Receptor-targeted therapy of human experimental urinary bladder cancers with cytotoxic LH-RH analog AN-152 (AEZS-108)

Szepesházi, Karoly; Keller, Gunhild; Block, Norman L.; Benten, Daniel; Halmos, Gábor; Szalontay, Luca; Vidaurre, Irving; Jászberényi, Miklós; Rick, Ferenc G.

doi:10.18632/oncotarget.546

Cited by 33 publications

(46 citation statements)

References 52 publications

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“…About 70%-80% of human ovarian cancers and about 80% of human endometrial carcinomas express LHRH receptors. The receptors are expressed in 86% of prostate cancers [28] and in all bladder cancers examined [29] as well as 46%-69% of uveal melanomas [30]. These findings all suggest a clinical utility for the presence of the receptor.…”

Section: Discussionmentioning

confidence: 77%

LHRH receptor expression in sarcomas of bone and soft tissue

Deivaraju¹,

Temple²,

Block³

et al. 2016

Hormone Molecular Biology and Clinical Investigation

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Aim: Luteinizing hormone releasing hormone (LHRH) is a neurohormone, secreted by the hypothalamus, which regulates the secretion of gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the pituitary. LHRH acts by binding to receptors located in the pituitary gland. These receptors (LHRH receptors) have also been found in the cytoplasm of many tumor cells that involve both the reproductive and non-reproductive organs. These receptors have been demonstrated in prostate and breast cancers, endometrial carcinomas, renal cell carcinoma, lymphoma, carcinoma of liver, pancreas and skin. So far, the expression of LHRH receptors on sarcomas (i.e. malignant tumors of mesenchymal origin) has not been studied, except for endometrial sarcomas. It has also been demonstrated that both LHRH agonists and antagonists can down-regulate these receptors and thus inhibit these tumor cells. Another major therapeutic implication is that these receptors can be targeted specifically by peptides conjugated to anti-cancer drugs. The purpose of this study was to determine if LHRH receptors are expressed in primary and/or metastatic sarcomas of human origin. Methods: We looked at LHRH receptor expression in 38 consecutive sarcoma specimens, using immunohistochemistry. The specimens were either from office biopsy or from resected tumor; these were confirmed as sarcomas by histopathological examination. The receptor staining characteristics and the staining intensity were also documented. The pattern of staining was classified either as "focal or diffuse staining of the cytoplasm" and the intensity of staining was graded on a scale from 1+ to 4+. Results: Positive receptor staining was seen in 25 of the 38 (66%) specimens. Twelve of the specimens stained diffusely and 13 had focally positive staining. Three tumors had 1+ staining, 10 had 2+ staining, six had 3+ staining, and six tumors had 4+ staining. The tumors included undifferentiated pleomorphic sarcoma, synovial sarcoma, osteosarcoma, myofibroblastic sarcoma, myxofibrosarcoma, liposarcoma, dermatofibrosarcoma protuberans, metastatic chondrosarcoma and chordoma. Conclusion: Sarcomas express LHRH receptors with a varying incidence and degree. Our study suggests that those sarcomas that are LHRH receptor positive could potentially be treated with targeted chemotherapy.

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Section: Discussionmentioning

confidence: 77%

LHRH receptor expression in sarcomas of bone and soft tissue

Deivaraju¹,

Temple²,

Block³

et al. 2016

Hormone Molecular Biology and Clinical Investigation

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“…In particular, GHRH can induce the differentiation of ovarian granulosa cells and other cells in the reproductive system and function as a growth factor in various normal tissues, benign tumors, and malignancies (2-4, 6, 11, 14-18). Previously, we also reported that antagonistic cytototoxic derivatives of some of these neuropeptides are able to inhibit the growth of several malignant cell lines (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14).…”

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confidence: 89%

“…The dismal outcome of this malignancy demands great efforts to find improved methods of treatment (1). Many compounds have been synthesized in our laboratory in the past few years that have proven to be effective against diverse malignant tumors (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). These are peptide analogs of hypothalamic hormones: luteinizing hormone-releasing hormone (LHRH), growth hormone-releasing hormone (GHRH), somatostatin, and analogs of other neuropeptides such as bombesin and gastrin-releasing peptide.…”

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confidence: 99%

“…These are peptide analogs of hypothalamic hormones: luteinizing hormone-releasing hormone (LHRH), growth hormone-releasing hormone (GHRH), somatostatin, and analogs of other neuropeptides such as bombesin and gastrin-releasing peptide. The receptors for these peptides have been found to be widely distributed in the human body, including in many types of cancers (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). The regulatory functions of these hypothalamic hormones and other neuropeptides are not confined to the hypothalamo-hypophyseal system or, even more broadly, to the central nervous system (CNS).…”

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confidence: 99%

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Potentiation of cytotoxic chemotherapy by growth hormone-releasing hormone agonists

Jászberényi

Rick

Popovics

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The dismal prognosis of malignant brain tumors drives the development of new treatment modalities. In view of the multiple activities of growth hormone-releasing hormone (GHRH), we hypothesized that pretreatment with a GHRH agonist, JI-34, might increase the susceptibility of U-87 MG glioblastoma multiforme (GBM) cells to subsequent treatment with the cytotoxic drug, doxorubicin (DOX). This concept was corroborated by our findings, in vivo, showing that the combination of the GHRH agonist, JI-34, and DOX inhibited the growth of GBM tumors, transplanted into nude mice, more than DOX alone. In vitro, the pretreatment of GBM cells with JI-34 potentiated inhibitory effects of DOX on cell proliferation, diminished cell size and viability, and promoted apoptotic processes, as shown by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide proliferation assay, ApoLive-Glo multiplex assay, and cell volumetric assay. Proteomic studies further revealed that the pretreatment with GHRH agonist evoked differentiation decreasing the expression of the neuroectodermal stem cell antigen, nestin, and up-regulating the glial maturation marker, GFAP. The GHRH agonist also reduced the release of humoral regulators of glial growth, such as FGF basic and TGFβ. Proteomic and geneexpression (RT-PCR) studies confirmed the strong proapoptotic activity (increase in p53, decrease in v-myc and Bcl-2) and antiinvasive potential (decrease in integrin α3) of the combination of GHRH agonist and DOX. These findings indicate that the GHRH agonists can potentiate the anticancer activity of the traditional chemotherapeutic drug, DOX, by multiple mechanisms including the induction of differentiation of cancer cells.peptide analogs | targeted therapy

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“…[7][8][9][10][11][12][13][14][15][16][17][18][19] Growth hormone-releasing hormone (GHRH), released by the hypothalamus, regulates the secretion of growth hormone (GH) by an action on specific receptors (GHRH-R) for GHRH in the pituitary gland. [7][8][9] In turn, GH induces the production of hepatic cancer specimens and multiple cancer cell lines.…”

Section: Introductionmentioning

confidence: 99%