Base de dados : MEDLINE
Pesquisa : D02.540.505.495 [Categoria DeCS]
Referências encontradas : 529 [refinar]
Mostrando: 1 .. 10   no formato [Detalhado]

página 1 de 53 ir para página                         

  1 / 529 MEDLINE  
              next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:29489698
[Au] Autor:Zuradelli M; Masci G; Ferraro E; Losurdo A; De Sanctis R; Torrisi R; Santoro A
[Ti] Título:Never too old to fight breast cancer: A case report.
[So] Source:Medicine (Baltimore);97(9):e9981, 2018 Mar.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RATIONALE: Breast cancer is the most common cancer affecting females worldwide and its lifetime risk increases with age. Human epidermal growth factor receptor gene-2 (HER-2) positive breast cancer represents about 20% of all breast cancers, 1 out of 10 is diagnosed in women over 70 years of age. It tends to be more aggressive and to spread more quickly than other subtypes, but the introduction in clinical practice of new anti-HER-2 agents combined with chemotherapy has significantly improved progression free and overall survival. Elderly patients are frequently undertreated because of concerns about their age, performance status, and comorbidities. Here, we report a case of an octogenarian patient treated with T-DM1 with brilliant results. PATIENT CONCERNS: An 87 years old woman affected with HER-2 positive breast cancer presented progression of disease with lymph node and skin metastases after 3 lines of chemoimmunotherapy. DIAGNOSES: Breast cancer in elderly patient, lymph node, and skin metastases. INTERVENTIONS: Chemoimmunotherapy (trastuzumab emtansine). OUTCOME: Objective response of the disease and significant clinical benefit. LESSONS: This case clearly suggests that age and comorbidities do not always represent an absolute contraindication to combined treatments.
[Mh] Termos MeSH primário: Antineoplásicos Imunológicos/uso terapêutico
Neoplasias da Mama/tratamento farmacológico
Maitansina/análogos & derivados
Trastuzumab/uso terapêutico
[Mh] Termos MeSH secundário: Idoso de 80 Anos ou mais
Neoplasias da Mama/química
Neoplasias da Mama/patologia
Feminino
Seres Humanos
Linfonodos/patologia
Metástase Linfática
Maitansina/uso terapêutico
Receptor ErbB-2/análise
Neoplasias Cutâneas/tratamento farmacológico
Neoplasias Cutâneas/secundário
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents, Immunological); 14083FR882 (Maytansine); EC 2.7.10.1 (ERBB2 protein, human); EC 2.7.10.1 (Receptor, ErbB-2); P188ANX8CK (Trastuzumab); SE2KH7T06F (ado-trastuzumab emtansine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180301
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000009981


  2 / 529 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28741467
[Au] Autor:Kubizek F; Eggenreich B; Spadiut O
[Ad] Endereço:Vienna University of Technology, Institute of Chemical Engineering, Research Area Biochemical Engineering, Gumpendorfer Strasse 1a, 1060 Vienna. Austria.
[Ti] Título:Status Quo in Antibody-Drug Conjugates - Can Glyco- Enzymes Solve the Current Challenges?
[So] Source:Protein Pept Lett;24(8):686-695, 2017.
[Is] ISSN:1875-5305
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Over the last years, a novel class of anti-cancer drugs named antibody-drug conjugates (ADCs) has been developed. Due to their limited off-target toxicity but highly potent cytotoxicity at tumor sites, ADCs have proven to be a good alternative to ordinary cancer treatment, such as chemotherapy or combination therapy. Numerous enhancements in antibody-drug engineering led to highly potent tumor targeting drugs with a wide therapeutic window. Two ADCs (Brentuximab vedotin and Trastuzumab emtansine) are already on the market and many others are in clinical trials. However, unstable linkers, low drug potency and unwanted bystander-effects are only some of the drawbacks of ADCs. Enzymes used in combination with prodrugs happen to be a promising alternative. The glyco-enzyme horseradish peroxidase (HRP) has proven to activate the hormone indole-3-acetic acid (IAA) to a highly potent cytotoxic drug. This combination of IAA and HRP has been investigated for the use in strategies such as gene-directed enzyme prodrug therapy (GDEPT) and antibody-directed enzyme prodrug therapy (ADEPT). This article reviews the current state of research in ADC engineering and describes the potential major enhancements through use of glycoenzymes in combination with a prodrug.
[Mh] Termos MeSH primário: Anticorpos Monoclonais/biossíntese
Antineoplásicos Imunológicos/uso terapêutico
Imunoconjugados/uso terapêutico
Maitansina/análogos & derivados
Terapia de Alvo Molecular
Neoplasias/tratamento farmacológico
Trastuzumab/uso terapêutico
[Mh] Termos MeSH secundário: Anticorpos Monoclonais/uso terapêutico
Antineoplásicos Imunológicos/metabolismo
Ensaios Clínicos como Assunto
Desenho de Drogas
Glicoconjugados/síntese química
Glicoconjugados/uso terapêutico
Peroxidase do Rábano Silvestre/metabolismo
Peroxidase do Rábano Silvestre/uso terapêutico
Seres Humanos
Imunoconjugados/química
Ácidos Indolacéticos/metabolismo
Maitansina/biossíntese
Maitansina/uso terapêutico
Neoplasias/genética
Neoplasias/metabolismo
Neoplasias/patologia
Pró-Fármacos/síntese química
Pró-Fármacos/uso terapêutico
Trastuzumab/biossíntese
Moduladores de Tubulina/síntese química
Moduladores de Tubulina/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Antineoplastic Agents, Immunological); 0 (Glycoconjugates); 0 (Immunoconjugates); 0 (Indoleacetic Acids); 0 (Prodrugs); 0 (Tubulin Modulators); 14083FR882 (Maytansine); 6U1S09C61L (indoleacetic acid); 7XL5ISS668 (brentuximab vedotin); EC 1.11.1.- (Horseradish Peroxidase); P188ANX8CK (Trastuzumab); SE2KH7T06F (ado-trastuzumab emtansine)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE
[do] DOI:10.2174/0929866524666170724105211


  3 / 529 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:29059433
[Au] Autor:Schwarz LJ; Hutchinson KE; Rexer BN; Estrada MV; Gonzalez Ericsson PI; Sanders ME; Dugger TC; Formisano L; Guerrero-Zotano A; Red-Brewer M; Young CD; Lantto J; Pedersen MW; Kragh M; Horak ID; Arteaga CL
[Ad] Endereço:Department of Medicine and Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN; Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Nashville, TN; Department of Cancer Biology, Vanderbilt University, Nashville, TN; Symphogen, Balleru
[Ti] Título:An ERBB1-3 Neutralizing Antibody Mixture With High Activity Against Drug-Resistant HER2+ Breast Cancers With ERBB Ligand Overexpression.
[So] Source:J Natl Cancer Inst;109(11), 2017 Nov 01.
[Is] ISSN:1460-2105
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Background: Plasticity of the ERBB receptor network has been suggested to cause acquired resistance to anti-human epidermal growth factor receptor 2 (HER2) therapies. Thus, we studied whether a novel approach using an ERBB1-3-neutralizing antibody mixture can block these compensatory mechanisms of resistance. Methods: HER2+ cell lines and xenografts (n ≥ 6 mice per group) were treated with the ERBB1-3 antibody mixture Pan-HER, trastuzumab/lapatinib (TL), trastuzumab/pertuzumab (TP), or T-DM1. Downregulation of ERBB receptors was assessed by immunoblot analysis and immunohistochemistry. Paired pre- and post-T-DM1 tumor biopsies from patients (n = 11) with HER2-amplified breast cancer were evaluated for HER2 and P-HER3 expression by immunohistochemistry and/or fluorescence in situ hybridization. ERBB ligands were measured by quantitative reverse transcription polymerase chain reaction. Drug-resistant cells were generated by chronic treatment with T-DM1. All statistical tests were two-sided. Results: Treatment with Pan-HER inhibited growth and promoted degradation of ERBB1-3 receptors in a panel of HER2+ breast cancer cells. Compared with TL, TP, and T-DM1, Pan-HER induced a similar antitumor effect against established BT474 and HCC1954 tumors, but was superior to TL against MDA-361 xenografts (TL mean = 2026 mm 3 , SD = 924 mm 3 , vs Pan-HER mean = 565 mm 3 , SD = 499 mm 3 , P = .04). Pan-HER-treated BT474 xenografts did not recur after treatment discontinuation, whereas tumors treated with TL, TP, and T-DM1 did. Post-TP and post-T-DM1 recurrent tumors expressed higher levels of neuregulin-1 (NRG1), HER3 and P-HER3 (all P < .05). Higher levels of P-HER3 protein and NRG1 mRNA were also observed in HER2+ breast cancers progressing after T-DM1 and trastuzumab (NRG1 transcript fold change ± SD; pretreatment = 2, SD = 1.9, vs post-treatment = 11.4, SD = 10.3, P = .04). The HER3-neutralizing antibody LJM716 resensitized the drug-resistant cells to T-DM1, suggesting a causal association between the NRG1-HER3 axis and drug resistance. Finally, Pan-HER treatment inhibited growth of HR6 trastuzumab- and T-DM1-resistant xenografts. Conclusions: These data suggest that upregulation of a NRG1-HER3 axis can mediate escape from anti-HER2 therapies. Further, multitargeted antibody mixtures, such as Pan-HER, can simultaneously remove and/or block targeted ERBB receptor and ligands, thus representing an effective approach against drug-sensitive and -resistant HER2+ cancers.
[Mh] Termos MeSH primário: Anticorpos Neutralizantes/uso terapêutico
Antineoplásicos/uso terapêutico
Neoplasias da Mama/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Anticorpos Monoclonais Humanizados/uso terapêutico
Neoplasias da Mama/química
Linhagem Celular Tumoral
Resistência a Medicamentos Antineoplásicos
Feminino
Seres Humanos
Ligantes
Maitansina/análogos & derivados
Maitansina/uso terapêutico
Camundongos
Camundongos Nus
Quinazolinas/uso terapêutico
Receptor do Fator de Crescimento Epidérmico/antagonistas & inibidores
Receptor ErbB-2/antagonistas & inibidores
Receptor ErbB-3/antagonistas & inibidores
Trastuzumab/uso terapêutico
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal, Humanized); 0 (Antibodies, Neutralizing); 0 (Antineoplastic Agents); 0 (Ligands); 0 (Quinazolines); 0VUA21238F (lapatinib); 14083FR882 (Maytansine); EC 2.7.10.1 (ERBB2 protein, human); EC 2.7.10.1 (ERBB3 protein, human); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); EC 2.7.10.1 (Receptor, ErbB-2); EC 2.7.10.1 (Receptor, ErbB-3); K16AIQ8CTM (pertuzumab); P188ANX8CK (Trastuzumab); SE2KH7T06F (ado-trastuzumab emtansine)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171024
[St] Status:MEDLINE
[do] DOI:10.1093/jnci/djx065


  4 / 529 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28973703
[Au] Autor:Cox K; Alford B; Soliman H
[Ad] Endereço:From the Lake Erie College of Osteopathic Medicine, Bradenton, Florida, the University of South Florida College of Medicine, Tampa, and the H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
[Ti] Título:Emerging Therapeutic Strategies in Breast Cancer.
[So] Source:South Med J;110(10):632-637, 2017 Oct.
[Is] ISSN:1541-8243
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The field of medical oncology is experiencing a period of rapid evolution owing to advances in the fields of genomics, tumor biology, and immunology. These disciplines have provided valuable insights into the heterogeneity between breast tumors, key oncogenic drivers, and the role of the immune system in the natural history of breast cancer. This knowledge is translating into many novel therapeutic strategies using personalized medicines, targeted drug delivery systems, and immunomodulatory agents in the treatment of both the early and metastatic stages of the disease. This review article attempts to cover the major developments in experimental therapeutics and how they relate to our understanding of breast cancer and its various biologic subtypes.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Inibidores da Aromatase/uso terapêutico
Neoplasias da Mama/tratamento farmacológico
Terapia de Alvo Molecular
Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico
Medicina de Precisão
Inibidores de Proteínas Quinases/uso terapêutico
Moduladores Seletivos de Receptor Estrogênico/uso terapêutico
[Mh] Termos MeSH secundário: Anticorpos Monoclonais/uso terapêutico
Anticorpos Monoclonais Humanizados/uso terapêutico
Neoplasias da Mama/metabolismo
Quinase 4 Dependente de Ciclina/antagonistas & inibidores
Quinase 6 Dependente de Ciclina/antagonistas & inibidores
Sistemas de Liberação de Medicamentos
Feminino
Seres Humanos
Imunoterapia
Ipilimumab
Maitansina/análogos & derivados
Maitansina/uso terapêutico
Receptor ErbB-2/metabolismo
Receptores Estrogênicos/metabolismo
Serina-Treonina Quinases TOR/antagonistas & inibidores
Trastuzumab
Neoplasias de Mama Triplo Negativas/tratamento farmacológico
Neoplasias de Mama Triplo Negativas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Antibodies, Monoclonal, Humanized); 0 (Antineoplastic Agents); 0 (Aromatase Inhibitors); 0 (Ipilimumab); 0 (Poly(ADP-ribose) Polymerase Inhibitors); 0 (Protein Kinase Inhibitors); 0 (Receptors, Estrogen); 0 (Selective Estrogen Receptor Modulators); 14083FR882 (Maytansine); 31YO63LBSN (nivolumab); 52CMI0WC3Y (atezolizumab); DPT0O3T46P (pembrolizumab); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.10.1 (ERBB2 protein, human); EC 2.7.10.1 (Receptor, ErbB-2); EC 2.7.11.22 (Cyclin-Dependent Kinase 4); EC 2.7.11.22 (Cyclin-Dependent Kinase 6); P188ANX8CK (Trastuzumab); SE2KH7T06F (ado-trastuzumab emtansine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171004
[St] Status:MEDLINE
[do] DOI:10.14423/SMJ.0000000000000709


  5 / 529 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28843653
[Au] Autor:Martin LP; Konner JA; Moore KN; Seward SM; Matulonis UA; Perez RP; Su Y; Berkenblit A; Ruiz-Soto R; Birrer MJ
[Ad] Endereço:Fox Chase Cancer Center, Philadelphia, PA, United States. Electronic address: lainie.martin@fccc.edu.
[Ti] Título:Characterization of folate receptor alpha (FRα) expression in archival tumor and biopsy samples from relapsed epithelial ovarian cancer patients: A phase I expansion study of the FRα-targeting antibody-drug conjugate mirvetuximab soravtansine.
[So] Source:Gynecol Oncol;147(2):402-407, 2017 Nov.
[Is] ISSN:1095-6859
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:PURPOSE: To characterize folate receptor alpha (FRα) expression in archival and fresh biopsy tumor samples from relapsed ovarian cancer patients. METHODS: Patients with ovarian tumors amenable to biopsy were eligible to enroll. Eligibility included a minimum requirement of FRα positivity in archival tumor samples (≥25% of cells with ≥2+ staining intensity). Patients received mirvetuximab soravtansine at 6mg/kg once every 3weeks. Core needle biopsies were collected before and after treatment and FRα levels assessed by immunohistochemistry. Descriptive statistics were used to summarize the association between receptor expression and response. RESULTS: Twenty-seven heavily pre-treated patients were enrolled. Six individuals (22%) did not have evaluable pre-treatment biopsies due to insufficient tumor cells. The concordance of FRα expression in archival and biopsy tissues was 71%, and no major shifts in receptor expression were seen in matched pre- and post-treatment biopsy samples. Adverse events were generally mild (≤grade 2) with keratopathy (48%), fatigue (44%), diarrhea, and blurred vision (each 37%) being the most common treatment-related toxicities. The confirmed objective response rate (ORR) was 22%, including two complete responses and four partial responses. Superior efficacy measures were observed in the subset of patients with the highest FRα levels (ORR, 31%; progression-free survival, 5.4months). CONCLUSION: Concordance of FRα expression in biopsy versus archival tumor samples suggests that archival tissue can reliably identify patients with receptor-positive tumors and is appropriate for patient selection in mirvetuximab soravtansine clinical trials. Regardless of the tissue source analyzed, higher FRα expression was associated with greater antitumor activity.
[Mh] Termos MeSH primário: Anticorpos Monoclonais Humanizados/administração & dosagem
Receptor 1 de Folato/biossíntese
Imunoconjugados/administração & dosagem
Maitansina/análogos & derivados
Neoplasias Epiteliais e Glandulares/tratamento farmacológico
Neoplasias Epiteliais e Glandulares/imunologia
Neoplasias Ovarianas/tratamento farmacológico
Neoplasias Ovarianas/imunologia
[Mh] Termos MeSH secundário: Adulto
Idoso
Anticorpos Monoclonais Humanizados/efeitos adversos
Feminino
Receptor 1 de Folato/imunologia
Seres Humanos
Imunoconjugados/efeitos adversos
Maitansina/administração & dosagem
Maitansina/efeitos adversos
Meia-Idade
Terapia de Alvo Molecular
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal, Humanized); 0 (Folate Receptor 1); 0 (Immunoconjugates); 0 (mirvetuximab soravtansine); 14083FR882 (Maytansine)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171108
[Lr] Data última revisão:
171108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170828
[St] Status:MEDLINE


  6 / 529 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28782796
[Au] Autor:Du ZQ; Zhang Y; Qian ZG; Xiao H; Zhong JJ
[Ad] Endereço:State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, and Laboratory of Molecular Biochemical Engineering and Advanced Fermentation Technology, Department of Bioengineering, School of Life Sciences and Biotechnology, Shanghai J
[Ti] Título:Combination of traditional mutation and metabolic engineering to enhance ansamitocin P-3 production in Actinosynnema pretiosum.
[So] Source:Biotechnol Bioeng;114(12):2794-2806, 2017 Dec.
[Is] ISSN:1097-0290
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ansamitocin P-3 (AP-3) is a maytansinoid with its most compelling antitumor activity, however, the low production titer of AP-3 greatly restricts its wide commercial application. In this work, a combinatorial approach including random mutation and metabolic engineering was conducted to enhance AP-3 biosynthesis in Actinosynnema pretiosum. First, a mutant strain M was isolated by N-methyl-N'-nitro-N-nitrosoguanidine mutation, which could produce AP-3 almost threefold that of wild type (WT) in 48 deep-well plates. Then, by overexpressing key biosynthetic genes asmUdpg and asm13-17 in the M strain, a further 60% increase of AP-3 production in 250-ml shake flasks was achieved in the engineered strain M-asmUdpg:asm13-17 compared to the M strain, and its maximum AP-3 production reached 582.7 mg/L, which is the highest as ever reported. Both the gene transcription levels and intracellular intermediate concentrations in AP-3 biosynthesis pathway were significantly increased in the M and M-asmUdpg:asm13-17 during fermentation compared to the WT. The good fermentation performance of the engineered strain was also confirmed in a lab-scale bioreactor. This work demonstrated that combination of random mutation and metabolic engineering could promote AP-3 biosynthesis and might be helpful for increasing the production of other industrially important secondary metabolites.
[Mh] Termos MeSH primário: Actinobacteria/fisiologia
Vias Biossintéticas/genética
Melhoramento Genético/métodos
Maitansina/análogos & derivados
Engenharia Metabólica/métodos
Mutação/genética
[Mh] Termos MeSH secundário: Actinobacteria/classificação
Maitansina/biossíntese
Especificidade da Espécie
Regulação para Cima/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
14083FR882 (Maytansine); 69279-90-9 (ansamitocins)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170808
[St] Status:MEDLINE
[do] DOI:10.1002/bit.26396


  7 / 529 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28705408
[Au] Autor:Menderes G; Bonazzoli E; Bellone S; Altwerger G; Black JD; Dugan K; Pettinella F; Masserdotti A; Riccio F; Bianchi A; Zammataro L; de Haydu C; Buza N; Hui P; Wong S; Huang GS; Litkouhi B; Ratner E; Silasi DA; Azodi M; Schwartz PE; Santin AD
[Ad] Endereço:Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
[Ti] Título:Superior in vitro and in vivo activity of trastuzumab-emtansine (T-DM1) in comparison to trastuzumab, pertuzumab and their combination in epithelial ovarian carcinoma with high HER2/neu expression.
[So] Source:Gynecol Oncol;147(1):145-152, 2017 Oct.
[Is] ISSN:1095-6859
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy. The objective of this study was to compare the anti-tumor activity of HER2/neu-targeting monoclonal antibodies, trastuzumab (T), pertuzumab (P), combination of trastuzumab and pertuzumab (T+P) and trastuzumab-emtansine (T-DM1) in EOC with high HER2/neu expression. METHODS: Primary EOC cell lines were established and cell blocks were analyzed for HER2/neu expression. Cytostatic, apoptotic and antibody-dependent cell-mediated cytotoxicity (ADCC) activities of T, P, T+P and T-DM1 were evaluated in vitro. The in vivo antitumor activity was tested in xenograft models with 3+ HER2/neu expression. RESULTS: High (3+) HER2/neu expression was detected in 40% of the primary EOC cell lines. T, P, T+P, and T-DM1 were similarly effective in inducing strong ADCC against primary EOC cell lines expressing 3+ HER2/neu. The combination of T and P was more cytostatic when compared with that of T or P used alone (p<0.0001 and p<0.0001, respectively). T-DM1 induced significantly more apoptosis when compared with T+P (p<0.0001). Finally, T-DM1 was significantly more effective in tumor growth inhibition in vivo in EOC xenografts overexpressing HER2/neu when compared to T alone, P alone and T+P (p=0.04). CONCLUSION: In vitro and in vivo experiments with 3+ HER2/neu expressing EOC revealed limited anti-tumor activity of T or P. T-DM1 showed superior anti-tumor activity to T and P as single agents and as a combination. Our preclinical data support the design of clinical studies with T-DM1 for the treatment of chemotherapy-resistant EOC overexpressing HER2/neu.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Carcinoma/tratamento farmacológico
Neoplasias Ovarianas/tratamento farmacológico
[Mh] Termos MeSH secundário: Adulto
Idoso
Animais
Anticorpos Monoclonais Humanizados/administração & dosagem
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
Carcinoma/metabolismo
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Modelos Animais de Doenças
Combinação de Medicamentos
Feminino
Seres Humanos
Maitansina/administração & dosagem
Maitansina/análogos & derivados
Camundongos
Camundongos SCID
Meia-Idade
Neoplasias Ovarianas/metabolismo
Receptor ErbB-2/metabolismo
Trastuzumab/administração & dosagem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal, Humanized); 0 (Drug Combinations); 14083FR882 (Maytansine); EC 2.7.10.1 (ERBB2 protein, human); EC 2.7.10.1 (Receptor, ErbB-2); K16AIQ8CTM (pertuzumab); P188ANX8CK (Trastuzumab)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170715
[St] Status:MEDLINE


  8 / 529 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28687619
[Au] Autor:Ríos-Luci C; García-Alonso S; Díaz-Rodríguez E; Nadal-Serrano M; Arribas J; Ocaña A; Pandiella A
[Ad] Endereço:Instituto de Biología Molecular y Celular del Cáncer, CSIC, Salamanca, Spain.
[Ti] Título:Resistance to the Antibody-Drug Conjugate T-DM1 Is Based in a Reduction in Lysosomal Proteolytic Activity.
[So] Source:Cancer Res;77(17):4639-4651, 2017 Sep 01.
[Is] ISSN:1538-7445
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate (ADC) that was approved recently to treat HER2 breast cancers. Despite its impressive clinical efficacy in many patients, intrinsic and acquired resistance to T-DM1 has emerged as a challenge. To identify mechanisms of T-DM1 resistance, we isolated several resistant HER2 clones exhibiting stable drug refractoriness and Genomic comparisons showed substantial differences among three of the isolated clones, indicating several potential mechanisms of resistance to T-DM1. However, we observed no differences in HER2 levels and signaling among the resistant models and parental HER2 cells. Bioinformatics studies suggested that intracellular trafficking of T-DM1 could underlie resistance to T-DM1, and systematic analysis of the path followed by T-DM1 showed that the early steps in the internalization of the drug were unaltered. However, in some of the resistant clones, T-DM1 accumulated in lysosomes. In these clones, lysosomal pH was increased and the proteolytic activity of these organelles was deranged. These results were confirmed in T-DM1-resistant cells from patient-derived HER2 samples. We postulate that resistance to T-DM1 occurs through multiple mechanisms, one of which is impaired lysosomal proteolytic activity. Because other ADC may use the same internalization-degradation pathway to deliver active payloads, strategies aimed at restoring lysosomal functionality might overcome resistance to ADC-based therapies and improve their effectiveness. .
[Mh] Termos MeSH primário: Anticorpos Monoclonais Humanizados/farmacologia
Neoplasias da Mama/patologia
Resistência a Medicamentos Antineoplásicos
Imunoconjugados/farmacologia
Lisossomos/metabolismo
Maitansina/análogos & derivados
Proteólise/efeitos dos fármacos
Receptor ErbB-2/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/farmacologia
Neoplasias da Mama/tratamento farmacológico
Neoplasias da Mama/enzimologia
Feminino
Perfilação da Expressão Gênica
Seres Humanos
Lisossomos/efeitos dos fármacos
Maitansina/farmacologia
Camundongos Endogâmicos BALB C
Camundongos Endogâmicos NOD
Camundongos Nus
Camundongos SCID
Trastuzumab
Células Tumorais Cultivadas
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal, Humanized); 0 (Antineoplastic Agents); 0 (Immunoconjugates); 14083FR882 (Maytansine); EC 2.7.10.1 (Receptor, ErbB-2); P188ANX8CK (Trastuzumab); SE2KH7T06F (ado-trastuzumab emtansine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170709
[St] Status:MEDLINE
[do] DOI:10.1158/0008-5472.CAN-16-3127


  9 / 529 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28682681
[Au] Autor:Harbeck N; Gluz O; Christgen M; Kates RE; Braun M; Küemmel S; Schumacher C; Potenberg J; Kraemer S; Kleine-Tebbe A; Augustin D; Aktas B; Forstbauer H; Tio J; von Schumann R; Liedtke C; Grischke EM; Schumacher J; Wuerstlein R; Kreipe HH; Nitz UA
[Ad] Endereço:Nadia Harbeck, Ludwig Maximilians University Hospital of Munich; Michael Braun, Red Cross Hospital Munich; Rachel Wuerstlein, University Hospital Munich, Munich; Nadia Harbeck, Oleg Gluz, Ronald Ernest Kates, Rachel Wuerstlein, and Ulrike Anneliese Nitz, The West German Study Group; Oleg Gluz, Raque
[Ti] Título:De-Escalation Strategies in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Early Breast Cancer (BC): Final Analysis of the West German Study Group Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early BC HER2- and Hormone Receptor-Positive Phase II Randomized Trial-Efficacy, Safety, and Predictive Markers for 12 Weeks of Neoadjuvant Trastuzumab Emtansine With or Without Endocrine Therapy (ET) Versus Trastuzumab Plus ET.
[So] Source:J Clin Oncol;35(26):3046-3054, 2017 Sep 10.
[Is] ISSN:1527-7755
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose Human epidermal growth factor receptor 2 (HER2)-positive/hormone receptor (HR)-positive breast cancer is a distinct subgroup associated with lower chemotherapy sensitivity and slightly better outcome than HER2-positive/HR-negative disease. Little is known about the efficacy of the combination of endocrine therapy (ET) with trastuzumab or with the potent antibody-cytotoxic, anti-HER2 compound trastuzumab emtansine (T-DM1) with or without ET for this subgroup. The West German Study Group trial, ADAPT (Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early Breast Cancer) compares pathologic complete response (pCR) rates of T-DM1 versus trastuzumab with ET in early HER2-positive/HR-positive breast cancer. Patients and Methods In this prospective, neoadjuvant, phase II trial, 375 patients with early breast cancer with HER2-positive and HR-positive status (n = 463 screened) were randomly assigned to 12 weeks of T-DM1 with or without ET or to trastuzumab with ET. The primary end point was pCR (ypT0/is/ypN0). Early response was assessed in 3-week post-therapeutic core biopsies (proliferation decrease ≥ 30% Ki-67 or cellularity response). Secondary end points included safety and predictive impact of early response on pCR. Adjuvant therapy followed national standards. Results Baseline characteristics were well balanced among the arms. More than 90% of patients completed the therapy per protocol. pCR was observed in 41.0% of patients treated with T-DM1, 41.5% of patients treated with T-DM1 and ET, and 15.1% with trastuzumab and ET ( P < .001). Early responders (67% of patients with assessable response) achieved pCR in 35.7% compared with 19.8% in nonresponders (odds ratio, 2.2; 95% CI, 1.24 to 4.19). T-DM1 was associated with a significantly higher prevalence of grade 1 to 2 toxicities, especially thrombocytopenia, nausea, and elevation of liver enzymes. Overall toxicity was low; seventeen therapy-related severe adverse events (T-DM1 arms v trastuzumab plus ET; 5.3% v 3.1%, respectively) were reported. Conclusion The ADAPT HER2-positive/HR-positive trial demonstrates that neoadjuvant T-DM1 (with or without ET) given for only 12 weeks results in a clinically meaningful pCR rate. Thus, a substantial number of patients are spared the adverse effects of systemic chemotherapy.
[Mh] Termos MeSH primário: Anticorpos Monoclonais Humanizados/uso terapêutico
Biomarcadores Tumorais/metabolismo
Neoplasias da Mama/tratamento farmacológico
Neoplasias da Mama/enzimologia
Maitansina/análogos & derivados
Medicina de Precisão/métodos
Receptor ErbB-2/biossíntese
[Mh] Termos MeSH secundário: Adulto
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Neoplasias da Mama/cirurgia
Feminino
Seres Humanos
Maitansina/uso terapêutico
Meia-Idade
Terapia Neoadjuvante
Estudos Prospectivos
Trastuzumab
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Antibodies, Monoclonal, Humanized); 0 (Biomarkers, Tumor); 14083FR882 (Maytansine); EC 2.7.10.1 (ERBB2 protein, human); EC 2.7.10.1 (Receptor, ErbB-2); P188ANX8CK (Trastuzumab); SE2KH7T06F (ado-trastuzumab emtansine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170707
[St] Status:MEDLINE
[do] DOI:10.1200/JCO.2016.71.9815


  10 / 529 MEDLINE  
              first record previous record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28677116
[Au] Autor:Takegawa N; Nonagase Y; Yonesaka K; Sakai K; Maenishi O; Ogitani Y; Tamura T; Nishio K; Nakagawa K; Tsurutani J
[Ad] Endereço:Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayamashi, Osaka, Japan.
[Ti] Título:DS-8201a, a new HER2-targeting antibody-drug conjugate incorporating a novel DNA topoisomerase I inhibitor, overcomes HER2-positive gastric cancer T-DM1 resistance.
[So] Source:Int J Cancer;141(8):1682-1689, 2017 Oct 15.
[Is] ISSN:1097-0215
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Anti-HER2 therapies are beneficial for patients with HER2-positive breast or gastric cancer. T-DM1 is a HER2-targeting antibody-drug conjugate (ADC) comprising the antibody trastuzumab, a linker, and the tubulin inhibitor DM1. Although effective in treating advanced breast cancer, all patients eventually develop T-DM1 resistance. DS-8201a is a new ADC incorporating an anti-HER2 antibody, a newly developed, enzymatically cleavable peptide linker, and a novel, potent, exatecan-derivative topoisomerase I inhibitor (DXd). DS-8201a has a drug-to-antibody-ratio (DAR) of 8, which is higher than that of T-DM1 (3.5). Owing to these unique characteristics and unlike T-DM1, DS-8201a is effective against cancers with low-HER2 expression. In the present work, T-DM1-resistant cells (N87-TDMR), established using the HER2-positive gastric cancer line NCI-N87 and continuous T-DM1 exposure, were shown to be susceptible to DS-8201a. The ATP-binding cassette (ABC) transporters ABCC2 and ABCG2 were upregulated in N87-TDMR cells, but HER2 overexpression was retained. Furthermore, inhibition of ABCC2 and ABCG2 by MK571 restored T-DM1 sensitivity. Therefore, resistance to T-DM1 is caused by efflux of its payload DM1, due to aberrant expression of ABC transporters. In contrast to DM1, DXd payload of DS-8201a inhibited the growth of N87-TDMR cells in vitro. This suggests that either DXd may be a poor substrate of ABCC2 and ABCG2 in comparison to DM1, or the high DAR of DS-8201a relative to T-DM1 compensates for increased efflux. Notably, N87-TDMR xenograft tumor growth was prevented by DS-8201a. In conclusion, the efficacy of DS-8201a as a treatment for patients with T-DM1-resistant breast or gastric cancer merits investigation.
[Mh] Termos MeSH primário: Anticorpos Monoclonais Humanizados/farmacologia
Camptotecina/análogos & derivados
Imunoconjugados/farmacologia
Neoplasias Gástricas/tratamento farmacológico
Inibidores da Topoisomerase I/farmacologia
[Mh] Termos MeSH secundário: Animais
Anticorpos Monoclonais Humanizados/química
Camptotecina/química
Camptotecina/farmacologia
Linhagem Celular Tumoral
Resistência a Medicamentos Antineoplásicos
Feminino
Seres Humanos
Imunoconjugados/química
Maitansina/análogos & derivados
Maitansina/farmacologia
Camundongos
Camundongos Endogâmicos BALB C
Camundongos Nus
Distribuição Aleatória
Receptor ErbB-2/biossíntese
Neoplasias Gástricas/enzimologia
Neoplasias Gástricas/imunologia
Inibidores da Topoisomerase I/química
Trastuzumab
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal, Humanized); 0 (DS-8201a); 0 (Immunoconjugates); 0 (Topoisomerase I Inhibitors); 14083FR882 (Maytansine); EC 2.7.10.1 (ERBB2 protein, human); EC 2.7.10.1 (Receptor, ErbB-2); P188ANX8CK (Trastuzumab); SE2KH7T06F (ado-trastuzumab emtansine); XT3Z54Z28A (Camptothecin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170706
[St] Status:MEDLINE
[do] DOI:10.1002/ijc.30870



página 1 de 53 ir para página                         
   


Refinar a pesquisa
  Base de dados : MEDLINE Formulário avançado   

    Pesquisar no campo  
1  
2
3
 
           



Search engine: iAH v2.6 powered by WWWISIS

BIREME/OPAS/OMS - Centro Latino-Americano e do Caribe de Informação em Ciências da Saúde