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1.
J Rehabil Med ; 56: jrm21372, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38659375

RESUMO

OBJECTIVE: To investigate the community integration of patients following stroke and determine the predictors of their level of community integration at 1-year follow-up. DESIGN: A multicenter, longitudinal, and observational study. SUBJECTS: Sixty-five inpatients (41 men) with a mean age of 56.9 (standard deviation = 17.0) years, who had their first stroke at least 1 month prior to this study were recruited from 4 rehabilitation inpatient wards in China. METHODS: In the initial assessment, the participants were evaluated using the Community Integration Questionnaire, the Fugl-Meyer Assessment, the Berg Balance Scale, the Modified Barthel Index, the Mini Mental State Examination, and the Modified Ashworth Scale. In the follow-up assessments, which were conducted via telephone no less than 1 year after discharge, the participants were evaluated using the Community Integration Questionnaire and also assessed for other disease-related conditions. RESULTS: The participants' scores on the Community Integration Questionnaire in the follow-up assessment were significantly greater than those at the initial assessment (p < 0.05). In addition, the participants' Community Integration Questionnaire scores in the follow-up assessment were significantly correlated with their ages, numbers of years of education, and Modified Barthel Index, Berg Balance Scale, Mini Mental State Examination scores in the initial assessment (p < 0.05), and marginally significantly correlated with their scores on Fugl-Meyer Assessment in the initial assessment (p = 0.058). The participants' ages, numbers of years of education, and Modified Barthel Index, Berg Balance Scale, Mini Mental State Examination, Fugl-Meyer Assessment of the lower extremity, and Fugl-Meyer Assessment scores in the initial assessment were predictive of their Community Integration Questionnaire scores at follow-up, with coefficients of determination ranging from 0.254 to 0.056 (p < 0.05). CONCLUSIONS: The level of community integration of the participants was generally low, but it was greater at 1-year follow-up than it was initially. Balance function and daily living ability may be key predictors of community integration of patients following stroke.


Assuntos
Integração Comunitária , Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Reabilitação do Acidente Vascular Cerebral/métodos , Estudos Longitudinais , Idoso , Acidente Vascular Cerebral/fisiopatologia , Inquéritos e Questionários , Adulto , China , Avaliação da Deficiência , Equilíbrio Postural/fisiologia
2.
Proc Natl Acad Sci U S A ; 120(30): e2221809120, 2023 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-37459541

RESUMO

Early in the COVID-19 pandemic, data suggested that males had a higher risk of developing severe disease and that androgen deprivation therapy might be associated with protection. Combined with the fact that TMPRSS2 (transmembrane serine protease 2), a host entry factor for the SARS-CoV-2 virus, was a well-known androgen-regulated gene, this led to an upsurge of research investigating androgen receptor (AR)-targeting drugs. Proxalutamide, an AR antagonist, was shown in initial clinical studies to benefit COVID-19 patients; however, further validation is needed as one study was retracted. Due to continued interest in proxalutamide, which is in phase 3 trials, we examined its ability to impact SARS-CoV-2 infection and downstream inflammatory responses. Proxalutamide exerted similar effects as enzalutamide, an AR antagonist prescribed for advanced prostate cancer, in decreasing AR signaling and expression of TMPRSS2 and angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 receptor. However, proxalutamide led to degradation of AR protein, which was not observed with enzalutamide. Proxalutamide inhibited SARS-CoV-2 infection with an IC50 value of 97 nM, compared to 281 nM for enzalutamide. Importantly, proxalutamide inhibited infection by multiple SARS-CoV-2 variants and synergized with remdesivir. Proxalutamide protected against cell death in response to tumor necrosis factor alpha and interferon gamma, and overall survival of mice was increased with proxalutamide treatment prior to cytokine exposure. Mechanistically, we found that proxalutamide increased levels of NRF2, an essential transcription factor that mediates antioxidant responses, and decreased lung inflammation. These data provide compelling evidence that proxalutamide can prevent SARS-CoV-2 infection and cytokine-induced lung damage, suggesting that promising clinical data may emerge from ongoing phase 3 trials.


Assuntos
COVID-19 , Neoplasias da Próstata , Masculino , Humanos , Animais , Camundongos , SARS-CoV-2/metabolismo , Androgênios , Antagonistas de Androgênios/uso terapêutico , Pandemias , Peptidil Dipeptidase A/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Interferon gama/uso terapêutico
3.
Acta Crystallogr F Struct Biol Commun ; 79(Pt 4): 95-104, 2023 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-36995121

RESUMO

Mutations in the androgen receptor (AR) ligand-binding domain (LBD) can cause resistance to drugs used to treat prostate cancer. Commonly found mutations include L702H, W742C, H875Y, F877L and T878A, while the F877L mutation can convert second-generation antagonists such as enzalutamide and apalutamide into agonists. However, pruxelutamide, another second-generation AR antagonist, has no agonist activity with the F877L and F877L/T878A mutants and instead maintains its inhibitory activity against them. Here, it is shown that the quadruple mutation L702H/H875Y/F877L/T878A increases the soluble expression of AR LBD in complex with pruxelutamide in Escherichia coli. The crystal structure of the quadruple mutant in complex with the agonist dihydrotestosterone (DHT) reveals a partially open conformation of the AR LBD due to conformational changes in the loop connecting helices H11 and H12 (the H11-H12 loop) and Leu881. This partially open conformation creates a larger ligand-binding site for AR. Additional structural studies suggest that both the L702H and F877L mutations are important for conformational changes. This structural variability in the AR LBD could affect ligand binding as well as the resistance to antagonists.


Assuntos
Receptores Androgênicos , Masculino , Humanos , Receptores Androgênicos/genética , Receptores Androgênicos/química , Receptores Androgênicos/metabolismo , Ligantes , Cristalografia por Raios X , Mutação , Estrutura Secundária de Proteína
4.
Breast Cancer Res Treat ; 189(3): 725-736, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34392453

RESUMO

PURPOSE: To evaluate GT0918, a 2nd-generation AR antagonist, for its AR down-regulation activity among breast cancer patients. METHODS: The effect of GT0918 on AR protein expression was evaluated in AR expression breast cancer cells and in breast cancer xenograft model. A 3 + 3 phase I dose-escalation study was launched in Peking University Cancer Hospital. The endpoints included dose finding, safety, pharmacokinetics, and antitumor activity. RESULTS: GT0918 was demonstrated to effectively suppress the expression of AR protein and the growth of AR-positive breast cancer tumors in mouse xenograft tumor models. All patients treated with GT0918 were at a QD dose-escalation of five dose levels from 100 to 500 mg. The most common treatment-related AEs of any grade were asthenia, anemia, decreased appetite, increased blood cholesterol, increased blood triglycerides, decreased white blood cell count, and increased low-density lipoprotein. Grade 3 AEs were fatigue (2 of 18, 11.1%), aspartate aminotransferase increase (1 of 18, 5.6%), alanine aminotransferase increase (1 of 18, 5.6%), and neutrophil count decrease (1 of 18, 5.6%). Clinical benefit rate (CBR) in 16 weeks was 23.1% (3/13). Among 7 AR-positive patients, 6 can evaluate efficacy, and 2 completed 23.5- and 25-cycle treatment, respectively (as of 2020/1/20). PK parameters showed a fast absorption profile of GT0918 in the single-dose study. GT0918 and its major metabolite reached steady-state serum concentration levels at day 21 after multiple dosing. CONCLUSION: GT0918 can effectively inhibit AR-positive breast cancer tumor growth. GT0918 was demonstrated well tolerated with a favorable PK profile. The suitable dose of GT0918 was 500 mg QD and may provide clinical benefits for AR-positive mBC.


Assuntos
Antagonistas de Receptores de Andrógenos , Neoplasias da Mama , Animais , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Camundongos , Oxazóis , Receptores Androgênicos , Tioidantoínas
5.
Invest New Drugs ; 30(3): 936-49, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21360050

RESUMO

LY2457546 is a potent and orally bioavailable inhibitor of multiple receptor tyrosine kinases involved in angiogenic and tumorigenic signalling. In biochemical and cellular assays, LY2457546 demonstrates potent activity against targets that include VEGFR2 (KDR), PDGFRß, FLT-3, Tie-2 and members of the Eph family of receptors. With activities against both Tie2 and Eph receptors, LY2457546 possesses an activity profile that distinguishes it from multikinase inhibitors. When compared head to head with sunitinib, LY2457546 was more potent for inhibition of endothelial tube formation in an in vitro angiogenesis co-culture model with an intermittent treatment design. In vivo, LY2457546 inhibited VEGF-driven autophosphorylation of lung KDR in the mouse and rat in a dose and concentration dependent manner. LY2457546 was well tolerated and exhibited efficacy in a 13762 syngeneic rat mammary tumor model in both once and twice daily continuous dosing schedules and in mouse human tumor xenograft models of lung, colon, and prostate origin. Additionally, LY2457546 caused complete regression of well-established tumors in an acute myelogenous leukemia (AML) FLT3-ITD mutant xenograft tumor model. The observed efficacy that was displayed by LY2457546 in the AML FLT3-ITD mutant tumor model was superior to sunitinib when both were evaluated using equivalent doses normalized to in vivo inhibition of pKDR in mouse lung. LY2457546 was well tolerated in non-clinical toxicology studies conducted in rats and dogs. The majority of the toxicities observed were similar to those observed with other multi-targeted anti-angiogenic kinase inhibitors (MAKs) and included bone marrow hypocellularity, hair and skin depigmentation, cartilage dysplasia and lymphoid organ degeneration and necrosis. Thus, the unique spectrum of target activity, potent in vivo anti-tumor efficacy in a variety of rodent and human solid tumor models, exquisite potency against a clinically relevant model of AML, and non-clinical safety profile justify the advancement of LY2457546 into clinical testing.


Assuntos
Acetanilidas/uso terapêutico , Inibidores da Angiogênese/uso terapêutico , Neoplasias Experimentais/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Acetanilidas/síntese química , Acetanilidas/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/farmacologia , Animais , Células CHO , Linhagem Celular Tumoral , Cricetinae , Cricetulus , Cães , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Nus , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Ensaios Antitumorais Modelo de Xenoenxerto , Tirosina Quinase 3 Semelhante a fms/genética
6.
Cancer Res ; 64(11): 3761-6, 2004 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-15172981

RESUMO

The mechanisms of resistance to the antimetabolite gemcitabine in non-small cell lung cancer have not been extensively evaluated. In this study, we report the generation of two gemcitabine-selected non-small cell lung cancer cell lines, H358-G200 and H460-G400. Expression profiling results indicated that there was evidence for changes in the expression of 134 genes in H358-G200 cells compared with its parental line, whereas H460-G400 cells exhibited 233 genes that appeared to be under- or overexpressed compared with H460 cells. However, only the increased expression of ribonucleotide reductase subunit 1 (RRM1), which appeared in both resistant cell lines, met predefined analysis criteria for genes to investigate further. Quantitative PCR analysis demonstrated H358-G200 cells had a greater than 125-fold increase in RRM1 RNA expression. Western blot analysis confirmed high levels of RRM1 protein in this line compared with the gemcitabine-sensitive parent. No significant change in the expression of RRM2 was observed in either cell line, although both gemcitabine-resistant cell lines had an approximate 3-fold increase in p53R2 protein. A partial revertant of H358-G200 cells had reduced levels of RRM1 protein (compared with G200 cells), without observed changes in RRM2 or p53R2. In vitro analyses of ribonucleotide reductase activity demonstrated that despite high levels of RRM1 protein, ribonucleotide reductase activity was not increased in H358-G200 cells when compared with parental cells. The cDNA encoding RRM1 from H358-G200 cells was cloned and sequenced but did not reveal the presence of any mutations. The results from this study indicate that the level of RRM1 may affect gemcitabine response. Furthermore, RRM1 may serve as a biomarker for gemcitabine response.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Proteínas Supressoras de Tumor/biossíntese , Carbono-Nitrogênio Ligases/biossíntese , Carbono-Nitrogênio Ligases/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Citosina Desaminase/biossíntese , Citosina Desaminase/genética , DCMP Desaminase/biossíntese , DCMP Desaminase/genética , Desoxicitidina Quinase/biossíntese , Desoxicitidina Quinase/genética , Resistencia a Medicamentos Antineoplásicos , Perfilação da Expressão Gênica , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Análise de Sequência com Séries de Oligonucleotídeos , Ribonucleosídeo Difosfato Redutase , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Gencitabina
7.
Biochem Pharmacol ; 67(6): 1111-21, 2004 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-15006547

RESUMO

Several of the ATP-binding cassette (ABC) transporters confer resistance to anticancer agents and/or antiviral agents when overexpressed in drug-sensitive cells. Recently a MRP1 (ABCC1) tricyclic isoxazole inhibitor, LY475776 was shown to be a glutathione-dependent photoaffinity label of human MRP1 and showed poor labeling of murine mrp1, an ortholog that does not confer anthracycline resistance. In the present study, the specificity of LY475776 was examined for its ability to modulate or photolabel orthologs of MRP1 and several other drug efflux transporters of the ABC transporter family. LY475776 modulated MRP1 and Pgp-mediated resistance (MDR, ABCB1) in, respectively, HeLa-T5 and CEM/VLB(100) cells to both vincristine and doxorubicin. LY475776 photolabeled 170kDa Pgp and was inhibited by the potent Pgp inhibitor LY335979 (Zosuquidar.3HCl). The labeling of the 190kDa MRP1 protein in membranes of HeLa-T5 cells was inhibited by substrates of MRP1 such as leukotriene C(4), vincrisine, and doxorubicin and by the inhibitor, MK571. LY475776 did not photolabel human MRP2 (ABCC2), MRP3 (ABCC3), MRP5 (ABCC5) or breast cancer resistance protein (ABCG2). Because LY475776 photolabels murine mrp1 less well than human MRP1 and binds to a region believed important for anthracycline binding, studies were conducted with monkey and canine MRP1 which also show a reduced ability to confer resistance to anthracyclines. Unlike murine mrp1, both orthologs were photolabeled well by LY475776. These studies indicate that the specificity of LY475776 is fairly limited to Pgp and MRP1 and further studies will help to define the binding regions.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Azidas/farmacologia , Isoxazóis/farmacologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Sequência de Aminoácidos , Animais , Divisão Celular/efeitos dos fármacos , Resistência a Múltiplos Medicamentos , Células HeLa , Humanos , Camundongos , Dados de Sequência Molecular , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Marcadores de Fotoafinidade , Homologia de Sequência de Aminoácidos , Especificidade da Espécie , Células Tumorais Cultivadas
8.
Mol Cancer Ther ; 1(14): 1335-42, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12516967

RESUMO

Human multidrug resistance protein 1 (MRP1) confers resistance to the Vinca alkaloids, the anthracyclines, and the epipodophyllotoxins. It is also capable of binding to and transporting the glutathione S-conjugate leukotriene C4 (LTC4) in isolated membrane vesicles. To explore species differences that exist between MRP orthologs, we cloned and characterized the mRNA encoding a canine ortholog of human MRP1-designated canine MRP1 (canMRP1). The canMRP1 mRNA encodes a protein of identical length as MRP1. Sequence alignment revealed that canMRP1 was 92% identical to MRP1 and 88% identical to murine mrp1. Five polymorphisms were identified in the canMRP1 cDNA coding sequence, including one resulting in an amino acid change from alanine to serine at aa149 (canMRP1-A and B alleles, respectively). canMRP1 was expressed and functionally characterized in HeLa and A2780 cells. Both alleles conferred an increased resistance to vincristine and etoposide and transported LTC4. The compound LY402913, a modulating agent developed against human MRP1, was able to sensitize canMRP1-expressing cells to vincristine. The modulation of canMRP1 by LY402913 was additionally confirmed by the calcein-AM accumulation assay. LY402913 inhibited the efflux of calcein in canMRP1-expressing cells. Thus, canMRP1 is similar to MRP1 in conferring resistance to vincristine and etoposide, transporting calcein-a.m., and being inhibited by LY402913. However, despite the high degree of sequence identity and functional similarity to MRP1, canMRP1 transgene failed to confer resistance to doxorubicin either in HeLa or A2780 cells. Knowledge of species differences between canine and human proteins will aid in the design of appropriate pharmacokinetic and toxicokinetic studies for the preclinical evaluation of MRP1 modulators.


Assuntos
Proteínas Associadas à Resistência a Múltiplos Medicamentos/química , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Trifosfato de Adenosina/metabolismo , Alelos , Sequência de Aminoácidos , Animais , Antineoplásicos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Clonagem Molecular , DNA Complementar/metabolismo , Cães , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/farmacologia , Etoposídeo/farmacologia , Citometria de Fluxo , Fluoresceínas/farmacologia , Células HeLa , Humanos , Immunoblotting , Concentração Inibidora 50 , Leucotrieno C4/metabolismo , Dados de Sequência Molecular , Polimorfismo Genético , RNA Mensageiro/metabolismo , Homologia de Sequência de Aminoácidos , Especificidade da Espécie , Transfecção , Células Tumorais Cultivadas , Vincristina/farmacologia
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