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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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001-es BibID:BIBFORM033658
035-os BibID:WOS:000078189200069
Első szerző:Varga József L.
Cím:Synthesis and biological evaluation of antagonists of growth hormone-releasing hormone with high and protracted in vivo activities / József L. Varga, Andrew V. Schally, Valér J. Csernus, Márta Zarándi, Gábor Halmos, Kate Groot, Zoltán Rékási
Dátum:1999
ISSN:0027-8424
Megjegyzések:Some antagonists of human growth hormone-releasing hormone (hGH-RH) synthesized previously were shown to inhibit in vivo proliferation of various human cancers in nude mice. However, the activity of these analogs requires an increase to assure clinical efficacy, In an attempt to prepare hGH-RH antagonists with a high and protracted activity, we synthesized and biologically tested 22 antagonistic analogs of hGH-RH(1-29)NH2. The ability of the antagonists to inhibit hGH-RH-induced GH release was evaluated in vitro in a superfused rat pituitary system, as well as in vivo after i.v. injection into rats. The binding affinity of the peptides to GH-RH receptors also was determined. All antagonistic analogs had the common core sequence [PhAc-Tyr(1),D-Arg(2), Phe(4-Cl)(6) (para-chlorophenylalanine), Abu(15) (alpha-aminobutyric acid),Nle(27)] hGH-RH(1-29)NH2 and contained Arg, D-Arg, homoarginine (Har), norleucine (Nle), and other substitutions. The following analogs were determined to have a high and/or protracted antagonistic activity: [PhAc-Tyr(1),D-Arg(2),Phe(4-Cl)(6),Arg(9),Abu(15),Nle(27),D-Arg(29)] hGH-RH (1-29)NH2 (JV-1-10), [PhAc-Tyr(1),D-Arg(2),Phe(4-Cl)(6),Abu(15),Nle(27) D-Arg(28),Har(29)] hGH-RH(1-29)NH2 (MZ-6-55), [PhAc-Tyr(1),D-Arg(2),Phe(4-Cl)(6), Arg(9),Abu(15),Nle(27),D-Arg(28),Har(29)] hGH-RH(1-29)NH2 (JV-1-36), and [PhAc-Tyr(1),D-Arg(2),Phe(4-Cl)(6), Har(9),Tyr(Me)(10),Abu(15),Nle(27),D-Arg(28),Har(29)]hGH-RH (1- 29)NH2 (JV-1-38). Among the peptides tested, analog JV-1-36 showed the highest GH-RH antagonistic activity in vitro and also induced a strong and prolonged inhibition of GH release in vivo for at least 30 min. The antagonist JV-1-38 was slightly less potent than JV-1-36 both in vitro and in vivo but proved to be very long-acting in vivo, suppressing the GH-RH-induced GH release even after 60 min. High and protracted in vivo activities of these antagonists indicate an improvement over earlier GH-RH analogs, Some of these hGH-RH antagonists could find clinical applications in the treatment of cancers dependent on insulin-like growth factors I and II.
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. - 96 : 2 (1999), p. 692-697. -
További szerzők:Schally, Andrew Victor Csernus Valér J. Zarándi Márta Halmos Gábor (1962-) (gyógyszerész, receptorfarmakológus, experimentális onkológus) Groot, Kate Rékási Zoltán
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