Luteinizing hormone-releasing hormone (LHRH): potential agent of molecular oncology
DOI:
https://doi.org/10.35954/SM2018.37.2.2Keywords:
Luteinizing Hormone, Molecular Imaging, Breast Neoplasms, Prostatic Neoplasms, Receptors, LHAbstract
Luteinizing hormone-releasing hormone is a decapeptide produced by the hypothalamus and has a fundamental role in the regulation of the pituitary/gonadal axis and in the ovarian cycle. It is able to bind to specific receptors on gonadal cells to regulate the synthesis and secretion of gonadotrophic hormones, luteinizing hormones and follicle stimulating hormones. In turn, it has been shown that specific receptors of the hormone releasing luteinizing hormone are overexpressed in breast, prostate, ovarian cancer, among others; which has allowed its use, both analogues and agonists, in therapy for these neoplasms, mainly in prostate and breast cancer. Therefore, we propose
to develop and optimize the gamma emitting radionuclide labeling, 99m-Technetium, of the LHRH peptide, in order to assess its potential use as a molecular imaging agent in oncology. For this purpose, the HYNIC-GSG-LHRH was purchased commercially. The 99mTc labeling was performed at 50°C in the presence of different co-ligands including Tricine, Ethylenediamine diacetic acid, Tricine/Ethylenediamine diacetic acid and Tricine/Nicotinic acid. The marking conditions (pH, concentration of co-ligands, concentration of the reducing agent (tin chloride), temperature and reaction time) were optimized in order to standardize the procedure. The radiochemical purities were evaluated by HPLC. Both the partition coefficients (Log P) and in vitro stability were determined in order to obtain a stable imaging agent of high radiochemical purity. In vitro biological affinity studies were performed in different human breast and prostate cell lines (MDA-MB-231, MCF7 and MDA-MB-435) and prostate (PC3, LnCap and Du-145), as well as their profile of biodistribution in murine models; in order to obtain an approximation to the biological behavior of the new radiotracer. We managed to label the conjugate HYNIC-GSG-LHRH with 99m-Tecnecio, using high specific activities using as co-ligands both Tricine and the Tricine/Nicotinic Acid mixture, obtaining high radiochemical purities (> 95%), high stability in vitro and low lipophilicity (Log P of -2,5 ± 0,05 and -2,82 ± 0,04, using Tricine and Tricine/Nicotinic Acid, respectively). The [99mTc] -HYNIC-GSG-LHRH/Tricine-Nicotinic Acid conjugate revealed a high specific binding affinity for the luteinizing hormone-releasing hormone receptors expressed in the breast and prostate cell lines. It was observed that the radiolabeled complex presents an optimal biodistribution profile to be used as a potential imaging agent.
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(1) World Health Organization [base de datos en in-ternet]. Lyon: International Agency for Resarch on Cáncer. Global Cancer Observatory; 2018 [fecha de acceso 19 ene 2018]. Disponible en: http://gco.iarc.fr/.
(2) Comisión Honoraria de Lucha Contra el Cancer. Situación epidemiológica del Uruguay en relación al cáncer. Montevideo; 2018 [actualizada enero 2018; fecha de acceso 5 ene 2018]. Disponible en: http://www.comisioncancer.org.uy/uc_513_1.html.
(3)Comisión Honoraria de Lucha Contra el Cán-cer. Cáncer de mama en Uruguay. Montevideo, 2018 [actualizada ene 2018; fecha de acceso 5 ene 2018]. Disponible en: http://www.comisioncancer.org.uy/uc_517_1.html.
(4) World Health Organization [base de datos en in-ternet]. Lyon: International Agency for Resarch on Cáncer. Global Cancer Observatory; 2018 [fecha de acceso 19 ene 2018]. Disponible en: https://gco.iarc.fr/today/fact-sheets-cancers.
(5) Comisión Honoraria de Lucha Contra el Cáncer. Cáncer en Uruguay 2010-2014, principales sitios (or-denados por incidencia). Montevideo, 2018 [actualiza-da ene 2018; fecha de acceso 5 feb 2018]. Disponible en: http://www.comisioncancer.org.uy/uc_209_1.html.
(6) Weissleder R, Mahmood U. Mol Imag Radiol 2001; 219(2):316-33.
(7) Nichol C, Kim EE. Molecular imaging and gene therapy. J Nuc Med 2001; 42(9):1368-1374.
(8) Reilly RM, Sandhu J, Alvarez-Diez TM, Gallinger S, Kirsh J, Stern H. Problems of Delivery of Monoclonal Antibodies. Pharmaceutical and pharmacokinetic solutions. Clinical Pharmacokinet 1995; 28(2):126-142.
(9) Ladner RC, Sato AK, Gorzelany J, de Souza M. Phage display-derived peptides as therapeutic alternatives to antibodies.Drug Discov Today 2004; 9(12):525-529.
(10) Stojilkovic SS, Reinhart J, Catt KJ. Gonadotropin-releasing hormone receptors: structureand signal transduction pathways. Endocr Rev 1994; 15(4):462-499.
(11) Schally AV. Hypothalamic hormones: from neu-roendocrinology to cancer therapy. Anticancer Drugs 1994; 5(2):115-130.
(12) Gründker C, Völker P, Griesinger F, Ramsawamy A, Nagay A, Schally AV, et al. Antitumor effects of the cytotoxic luteinizing hormone–releasing hormone analog AN-152 on human endometrial and ovarian cancers xenografted into nude mice. Am J Obstet Gynecol 2002; 187(3):528-537.
(13) Chen A, Kaganovsky E, Rahimipour S, Ben-Aroya N, Okon E, Koch Y. Two Forms of Gonadotropin-releasing Hormone (GnRH) Are Expressed in Human Breast Tissue and Overexpressed in Breast Cancer: A Putative Mechanism for the Antiproliferative Effect of GnRH by Down-Regulation of Acidic Ribosomal Phosphoproteins P1 and P2. Cancer Res 2002; 62(4):1036-1044.
(14) Schally A, Cumaru-Schally AM. Hypothalamic and other peptide hormones. En: Frei BR, Kufe E, Morton DE, Weischselbaum DL, et al. Holland-Frei Cancer Medicine. Chapter 61. 6a. ed. Baltimore: Williams and Wilkins, 1997.
(15) Schally AV, Comaru-Schally AM, Nagy A, Kovacs M, Szepeshazi K, Plonowski A, et al. Hypothalamic hormones and cancer. Front Neuroendocrinol 2001; 22(4):248-91.
(16) Fekete M, Wittliff JL, Schally AV. Characteristics and Distribution of Receptors for [D-TRP6]-Luteinizing Hormone-Releasing Hormone, Somatostatin,Epidermal Growth Factor, and Sex Steroids in 500 BiopsySamples of Human Breast Cancer.J Clin Lab Anal 1989; 3(3):137-147.
(17) Ben-Yehudah A, Lorberboum-Galski H. Targeted cancer therapy with gonadotropin-releasing hormone chimeric proteins. Expert Rev Anticancer Ther 2004; 4(1):151-161.
(18) Pati D, Habibi HR. Inhibition of human hepatocarcinoma cell proliferation by mammalian and fish gonadotropin-releasing hormones. Endocrinol 1995; 136(1):75-84.
(19) Krebs LJ, Wang X, Nagy A, Schally AV, Prasad PN, Liebow C. A conjugate of doxorubicin and an analog of Luteinizing Hormone-Releasing Hormone shows increased efficacy against oral andlaryngeal cancers. Oral Oncology 2002; 38(7):657-663.
(20) Van Groeninghen JC, Kiesel L, Winkler D, Zwirner M. Effects of luteinising-hormone-releasing hormone on nervous-system tumours. Lancet 1998; 352(9125):372-373.
(21) Moretti RM, Montagnani Marelli M, Van Groeninghen JC, Limota P. Locally Expressed LHRH Receptors Mediate the Oncostatic and Antimetastatic Activity of LHRH Agonists on Melanoma Cells. J Clin Endocrinol Metab 2002; 87(8):3791-3797.
(22) Friess H, Büchler M, Kiesel L, Krüger M, Beger HG. LH-RH receptors in the human pancreas. Int J Pancreatol 1991; 10(2):151-159.
(23) Sion-Vardi N, Kaneti J, Segal-Abramson T, Giat J, Levy J, Sharoni Y. Gonadotropin-releasing hormone specific binding sites in normal and malignant renal tissue. J Urol 1992; 148(5):1568-1570.
(24) Liu SV, Tasao-Wei DD, Xiong S, Groshen S, Dorff TB, Quinn DI, et al. Phase I, dose-escalation study of the targeted cytotoxic LHRH analog AEZS-108 in patients with castration- and taxane-resistant prostate cancer. Clin Cancer Res 2014; 20(24):6277-83.
(25) Engel JB, Schally AV, Dietl J, Rieger L, Hönig A. Targeted therapy of breast and gynecological cancers with cytotoxic analogues of peptide hormones. Mol Pharm 2007; 4(5):625-658.
(26) Meszaros LK, Dose A, Biagini SCG, Blower PJ. Synthesis and evaluation of analogues of HYNIC as bifunctional chelators for technetium.Dalton Transactions 2011; 40(23):6260-6267.
(27) Abrams MJ, Juweid M, tenKate CI, Schwartz DA, Hauser MM, Gaul FE, et al. Technetium-99m-Human Polyclonal IgG Radiolabeled via the Hydrazino Nicotinamide Derivative for Imaging Focal Sites of Infection in Rats.J Nucl Medicine 1990; 31(12):2022-2028.
(28) Jurisson S, Berning D, Jia W, Ma D. Coordination Compounds in Nuclear Medicine. Chem Rev 1993; 93(3):1137-56.
(29) Dilworth JR, Parrottb JS. The biomedical chemistry of technetium and rhenium. Chem Soc Rev 1998; 27(1):43-55.
(30) Camacho X, Machado CL, García MF, Fernández M, Oddone N, Benech J. Tocilizumab labeling with 99mTechnetium via HYNIC as a molecular diagnostic agent for Multiple Myeloma. Anticancer Agents Med Chem 2017; 17(9):1267-1277.
(31) Camacho X, Machado CL, García MF, Gambini JP, Banchero A, Fernández M, et al. Technetium-99m- or Cy7-Labeled Rituximab as an Imaging Agent for Non-Hodgkin Lymphoma. Oncology 2017; 15(92):229-42.
(32) Calzada V, García MF, Alonso-Martínez LM, Camacho X, Goicochea E, Fernández M, et al. Fab(nimotuzumab)-HYNIC-99mTc: Antibody fragmentation for molecular imaging agents. Anticancer Agents Med Chem 2016; 16(9):1184-9.
(33) Camacho X, García MF, Calzada V, Fernández M, Alonso O Gambini JP, et al. 99mTc-labeled Bevacizumab vía HYNIC for Imaging of Melanoma. J Anal Oncology 2014; 3:53-64.
(34) García MF, Calzada V, Camacho X, Goicochea E, Gambini JP, Quinn TP, et al.Microwave-assisted Synthesis of HYNIC Protected Analogue for 99mTc Labeled Antibody. Curr Radiopharm 2014; 7(2):84-90.
(35) Hnatowich J, Virzi F, Fogarasi M, Rusckowski M, Winnard P Jr. Can a cysteine challenge assay predict the in vivo behavior of 99mTc-labeled antibodies? Nucl Med Biol 1994; 21(8):1035-44.
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