus exists on further therapy. Oral etoposide (VP-16) has shown clinical efficacy in advanced small cell lung carcinoma, breast cancer, germ cell tumors, and lymphomas, A synergistic effect between etoposide and alkylating agents such as estramustine was recently reported. We began a prospective Phase II study of an oral combination of cyclophosphamide (CPM) and VP-16 in patients with hormone-refractory [correction of refactory] prostate carcinoma (HRPC). METHODS Patients were orally treated with CPM (100 mg/day) and VP-16 (50 mg/day) for 14 days every 28 days. Therapy continued until there was evidence of disease progression. RESULTS From November, 1992, to February, 1995, 20 patients with HRPC were entered into the study. Patients were eligible if they had an ECOG performance status (PS) of 0 to 2. All of the patients presented with bone metastasis, and 70% presented with bone pain. Seventy-five percent had failed at least two hormonal manipulations. The mean duration of treatment was 5 months (range 2-12). Performance status improved in 26% of the patients, and bone pain was relieved in 71%. An objective response was defined as a decrease of 50% or more in the prostate-specific antigen (PSA) level. One patient demonstrated a complete response, and six patients had partial responses assessed by PSA plasma levels (objective response rate: 35%). The mean duration of response was 8 +/- 6 months (range: 2-24). Median survival was 11 months. Toxicities were minimal. CONCLUSIONS The combination of oral CPM and VP-16 may be an active and well tolerated regimen for patients with HRPC.
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Affiliation(s)
- C Maulard-Durdux
- Department of Oncology-Radiation Therapy, Saint Louis Hospital, Paris, France
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