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1.

001-es BibID:BIBFORM033631
035-os BibID:WOS:000088208700022 PMID:10891548
Első szerző:Halmos Gábor (gyógyszerész, receptorfarmakológus, experimentális onkológus)
Cím:Down-regulation and change in subcellular distribution of receptors for luteinizing hormone-releasing hormone in OV-1063 human epithelial ovarian cancers during therapy with LH-RH antagonist Cetrorelix / Gábor Halmos, Andrew V. Schally, Zsuzsanna Kahan
Dátum:2000
Megjegyzések:The inhibition of growth of various hormone-dependent cancers by analogs of luteinizing hormone-releasing hormone (LH-RH) may be exerted in port through receptors for LH-RN present on tumor cells, but the direct mode of action of LH-RH agonists and antagonists is still not completely understood. The aim of this study was to investigate the effects of agonist [D-Trp(6)]LH-RH and antagonist Cetrorelix, administered s.c, at a dose of 100 mu g/day for 3 weeks on the binding characteristics and subcellular localization of receptors for LH-RH in OV-1063 human epithelial ovarian cancers xenografted into nude mice. Using radioligand binding studies, following in vitro desaturation, we demonstrated the presence of specific, high affinity binding sites for LH-RH in both cell membrane and nuclear fraction of OV-1063 tumors. Treatment with Cetrorelix, but not [D-Trp(6)]LH-RH, caused about 60% reduction (p<0.01) in tumor volume and weight. [D-Trp(6)]LH-RH decreased the number of LH-RN receptors on OV-1063 tumor membranes by 44% after 14 days (p<0.01), and the concentration of receptors remained at that level on day 21. The maximal binding capacity of receptors for LH-RH in the nuclei was significantly higher (p<0.05) after 3 weeks of treatment with [D-Trp(6)]LH-RH, Cetrorelix decreased the concentration of membrane receptors for LH-RH by 53% (p<0.01) after 14 days and the levels on day 21 were even lower, showing a 70% reduction (p<0.01). In contrast, the number of LH-RN binding sites in the nuclear pellet was significantly increased (p<0.01) by Cetrorelix at that time. Our results demonstrate for the first time that the down-regulation of LH-RN receptors on the cell membranes of OV-1063 human ovarian cancers after therapy with antagonist Cetrorelix or agonist [D-Trp(6)]LH-RH is associated with an increase in receptor concentration in the nuclei. These phenomena could be related to the internalization and subcellular translocation of receptors in these tumor cells.
Tárgyszavak:Orvostudományok Gyógyszerészeti tudományok idegen nyelvű folyóiratközlemény külföldi lapban
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Megjelenés:International Journal of Oncology. - 17 : 2 (2000), p. 367-373. -
További szerzők:Schally, Andrew Victor Kahán Zsuzsa
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2.

001-es BibID:BIBFORM033660
035-os BibID:PMID:10375109 WOS:000080777900017
Első szerző:Kahán Zsuzsa
Cím:Complete regression of MX-1 human breast carcinoma xenografts after targeted chemotherapy with a cytotoxic analog of luteinizing hormone-releasing hormone, AN-207 / Zsuzsanna Kahán, Attila Nagy, Andrew V. Schally, Gábor Halmos, José M. Arencibia, Kate Groot
Dátum:1999
ISSN:0008-543X
Megjegyzések:BACKGROUND: Receptors for luteinizing hormone-releasing hormone (LH-RH) are found in about 50% of human breast carcinomas. A highly potent cytotoxic agent, 2-pyrrolinodoxorubicin (AN-201), was linked to the agonist [D-Lys6]LH-RH to form a cytotoxic LH-RH analog, AN-207, that can be targeted to LH-RH receptors on breast carcinomas. METHODS: Nude mice bearing MX-1 hormone-independent, doxorubicin-resistant human breast carcinomas were injected intravenously with vehicle (control), 250 nmol/kg doses of AN-201, AN-207, or an unconjugated mixture of AN-201 and [D-Lys6]LH-RH. Tumor growth and changes in hematologic parameters were evaluated. Receptors for LH-RH were investigated by radioreceptor assays, and the expression of their mRNA was determined by reverse transcriptase-polymerase chain reaction. RESULTS: AN-207 caused complete regression of MX-1 tumors in all 10 animals, and they were still tumor free 60 days after treatment. In contrast, after therapy with AN-201 or the mixture of AN-201 and [D-Lys6]LH-RH, the regression of most MX-1 tumors was only transitory. AN-201 caused the death of 1 of the 10 animals and significantly greater leukopenia than AN-207, which produced no toxic deaths. Radioreceptor assays revealed high affinity binding sites for LH-RH on tumor cell membranes. The expression of mRNA for LH-RH receptors also was found in tumors. CONCLUSIONS: The results of this study indicate that powerful, targeted cytotoxic LH-RH analogs such as AN-207 could be considered for the treatment of human breast carcinomas that possesses receptors for LH-RH.
Tárgyszavak:Orvostudományok Gyógyszerészeti tudományok idegen nyelvű folyóiratközlemény külföldi lapban
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Megjelenés:Cancer. - 85 : 12 (1999), p. 2608-2615. -
További szerzők:Nagy Attila Schally, Andrew Victor Halmos Gábor (1962-) (gyógyszerész, receptorfarmakológus, experimentális onkológus) Arencibia, José M. Groot, Kate
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3.

001-es BibID:BIBFORM033641
Első szerző:Kahán Zsuzsa
Cím:Administration of a targeted cytotoxic analog of luteinizing hormone-releasing hormone inhibits growth of estrogen-independent MDA-MB-231 human breast cancers in nude mice / Zsuzsanna Kahán, Attila Nagy, Andrew V. Schally, Gábor Halmos, José M. Arencibia, Kate Groot
Dátum:2000
ISSN:0167-6806
Megjegyzések:Receptor targeted chemotherapy is less toxic and more effective than conventional chemotherapy. Receptors for luteinizing hormone-releasing hormone (LH-RH) are found in about 50% of human breast cancers. Highly potent cytotoxic radical 2-pyrrolinodoxorubicin (AN-201) was linked to the agonistic analog [D-Lys6]LH-RH to form cytotoxic LH-RH analog AN-207. We evaluated whether AN-207 could be targeted to the hormone-independent MDA-MB-231 human breast cancers. Nude mice bearing MDA-MB-231 tumors were injected i.v. with 250 nmol/kg doses of cytotoxic radical AN-201, cytotoxic LH-RH analog AN-207, the unconjugated mixture of AN-201 and carrier [D-Lys6]LH-RH, [D-Lys6]LH-RH alone and vehicle (control). The growth of MDA-MB-231 tumors in animals given a single dose of AN-207 was inhibited significantly (p = 0.01) for 3 weeks after injection, whereas tumors in all the other groups grew steadily. All cytotoxic compounds produced leukopenia, but the strongest lymphocyte suppression was caused by cytotoxic radical AN-201. Three weeks after treatment, the presence of mRNA for LH-RH receptors was demonstrated by RT-PCR in all the groups and radioreceptor assays demonstrated high-affinity binding sites for LH-RH on tumor cell membranes of control animals and those treated with AN-201, the carrier peptide alone or in combination with AN-201. At this time point binding assays did not reveal the expression of membrane proteins in tumors treated with AN-207, but 60 days after administration of AN-207, high affinity LH-RH binding sites were found again in MDA-MB-231 tumors. These results indicate that cytotoxic LH-RH analog AN-207 could be utilized for receptor targeted chemotherapy of breast cancers expressing receptors for LH-RH.
Tárgyszavak:Orvostudományok Gyógyszerészeti tudományok idegen nyelvű folyóiratközlemény külföldi lapban
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Megjelenés:Breast Cancer Research and Treatment. - 59 : 3 (2000), p. 255-262. -
További szerzők:Nagy Attila Schally, Andrew Victor Halmos Gábor (1962-) (gyógyszerész, receptorfarmakológus, experimentális onkológus) Arencibia, José M. Groot, Kate
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4.

001-es BibID:BIBFORM033643
Első szerző:Kahán Zsuzsa
Cím:Antagonists of growth hormone-releasing hormone arrest the growth of MDA-MB-468 estrogen-independent human breast cancers in nude mice / Zsuzsanna Kahán, József L. Varga, Andrew V. Schally, Zoltán Rékási, Patricia Armatis, Ioulia Chatzistamou, Tamás Czömpöly, Gábor Halmos
Dátum:2000
ISSN:0167-6806
Megjegyzések:Since antagonists of growth hormone-releasing hormone (GH-RH) inhibit proliferation of various tumors, in this study we investigated the effects of GH-RH antagonists MZ-5-156 or JV-1-36 on growth of estrogen-independent MDA-MB-468 human breast cancers xenografted into nude mice. Both GH-RH antagonists administered at a dose of 20 microg/day induced regression of some and growth-arrest of other tumors, while control tumors continued to grow. After 5 weeks of therapy with MZ-5-156 or JV-1-36, final volume and weight of MDA-MB-468 tumors were significantly decreased (all p values < 0.001) and serum IGF-I levels as well as tumor IGF-I mRNA expression were reduced as compared with controls. High affinity binding sites for IGF-I were detected by the ligand binding method. Gene expression of human IGF-I receptors, as measured by the RT-PCR, was not significantly different in control and treated MDA-MB-468 tumors. In cell culture, IGF-I did not stimulate, GH-RH slightly stimulated, while MZ-5-156 and JV-1-36 inhibited proliferation of MDA-MB-468 cells known to possess defective insulin and IGF-I receptor signaling. The expression of mRNA for human GH-RH was found in five of 8 tumors treated with GH-RH antagonists, and in one of the five control tumors. These results suggest that GH-RH antagonists inhibit MDA-MB-468 breast cancers possibly through mechanisms involving interference with locally produced GH-RH.
Tárgyszavak:Orvostudományok Gyógyszerészeti tudományok idegen nyelvű folyóiratközlemény külföldi lapban
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Megjelenés:Breast Cancer Research and Treatment. - 60 : 1 (2000), p. 71-79. -
További szerzők:Varga József L. Schally, Andrew Victor Rékási Zoltán Armatis, Patricia Chatzistamou, Ioulia Czömpöly Tamás Halmos Gábor (1962-) (gyógyszerész, receptorfarmakológus, experimentális onkológus)
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5.

001-es BibID:BIBFORM033650
Első szerző:Kahán Zsuzsa
Cím:Inhibition of growth of MDA-MB-468 estrogen-independent human breast carcinoma by bombesin/gastrin-releasing peptide antagonists RC-3095 and RC-3940-II / Zsuzsanna Kahán, Baodong Sun, Andrew V. Schally, José M. Arencibia, Ren-Zhi Cai, Kate Groot, Gábor Halmos
Dátum:2000
ISSN:0008-543X
Megjegyzések:BACKGROUND: The growth of breast carcinoma is promoted by autocrine growth factors such as the bombesin (BN)-like peptides and epidermal growth factor (EGF). The stimulatory action of BN-like peptides can be blocked by the use of BN/gastrin-releasing peptide (GRP) antagonists. METHODS: The authors investigated the effects of synthetic BN/GRP antagonists RC-3095 and RC-3940-II on tumor growth and the expression of mRNA for EGF receptors and three BN receptor subtypes in MDA-MB-468 human breast carcinoma. Athymic nude mice with xenografts of MDA-MB-468 human breast carcinoma were injected subcutaneously for 6 weeks with RC-3940-II at doses of 20 or 40 microg/day. In another study, the effects of RC-3940-II and RC-3095 were compared. RESULTS: RC-3940-II caused a significant and dose-dependent growth inhibition of MDA-MB-468 tumors in nude mice; therapy with either dose of RC-3940-II significantly (P<0.01) reduced the mean final tumor volume and weight compared with controls. RC-3940-II induced a persistent regression of > 50% of all tumors. One of 3 tumors treated with 20 microg of RC-3940-II and 3 of 5 tumors treated with 40 microg were found to have regressed completely by the end of the study. When RC-3940-II and RC-3095 were compared at the dose of 20 microg/day, both powerfully suppressed growth of MDA-MB-468 tumors, with RC-3940-II causing a complete regression of 2 tumors and RC-3095 a complete regression of 1 tumor. Receptor analyses of untreated MDA-MB-468 tumors revealed an overexpression of EGF receptors and two classes of binding sites for BN/GRP. mRNAs for receptors of GRP, neuromedin B, and BN receptor subtype-3 were detected by reverse transcriptase-polymerase chain reaction. CONCLUSIONS: A virtual arrest of growth or regression of MDA-MB-468 human breast carcinoma after therapy with RC-3940-II and RC-3095 indicates that these BN/GRP antagonists could provide a new treatment modality for breast tumors expressing BN and EGF receptors.
Tárgyszavak:Orvostudományok Gyógyszerészeti tudományok idegen nyelvű folyóiratközlemény külföldi lapban
külföldön készült közlemény
Megjelenés:Cancer. - 88 : 6 (2000), p. 1384-1392. -
További szerzők:Sun, Baodong Schally, Andrew Victor Arencibia, José M. Cai, Ren-Zhi Groot, Kate Halmos Gábor (1962-) (gyógyszerész, receptorfarmakológus, experimentális onkológus)
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6.

001-es BibID:BIBFORM033667
035-os BibID:WOS:000072115900079
Első szerző:Nagy Attila
Cím:Synthesis and biological evaluation of cytotoxic analogs of somatostatin containing doxorubicin or its intensely potent derivative, 2-pyrrolinodoxorubicin / Attila Nagy, Andrew V. Schally, Gábor Halmos, Patricia Armatis, Ren-Zhi Cai, Valér Csernus, Magdolna Kovács, Miklós Koppán, Károly Szepesházi, Zsuzsanna Kahán
Dátum:1998
ISSN:0027-8424
Megjegyzések:To create cytotoxic hybrid analogs of somatostatin (SST), octapeptides RC-160 (D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2) and RC-121 (D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NB2) were linked to doxorubicin (DOX) or its superactive derivative, 2-pyrrolino-DOX (AN-201). The conjugation was performed by coupling N-9-fluorenylmethoxycarbonyl (N-Fmoc)-DOX-14-O-hemiglutarate or 2-pyrrolino-DOX-14-O-hemiglutarate to the amino terminus of [Lys(Fmoc)(5)]RC-160 yielding AN-163 and AN-258, respectively, after deprotection. The respective cytotoxic conjugates of RC-121 (AN-162 and AN-238) were prepared similarly, In vitro tests on human cancer cell lines-MKN-45 gastric cancer, MDA-MB-231 breast cancer, PC-3 prostate cancer, and MIA PaCa-2 pancreatic cancer-demonstrated that the antiproliferative activity of the cytotoxic radicals in these conjugates,vas virtually retained. In H-345 human small cell lung carcinoma cell line, conjugates of RC-121 preserved the cytotoxic activity of their radicals, but the hybrids with RC-160 showed approximate to 10 times lower activity. The ability of the carriers and the hybrids to inhibit the binding of I-125-labeled RC-160 to receptors for SST on rat pituitary membrane preparation was also determined. The cytotoxic conjugates inhibited 50% of the specific binding of the radioligand in the nanomolar concentration range (IC50 < 80 nM). When SST-like activities of AN-238 and its carrier, RC-121, were compared in the rat pituitary superfusion system, both compounds were found to suppress a stimulated growth hormone release at nanomolar concentrations. Preliminary studies in animal models of breast and prostate cancers showed that AN-238 is less toxic than AN-201 and more potent in inhibiting tumor growth. These highly active cytotoxic analogs of SST have been designed as targeted antitumor agents for the treatment of various cancers expressing receptors for SST octapeptides.
Tárgyszavak:Orvostudományok Gyógyszerészeti tudományok idegen nyelvű folyóiratközlemény külföldi lapban
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Megjelenés:Proceedings of The National Academy of Sciences of The United States of America. - 95 : 4 (1998), p. 1794-1799. -
További szerzők:Schally, Andrew Victor Halmos Gábor (1962-) (gyógyszerész, receptorfarmakológus, experimentális onkológus) Armatis, Patricia Cai, Ren-Zhi Csernus Valér J. Kovács Magdolna Koppán Miklós Szepesházi Károly Kahán Zsuzsa
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