Receptors for luteinizing hormone‐releasing hormone, somatostatin, prolactin, and epidermal growth factor in rat and human prostate cancers and in benign prostate hyperplasia

Fekete, M.; Redding, Tommie W.; Comaru‐Schally, Ana Maria; Pontes, J. Edson; Connelly, Robert; Srkalović, Gordan; Schally, Andrew V.

doi:10.1002/pros.2990140302

Cited by 119 publications

(61 citation statements)

References 32 publications

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“…Thus, high-affinity binding sites for LHRH are present in most human prostate cancer samples (29)(30)(31). Receptors for LHRH were also detected in PC-82, LNCaP, and DU-145 human prostate cancer lines and Dunning rat prostate cancers (29)(30)(31)(32)(33). The expression of mRNA for LHRH receptors was also found in PC-82, DU-145 and LNCaP tumors and in most human prostate cancer specimens (31,33,34).…”

Section: Receptors For Lhrhmentioning

confidence: 88%

“…Specific membrane receptors for LHRH have been found in various animal and human cancers (23,24,28). Thus, high-affinity binding sites for LHRH are present in most human prostate cancer samples (29)(30)(31). Receptors for LHRH were also detected in PC-82, LNCaP, and DU-145 human prostate cancer lines and Dunning rat prostate cancers (29)(30)(31)(32)(33).…”

Section: Receptors For Lhrhmentioning

confidence: 99%

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Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their receptors on tumors

Schally

Nagy²

1999

European Journal of Endocrinology

266

228

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In view of non-specific toxicity of most chemotherapeutic agents against normal cells, the development of targeted chemotherapy is warranted. Efficient targeting of chemotherapeutic drugs to the cancerous area could be of great benefit for patients with advanced or metastatic tumors. Targeted cytotoxic peptide conjugates are hybrid molecules composed of a peptide carrier which binds to receptors on tumors and a cytotoxic moiety. New cytotoxic analogs of LHRH, AN-152 in which doxorubicin (DOX) is linked to ]LHRH, and AN-207 which consists of 2-pyrrolino-DOX (AN-201) coupled to the same carrier, show high-affinity binding and are much less toxic and more effective in vivo than their respective radicals in inhibiting tumor growth in LHRH receptor-positive models of human ovarian, mammary, or prostatic cancer. These results suggest that targeted cytotoxic LHRH analogs such as AN-207 could be considered for treatment of these cancers. The presence of receptors for bombesinlike peptides on a wide variety of tumors prompted us to use some of our bombesin/gastrin-releasing peptide antagonists as carrier molecules. Cytotoxic bombesin analogs, such as AN-215 containing AN-201, might find application in the treatment of small cell lung carcinoma (SCLC), and colorectal, gastric, pancreatic, mammary, and prostatic cancers. Since somatostatin receptors are found in various human neoplasms and the receptor subtypes to which octapeptide analogs bind with high affinity have been identified, we synthesized several cytotoxic somatostatin analogs including AN-162 and AN-238 containing DOX and 2-pyrrolino-DOX respectively, linked to octapeptide RC-121. Cytotoxic somatostatin analog AN-238 efficaciously inhibits growth of human breast or prostate cancers expressing somatostatin receptors-2 and -5 and can be used for receptor-targeted chemotherapy. Cytotoxic somatostatin analogs might also find applications for the therapy of human pancreatic, colorectal, and gastric cancer as well as brain tumors and non-SCLC. Cytotoxic compounds linked to analogs of hormonal peptides like LHRH, bombesin, and somatostatin that can be targeted to certain tumors possessing receptors for those peptides could be an important addition to oncological armamentarium.

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Section: Receptors For Lhrhmentioning

confidence: 88%

Section: Receptors For Lhrhmentioning

confidence: 99%

Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their receptors on tumors

Schally

Nagy²

1999

European Journal of Endocrinology

266

228

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“…This action of GnRH is mediated through high-affinity receptors present in the cell membranes of gonadotropes. In addition to the role of GnRH in the regulation of gonadotropin secretion it has been reported to have extrapituitary effects in influencing tumor cell growth in a number of human tumors and tumor cell lines (2)(3)(4)(5)(6)(7)(8)(9)(10). Inhibition of cell growth and [ 3 H]thymidine incorporation in tumor cells in culture by GnRH agonists and antagonists and the presence of GnRH receptors in these tumors and tumor cell lines (5,6,(8)(9)(10)(11)(12) suggest a direct effect of GnRH agonists and antagonists on cell growth and proliferation.…”

Section: Introductionmentioning

confidence: 99%

Molecular structure of the human gonadotropin-releasing hormone receptor gene

Kakar

1997

European Journal of Endocrinology

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GnRH receptors belong to the family of G protein-coupled receptor proteins and have been localized to the anterior pituitary, brain and reproductive organs as well as many steroid-dependent tumor tissues. Recently, cDNAs for the GnRH receptors of several species including the human have been cloned. To determine the structure of the gene encoding the human GnRH receptor, we isolated the receptor gene clones from the human genomic libraries. Comparison of the genomic and cDNA sequences revealed that the human GnRH receptor gene is composed of three exons and two introns and spans over 20 kb in size. Exon 1 encodes the 5 0 untranslated sequence and nucleotide þ 1 to þ 522 in the open reading frame, exon 2 encodes nucleotide þ 523 to þ 742 and exon 3 encodes nucleotide þ 743 to þ 987 in the open reading frame as well as the 3 0 untranslated sequence. Southern blot analysis of genomic DNA and localization of the GnRH receptor gene to a single site on human chromosome 4 (4q13) indicate the presence of a single copy of the gene in the human genome. Several regulatory sequences for various hormones and other regulatory factors were identified, including PEA-3, AP-1, AP-2, and Pit-1 sites. In addition, glucocorticoid/progesterone response element, thyroid hormone response element, and cAMP response element sequences were identified. Reverse transcriptase-primer extension and 5 0 RACE analysis of the human pituitary RNA demonstrated the presence of multiple transcriptional start sites upstream of the translational start site. Analysis of the 5 0 flanking region of the gene also revealed the presence of multiple TATA and CAAT sequences. The finding of multiple transcriptional start sites raises the possibility of tissue-specific regulation and the existence of variable size transcripts. Chimeras containing 1.26 kb (¹534 to 728) of the 5 0 flanking region of the receptor gene and the luciferase (Luc) gene expressed a significant luciferase activity when transfected into a human endometrial tumor cell line (HEC-1A) and a breast tumor cell line (MCF-7) but not in a mouse pituitary gonadotrope cell line (aT3-1), suggesting the existence of multiple promoter elements in the gene. These findings indicate a multiplicity of regulation of expression of the GnRH receptor and provide the substrate for detailed investigation in the reproductive system.

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“…The clinical application of GnRH analogues in the treatment of hormone-dependent malignancies is primarily based on their ability to inhibit the hypophysealÁ/gonadal axis through the desensitization of gonadotropes and hence the suppression of circulating levels of sex steroids [21,22]. In addition, specific membrane receptors for GnRH, at least type I, have been found in a high percentage of human prostate tumours and various rat and human PC cell lines [1,2,4,10,16,17]. These receptors mediate inhibiting effects of GnRH analogues in vitro suggesting that direct inhibitory effects on the tumour may be of importance also in vivo.…”

Section: Discussionmentioning

confidence: 99%

Alteration of gonadotropin-releasing hormone receptor expression with the progression of prostate cancer in the Dunning rat adenocarcinoma sublines

2005

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Inhibitory effects of GnRH analogues on tumour growth in vitro suggests that such direct effects may be of importance also in vivo. However, the role of GnRH receptors (GnRH-R) in prostate tumour progression is largely unknown. The aim was therefore to investigate the variation of GnRH-R expression with prostate tumour progression using Dunning rat adenocarcinoma sublines representing different prostate tumour grades. GnRH-R levels were quantified in the rat dorsolateral (DLP) and Dunning sublines (PAP, AT-1, AT-2, AT-3, MatLyLu) using competitive RT Á/PCR and Western blot. The results showed that all Dunning sublines had significantly elevated GnRH-R mRNA expression levels compared with DLP. Comparison of GnRH-R mRNA levels between different tumour grades revealed no difference in mRNA expression. However, the anaplastic and highly metastatic AT-3 and MatLyLu tumours displayed a tendency for lower GnRH-R mRNA values than the non-metastatic tumour sublines. Our data demonstrate the expression of GnRH-R in normal rat DLP and in different Dunning sublines. However, GnRH-R seems not to be involved in tumour progression.

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Receptors for luteinizing hormone‐releasing hormone, somatostatin, prolactin, and epidermal growth factor in rat and human prostate cancers and in benign prostate hyperplasia

Cited by 119 publications

References 32 publications

Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their receptors on tumors

Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their receptors on tumors

Molecular structure of the human gonadotropin-releasing hormone receptor gene

Alteration of gonadotropin-releasing hormone receptor expression with the progression of prostate cancer in the Dunning rat adenocarcinoma sublines

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