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Andrew V. Schally - One of the best experts on this subject based on the ideXlab platform.
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Combining Growth Hormone-Releasing Hormone Antagonist With Luteinizing Hormone-Releasing Hormone Antagonist Greatly Augments Benign Prostatic Hyperplasia Shrinkage
The Journal of urology, 2012Co-Authors: Ferenc G Rick, Luca Szalontay, Karoly Szepeshazi, Marta Zarandi, Norman L. Block, Andrew V. Schally, Mehrdad Nadji, Irving Vidaurre, Magdolna Kovacs, Zoltan RekasiAbstract:Purpose: Benign prostatic hyperplasia often affects aging men. Antagonists of the neuropeptide growth Hormone-Releasing Hormone reduced prostate weight in an androgen induced benign prostatic hyperplasia model in rats. Luteinizing Hormone-Releasing Hormone antagonists also produce marked, protracted improvement in lower urinary tract symptoms, reduced prostate volume and an increased urinary peak flow rate in men with benign prostatic hyperplasia. We investigated the influence of a combination of antagonists of growth Hormone-Releasing Hormone and Luteinizing Hormone-Releasing Hormone on animal models of benign prostatic hyperplasia.Materials and Methods: We evaluated the effects of the growth Hormone-Releasing Hormone antagonist JMR-132, given at a dose of 40 μg daily, the Luteinizing Hormone-Releasing Hormone antagonist cetrorelix, given at a dose of 0.625 mg/kg, and their combination on testosterone induced benign prostatic hyperplasia in adult male Wistar rats in vivo. Prostate tissue was examined bio...
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triple negative breast cancers express receptors for Luteinizing Hormone releasing Hormone lhrh and respond to lhrh antagonist cetrorelix with growth inhibition
International Journal of Oncology, 2009Co-Authors: S Buchholz, Jorg B Engel, Ferenc G Rick, Luca Szalontay, Florian Hohla, Awtar Krishan, Stephan Seitz, Andrew V. Schally, Andrea PapadiaAbstract:The aim of the present study was to evaluate the expression of receptors for Luteinizing Hormone-Releasing Hormone (LHRH) in human specimens of triple-negative breast cancers (TNBC). In addition, we used in vitro and in vivo models of TNBC to investigate if these receptors are suitable targets for the treatment with the LHRH antagonist Cetrorelix. Receptors for LHRH were expressed in all tumor samples and in the TNBC cell lines HCC1806 and HCC1937. The proliferation of both TNBC cell lines was significantly inhibited in vitro by 1 μM Cetrorelix. Injections of 3 mg Cetrorelix on day 1 and 21 resulted in a significant growth inhibition of HCC1806 tumors xenografted into nude mice. Tumors of mice treated with Cetrorelix expressed less mRNA for EGFR and HER3 receptors than untreated tumors. After treatment of cells with Cetrorelix a flow cytometric analysis of the cell cycle revealed a decrease in S-phase. Given the low toxicity and clinical availability of Cetrorelix, this peptide antagonist should be considered for phase II studies in patients with advanced TNBC.
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Luteinizing Hormone-Releasing Hormone Receptor-Targeted Chemotherapy Using AN-152
Neuroendocrinology, 2009Co-Authors: Gunter Emons, Andrew V. Schally, Herbert Sindermann, Jürgen Engel, Carsten GrundkerAbstract:The Luteinizing Hormone-Releasing Hormone (LHRH; also known as gonadotropin-releasing Hormone) receptor can be utilized for targeted chemotherapy with cytotoxic LHRH analogues such as AN-152, in which
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drug insight clinical use of agonists and antagonists of Luteinizing Hormone releasing Hormone
Nature Clinical Practice Endocrinology & Metabolism, 2007Co-Authors: Jorg B Engel, Andrew V. SchallyAbstract:This article reviews the clinical uses of agonists and antagonists of Luteinizing-Hormone-Releasing Hormone (LHRH), also known as gonadotropin-releasing Hormone. In particular, the state of the art treatment of breast, ovarian and prostate cancer, reproductive disorders, uterine leiomyoma, endometriosis and benign prostatic hypertrophy is reported. Clinical applications of LHRH agonists are based on gradual downregulation of pituitary receptors for LHRH, which leads to inhibition of the secretion of gonadotropins and sex steroids. LHRH antagonists immediately block pituitary LHRH receptors and, therefore, achieve rapid therapeutic effects. LHRH agonists and antagonists can be used to treat uterine leiomyoma and endometriosis; furthermore, both types of LHRH analogs are used to block the secretion of endogenous gonadotropins in ovarian-stimulation programs for assisted reproduction. The preferred primary treatment of patients with advanced, androgen-dependent prostate cancer is based on the periodic administration of depot preparations of LHRH agonists; these agonists can be likewise used to treat estrogen-sensitive breast cancer in premenopausal women. LHRH antagonists have been successfully used to treat prostate cancer and benign prostatic hypertrophy. Since receptors for LHRH are present on a variety of human tumors, (notably breast, prostate, ovarian, endometrial and renal cancers), cytotoxic therapy that targets these tumors with hybrid molecules of LHRH might be possible in the near future. Analogs of LHRH are now a well-established means of treating sex-steroid-dependent, benign and malignant disorders.
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receptors for Luteinizing Hormone releasing Hormone expressed on human renal cell carcinomas can be used for targeted chemotherapy with cytotoxic Luteinizing Hormone releasing Hormone analogues
Clinical Cancer Research, 2005Co-Authors: Gunhild Keller, Andrew V. Schally, Timo Gaiser, Attila Nagy, Benjamin Baker, Gabor Halmos, Jorg B EngelAbstract:Purpose: To determine the expression of Luteinizing Hormone releasing Hormone (LHRH) receptors in specimens and cell lines of human renal cell carcinoma (RCC) and to evaluate the antitumor efficacy of targeted therapy with a cytotoxic analogue of LHRH, AN-207, in vivo. AN-207, consisting of [D-Lys 6 ] LHRH linked to a cytotoxic radical, 2-pyrrolinodoxorubicin (AN-201), binds with high affinity to LHRH receptors and can be targeted to tumors expressing these receptors. Experimental Design: The expression of LHRH receptors was investigated in 28 surgically removed specimens of human renal cell carcinoma (RCC) by immunohistochemistry and in three human RCC cell lines A-498, ACHN, and 786-0 by radioreceptor assays, Western immunoblotting, and reverse transcription-PCR analysis. Antitumor efficacy of AN-207 was examined in experimental models of these cell lines. Results: Positive staining for LHRH receptors was found in all (28 of 28) of the examined human RCC specimens. mRNA for LHRH receptor, receptor protein, and LHRH binding sites were detected in all three cell lines. AN-207 significantly ( P in vivo producing a 67.8% to 73.8% decrease in tumor volume and a 62.2% to 77.3% reduction in tumor weight. Nontargeted cytotoxic radical AN-201 had no significant antitumor effects. Blockade of LHRH receptors by an excess of LHRH agonist Decapeptyl suppressed tumor inhibitory effects of AN-207. Conclusions: Our findings indicate that LHRH receptors are expressed in human RCC specimens and can be used for targeted chemotherapy with cytotoxic LHRH analogues.
Susan Wray - One of the best experts on this subject based on the ideXlab platform.
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Luteinizing Hormone-Releasing Hormone (LHRH) Neurons Maintained in Hypothalamic Slice Explant Cultures Exhibit a Rapid LHRH mRNA Turnover Rate
2013Co-Authors: Jennifer A Maurer, Susan WrayAbstract:Evidence indicates that neuropeptide gene expression is tightly coupled to biosynthesis and secretion. Moreover, rhythmic gene expression often accompanies rhythmic secretion. Luteinizing Hormone-Releasing Hormone (LHRH) neurosecretion, which regulates gonadal function, is pulsatile, with interpulse intervals of �1 hr and pulse decays of �30 min in rats. As a basis for a rapid fall in peptide secretion, we hypothesize that LHRH mRNA levels rapidly decay. To address this hypothesis, we examined LHRH mRNA turnover in primary postnatal LHRH neurons maintained in long-term hypothalamic/preoptic area slice explant cultures, using in situ hybridization histochemistry (ISHH). Relative LHRH mRNA content per cell was quantitated by single-cell analysis after transcription inhibition with 5,6dichloro-1-D-ribofuranosyl-benzimidazole (DRB) or actinomycin D. Cultures were maintained in serum-free medium with tetrodotoxi
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Luteinizing Hormone releasing Hormone lhrh neurons maintained in hypothalamic slice explant cultures exhibit a rapid lhrh mrna turnover rate
The Journal of Neuroscience, 1997Co-Authors: Jennifer A Maurer, Susan WrayAbstract:Evidence indicates that neuropeptide gene expression is tightly coupled to biosynthesis and secretion. Moreover, rhythmic gene expression often accompanies rhythmic secretion. Luteinizing Hormone-Releasing Hormone (LHRH) neurosecretion, which regulates gonadal function, is pulsatile, with interpulse intervals of ∼1 hr and pulse decays of in situ hybridization histochemistry (ISHH). Relative LHRH mRNA content per cell was quantitated by single-cell analysis after transcription inhibition with 5,6-dichloro-1-d-ribofuranosyl-benzimidazole (DRB) or actinomycin D. Cultures were maintained in serum-free medium with tetrodotoxin to suppress spontaneous electrical activity and hence assess only intrinsic cellular activity. A plot of LHRH mRNA level per cell versus DRB treatment time showed a rapid initial decay of LHRH mRNA ( t ½ , 5–13 min), followed by a slower decay rate ( t ½ , 329–344 hr). LHRH cell number after drug treatment as determined by immunocytochemistry did not change. Comparison of mammalian LHRH mRNA 3′-untranslated regions showed two conserved regions. These data indicate that, in primary LHRH neurons, LHRH mRNA has an intrinsically high rate of turnover and a mRNA stabilization component. Foremost, decay of LHRH mRNA, the fastest reported for a neuropeptide to date, corresponds to the decay of LHRH peptide pulses.
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a subset of peripherin positive olfactory axons delineates the Luteinizing Hormone releasing Hormone neuronal migratory pathway in developing mouse
Developmental Biology, 1994Co-Authors: Susan Wray, R Qualls, S M FueshkoAbstract:Luteinizing Hormone releasing Hormone (LHRH) neurons in the CNS are derived from cells of the olfactory placode and thereafter migrate from the olfactory pit into the diencephalon. In this study, we examined embryonic LHRH neurons and the LHRH migratory pathway for several markers. During development, N-CAM and peripherin mRNA were expressed by olfactory epithelia, but not by LHRH cells. In nasal regions, olfactory axons were not immunostained by laminin or fibronectin antibodies, but were robustly peripherin and N-CAM immunoreactive. Although the majority of these axonal tracks entered the developing olfactory bulbs, a small population of peripherin positive but N-CAM negative axons turned caudally into the developing forebrain. LHRH cells were consistently juxtaposed to these axons. We propose that this peripherin positive/N-CAM negative fiber track is the anatomical pathway upon which LHRH cells migrate from the olfactory pit into the diencephalon.
Kaneto Uekama - One of the best experts on this subject based on the ideXlab platform.
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Spectroscopic Characterization of the Inclusion Complex of a Luteinizing Hormone-Releasing Hormone Agonist, Buserelin Acetate, with Dimethyl-β-cyclodextriin
Chemical & pharmaceutical bulletin, 1997Co-Authors: Kazutaka Matsubara, Tetsumi Irie, Kaneto UekamaAbstract:Inclusion complexation of buserelin acetate, an agonist of Luteinizing Hormone-Releasing Hormone, with dimethyl-β-cyclodextrin (DM-β-CyD) in aqueous solution was studied spectroscopically and its mode of interaction was assessed. Ultraviolet absorption and circular dichroism (CD) spectroscopies indicate that the aromatic side chains of buserelin acetate, L-tryptophan and L-tyrosine residues, are incorporated into the hydrophobic environment of the DM-β-CyD cavity. Furthermore, proton and carbon-13 nuclear magnetic resonance spectroscopies suggest that in addition to the two aromatic side chains, a tertiary butyl D-serine residue is inserted into the DM-β-CyD cavity from the secondary hydroxyl side. On the other hand, the continuous variation plots for the buserelin acetate : DM-β-CyD system showed a 1 : 1 stoichiometry of the complex. Therefore, the complexation should be initiated by the inclusion of one of the three binding sites on the buserelin molecule into DM-β-CyD, which may in turn prevent the further access of the second cyclodextrin to the other binding sites, probably due to steric hindrance and/or conformation changes of the peptide. These structural features of the complex would account for the stabilizing effect of DM-β-CyD on the enzymatic degradation of buserelin acetate.
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Protection afforded by maltosyl-β-cyclodextrin against α- chymotrypsin-catalyzed hydrolysis of a Luteinizing Hormone-Releasing Hormone agonist, buserelin acetate
Pharmaceutical research, 1997Co-Authors: Kazutaka Matsubara, Tetsumi Irie, Yukihiro Ando, Kaneto UekamaAbstract:Purpose. The present study addresses how maltosyl-β-cyclodextrin (G2-β-CyD) impacts upon the α-chymotrypsin-catalyzed hydrolysis of buserelin acetate, an agonist of Luteinizing Hormone-Releasing Hormone with emphasis upon the direct effect of G2-β-CyD on the activity of the protease.
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improvement of nasal bioavailability of Luteinizing Hormone releasing Hormone agonist buserelin by cyclodextrin derivatives in rats
Journal of Pharmaceutical Sciences, 1995Co-Authors: Kazutaka Matsubara, Tetsumi Irie, Kazuya Abe, Kaneto UekamaAbstract:The effects of chemically modified cyclodextrins on the nasal absorption of buserelin, an agonist of Luteinizing Hormone-Releasing Hormone, were investigated in anesthetized rats. Of the cyclodextrins tested, dimethyl-beta-cyclodextrin (DM-beta-CyD) was the most effective in improving the rate and extent of the nasal bioavailability of buserelin. Fluorescence spectroscopic studies indicated that the cyclodextrins formed inclusion complexes with buserelin, which may reduce the diffusibility of buserelin across the nasal epithelium and may participate in the protection of the peptide against enzymatic degradation in the nasal mucosa. Additionally, the cyclodextrins increased the permeability of the nasal mucosa, which was the primary determinant based on the multiple regression analysis of the nasal absorption enhancement of buserelin. Scanning electron microscopic observations revealed that DM-beta-CyD induced no remarkable changes in the surface morphology of the nasal mucosa at a minimal concentration necessary to achieve substantial absorption enhancement. The present results suggest that DM-beta-CyD could improve the nasal bioavailability of buserelin and is well-tolerated by the nasal mucosa of the rat.
Ferenc G Rick - One of the best experts on this subject based on the ideXlab platform.
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Combining Growth Hormone-Releasing Hormone Antagonist With Luteinizing Hormone-Releasing Hormone Antagonist Greatly Augments Benign Prostatic Hyperplasia Shrinkage
The Journal of urology, 2012Co-Authors: Ferenc G Rick, Luca Szalontay, Karoly Szepeshazi, Marta Zarandi, Norman L. Block, Andrew V. Schally, Mehrdad Nadji, Irving Vidaurre, Magdolna Kovacs, Zoltan RekasiAbstract:Purpose: Benign prostatic hyperplasia often affects aging men. Antagonists of the neuropeptide growth Hormone-Releasing Hormone reduced prostate weight in an androgen induced benign prostatic hyperplasia model in rats. Luteinizing Hormone-Releasing Hormone antagonists also produce marked, protracted improvement in lower urinary tract symptoms, reduced prostate volume and an increased urinary peak flow rate in men with benign prostatic hyperplasia. We investigated the influence of a combination of antagonists of growth Hormone-Releasing Hormone and Luteinizing Hormone-Releasing Hormone on animal models of benign prostatic hyperplasia.Materials and Methods: We evaluated the effects of the growth Hormone-Releasing Hormone antagonist JMR-132, given at a dose of 40 μg daily, the Luteinizing Hormone-Releasing Hormone antagonist cetrorelix, given at a dose of 0.625 mg/kg, and their combination on testosterone induced benign prostatic hyperplasia in adult male Wistar rats in vivo. Prostate tissue was examined bio...
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triple negative breast cancers express receptors for Luteinizing Hormone releasing Hormone lhrh and respond to lhrh antagonist cetrorelix with growth inhibition
International Journal of Oncology, 2009Co-Authors: S Buchholz, Jorg B Engel, Ferenc G Rick, Luca Szalontay, Florian Hohla, Awtar Krishan, Stephan Seitz, Andrew V. Schally, Andrea PapadiaAbstract:The aim of the present study was to evaluate the expression of receptors for Luteinizing Hormone-Releasing Hormone (LHRH) in human specimens of triple-negative breast cancers (TNBC). In addition, we used in vitro and in vivo models of TNBC to investigate if these receptors are suitable targets for the treatment with the LHRH antagonist Cetrorelix. Receptors for LHRH were expressed in all tumor samples and in the TNBC cell lines HCC1806 and HCC1937. The proliferation of both TNBC cell lines was significantly inhibited in vitro by 1 μM Cetrorelix. Injections of 3 mg Cetrorelix on day 1 and 21 resulted in a significant growth inhibition of HCC1806 tumors xenografted into nude mice. Tumors of mice treated with Cetrorelix expressed less mRNA for EGFR and HER3 receptors than untreated tumors. After treatment of cells with Cetrorelix a flow cytometric analysis of the cell cycle revealed a decrease in S-phase. Given the low toxicity and clinical availability of Cetrorelix, this peptide antagonist should be considered for phase II studies in patients with advanced TNBC.
Jorg B Engel - One of the best experts on this subject based on the ideXlab platform.
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triple negative breast cancers express receptors for Luteinizing Hormone releasing Hormone lhrh and respond to lhrh antagonist cetrorelix with growth inhibition
International Journal of Oncology, 2009Co-Authors: S Buchholz, Jorg B Engel, Ferenc G Rick, Luca Szalontay, Florian Hohla, Awtar Krishan, Stephan Seitz, Andrew V. Schally, Andrea PapadiaAbstract:The aim of the present study was to evaluate the expression of receptors for Luteinizing Hormone-Releasing Hormone (LHRH) in human specimens of triple-negative breast cancers (TNBC). In addition, we used in vitro and in vivo models of TNBC to investigate if these receptors are suitable targets for the treatment with the LHRH antagonist Cetrorelix. Receptors for LHRH were expressed in all tumor samples and in the TNBC cell lines HCC1806 and HCC1937. The proliferation of both TNBC cell lines was significantly inhibited in vitro by 1 μM Cetrorelix. Injections of 3 mg Cetrorelix on day 1 and 21 resulted in a significant growth inhibition of HCC1806 tumors xenografted into nude mice. Tumors of mice treated with Cetrorelix expressed less mRNA for EGFR and HER3 receptors than untreated tumors. After treatment of cells with Cetrorelix a flow cytometric analysis of the cell cycle revealed a decrease in S-phase. Given the low toxicity and clinical availability of Cetrorelix, this peptide antagonist should be considered for phase II studies in patients with advanced TNBC.
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drug insight clinical use of agonists and antagonists of Luteinizing Hormone releasing Hormone
Nature Clinical Practice Endocrinology & Metabolism, 2007Co-Authors: Jorg B Engel, Andrew V. SchallyAbstract:This article reviews the clinical uses of agonists and antagonists of Luteinizing-Hormone-Releasing Hormone (LHRH), also known as gonadotropin-releasing Hormone. In particular, the state of the art treatment of breast, ovarian and prostate cancer, reproductive disorders, uterine leiomyoma, endometriosis and benign prostatic hypertrophy is reported. Clinical applications of LHRH agonists are based on gradual downregulation of pituitary receptors for LHRH, which leads to inhibition of the secretion of gonadotropins and sex steroids. LHRH antagonists immediately block pituitary LHRH receptors and, therefore, achieve rapid therapeutic effects. LHRH agonists and antagonists can be used to treat uterine leiomyoma and endometriosis; furthermore, both types of LHRH analogs are used to block the secretion of endogenous gonadotropins in ovarian-stimulation programs for assisted reproduction. The preferred primary treatment of patients with advanced, androgen-dependent prostate cancer is based on the periodic administration of depot preparations of LHRH agonists; these agonists can be likewise used to treat estrogen-sensitive breast cancer in premenopausal women. LHRH antagonists have been successfully used to treat prostate cancer and benign prostatic hypertrophy. Since receptors for LHRH are present on a variety of human tumors, (notably breast, prostate, ovarian, endometrial and renal cancers), cytotoxic therapy that targets these tumors with hybrid molecules of LHRH might be possible in the near future. Analogs of LHRH are now a well-established means of treating sex-steroid-dependent, benign and malignant disorders.
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receptors for Luteinizing Hormone releasing Hormone expressed on human renal cell carcinomas can be used for targeted chemotherapy with cytotoxic Luteinizing Hormone releasing Hormone analogues
Clinical Cancer Research, 2005Co-Authors: Gunhild Keller, Andrew V. Schally, Timo Gaiser, Attila Nagy, Benjamin Baker, Gabor Halmos, Jorg B EngelAbstract:Purpose: To determine the expression of Luteinizing Hormone releasing Hormone (LHRH) receptors in specimens and cell lines of human renal cell carcinoma (RCC) and to evaluate the antitumor efficacy of targeted therapy with a cytotoxic analogue of LHRH, AN-207, in vivo. AN-207, consisting of [D-Lys 6 ] LHRH linked to a cytotoxic radical, 2-pyrrolinodoxorubicin (AN-201), binds with high affinity to LHRH receptors and can be targeted to tumors expressing these receptors. Experimental Design: The expression of LHRH receptors was investigated in 28 surgically removed specimens of human renal cell carcinoma (RCC) by immunohistochemistry and in three human RCC cell lines A-498, ACHN, and 786-0 by radioreceptor assays, Western immunoblotting, and reverse transcription-PCR analysis. Antitumor efficacy of AN-207 was examined in experimental models of these cell lines. Results: Positive staining for LHRH receptors was found in all (28 of 28) of the examined human RCC specimens. mRNA for LHRH receptor, receptor protein, and LHRH binding sites were detected in all three cell lines. AN-207 significantly ( P in vivo producing a 67.8% to 73.8% decrease in tumor volume and a 62.2% to 77.3% reduction in tumor weight. Nontargeted cytotoxic radical AN-201 had no significant antitumor effects. Blockade of LHRH receptors by an excess of LHRH agonist Decapeptyl suppressed tumor inhibitory effects of AN-207. Conclusions: Our findings indicate that LHRH receptors are expressed in human RCC specimens and can be used for targeted chemotherapy with cytotoxic LHRH analogues.
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human malignant melanomas express receptors for Luteinizing Hormone releasing Hormone allowing targeted therapy with cytotoxic Luteinizing Hormone releasing Hormone analogue
Cancer Research, 2005Co-Authors: Gunhild Keller, Andrew V. Schally, Timo Gaiser, Attila Nagy, Benjamin Baker, Gabriela Westphal, Gabor Halmos, Jorg B EngelAbstract:Cytotoxic analogue of Luteinizing Hormone releasing Hormone (LHRH), AN-207, binds with high affinity to LHRH receptors and can be targeted to tumors expressing these receptors. We investigated the expression of LHRH receptors in surgical specimens of human malignant melanoma and evaluated the effects of AN-207 in models of human melanoma. Human melanoma specimens derived from primary tumors or metastases were examined for LHRH receptor expression by immunohistochemistry. Binding assays, Western immunoblotting, and reverse transcription-PCR analyses were used to investigate LHRH receptors in MRI-H255 and MRI-H187 transplantable human melanoma tumor lines. Antitumor effects of AN-207 and its components were evaluated in vivo in nude mice bearing xenografts of either melanoma tumor line. All 19 human melanoma specimens examined showed positive staining for LHRH receptors. The mRNA for LHRH receptors, receptor protein and binding sites for LHRH were detected in both transplantable melanoma tumor lines. AN-207 significantly inhibited the growth of MRI-H255 and MRI-H187 xenografts in vivo, reducing tumor volume by 59.9% to 79.2% and tumor weight by 61.0% to 76.9% (all P < 0.05). The components of AN-207 (LH-RH analogue carrier and cytotoxic radical AN-201 as single drugs or as an unconjugated mixture) had no significant effects. Blockade of LHRH receptors by an excess of LHRH agonist Decapeptyl suppressed the effects of AN-207. LHRH receptors are expressed in a very high percentage of human malignant melanoma specimens and can be used for targeted chemotherapy with cytotoxic LHRH analogue AN-207.
