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1.
Mol Cell Endocrinol ; 124(1-2): 151-61, 1996 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-9027334

RESUMO

The ability of human chorionic gonadotropin (hCG) to distinguish lutropin (LHR) and follitropin (FSHR) receptors is controlled principally by beta-subunit residues 94-117. To learn how residues 94-96 (Arg-Arg-Ser) influence LHR binding, we studied the effects of replacing them on the LH and FSH activities of a bifunctional hCG analog in which residues 101-109 were derived from FSH. Analogs containing 1-3 arginines and no aspartates at residues 94-96 bound LHR with 25-400% the potency of hCG. When residues 94-96 were neutral or contained 1-3 aspartates, LHR binding was reduced 6-100 fold but remained at least ten-fold greater than the negative control analog containing residues 94-117 derived from FSH. Residues 94-96 had little influence on FSHR binding. These observations support a model [Moyle et al. (1995) J. Biol. Chem. 270:20,020] in which residues 94-96 influence LHR binding specificity primarily through an effect on hormone conformation rather than by direct participation in essential high affinity receptor contacts.


Assuntos
Gonadotropina Coriônica Humana Subunidade beta/metabolismo , Receptores do LH/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Células CHO , Gonadotropina Coriônica Humana Subunidade beta/análogos & derivados , Gonadotropina Coriônica Humana Subunidade beta/química , Gonadotropina Coriônica Humana Subunidade beta/genética , Gonadotropina Coriônica Humana Subunidade beta/farmacologia , Cricetinae , Hormônio Foliculoestimulante , Subunidade beta do Hormônio Folículoestimulante , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Mutagênese Insercional , Conformação Proteica , Ratos , Receptores do FSH/metabolismo , Receptores do LH/química , Proteínas Recombinantes de Fusão , Transdução de Sinais/fisiologia
2.
Breast Cancer Res Treat ; 78(1): 17-27, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12611453

RESUMO

We have prepared conjugates of a membrane disrupting lytic peptide (hecate) and a 15-amino acid segment of the beta-chain of CG and hecate and the decapeptide, luteinizing hormone releasing hormone (LHRH). We have tested the concept that these conjugates will target breast cancer cells expressing LH/CG or LHRH receptors. In previous studies, we were able to destroy prostate cancers in vitro and in vivo with lytic peptide conjugates. Hecate, hecate-betaCG and LHRH-hecate were added to cultures of the human breast cancer cell lines MCF-7 and MDA-MB-435S. Hecate and its conjugates showed concentration dependent toxicity to both cell lines. The lytic peptide alone showed similar EC50 values for both cell lines; however, there was a significant difference between the EC50 values when the conjugates were tested. The hormone dependent MCF-7 cell line was less sensitive to the betaCG conjugate than to the LHRH conjugate; the reverse was found for the hormone independent MDA-MB-435S cells. Removal of steroids decreased the sensitivity of MCF-7 cells to both lytic peptide conjugates and this sensitivity could be restored by adding estradiol. Activation of protein kinase C further increased the sensitivity to the drug. MDA-MB-435S xenografts were established in intact female athymic nude mice, which were treated once a week for 3 weeks with hecate-betaCG via the lateral tail vein. The ability of hecate-betaCG to destroy xenografts of human breast cancer cells (MDA-MB-435S) in nude mice was demonstrated for the first time. We conclude that hecate-betaCG and LHRH-hecate conjugates could serve as useful drugs for the treatment of breast cancer.


Assuntos
Membrana Celular/efeitos dos fármacos , Gonadotropina Coriônica Humana Subunidade beta/farmacologia , Hormônio Liberador de Gonadotropina/farmacologia , Neoplasias Mamárias Experimentais/fisiopatologia , Meliteno/análogos & derivados , Meliteno/farmacologia , Neoplasias Hormônio-Dependentes/fisiopatologia , Sequência de Aminoácidos , Animais , Membrana Celular/patologia , Gonadotropina Coriônica Humana Subunidade beta/análogos & derivados , Feminino , Hormônio Liberador de Gonadotropina/análogos & derivados , Neoplasias Mamárias Experimentais/tratamento farmacológico , Camundongos , Camundongos Nus , Modelos Animais , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
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