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1.
Eur J Pharm Biopharm ; 201: 114386, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38950717

RESUMO

The goal of the study was to fabricate folic acid functionalized docetaxel (DOC)/erlotinib (ERL)-loaded solid lipid nanoparticles (SLNs) to synergistically increase the anticancer activity against triple-negative breast cancer. DOC/ERL-SLNs were prepared by the high shear homogenization - ultrasound dispersion method (0.1 % w/v for DOC, and 0.3 %w/v for ERL) and optimized using Plackett Burman Design (PBD) followed by Box Behnken Design (BBD). The optimized SLNs demonstrated particle size < 200 nm, PDI < 0.35, and negative zeta potential with entrapment and loading efficiency of ∼80 and ∼4 %, respectively. The SLNs and folic acid functionalized SLNs (FA-SLNs) showed sustained release for both drugs, followed by Higuchi and Korsemeyer-Peppas drug release models, respectively. Further, the in vitro pH-stat lipolysis model demonstrated an approximately 3-fold increase in the bioaccessibility of drugs from SLNs compared to suspension. The TEM images revealed the spherical morphology of the SLNs. DOC/ERL loaded SLNs showed dose- and time-dependent cytotoxicity and exhibited a synergism at a molar ratio of 1:3 in TNBC with a combination index of 0.35 and 0.37, respectively. FA-DOC/ERL-SLNs showed enhanced anticancer activity as evidenced by MMP and ROS assay and further inhibited the colony-forming ability and the migration capacity of TNBC cells. Conclusively, the study has shown that SLNs are encouraging systems to improve the pharmaceutical attributes of poorly bioavailable drugs.


Assuntos
Docetaxel , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Cloridrato de Erlotinib , Lipídeos , Nanopartículas , Tamanho da Partícula , Neoplasias de Mama Triplo Negativas , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Docetaxel/administração & dosagem , Docetaxel/farmacologia , Docetaxel/farmacocinética , Humanos , Nanopartículas/química , Cloridrato de Erlotinib/administração & dosagem , Cloridrato de Erlotinib/farmacologia , Cloridrato de Erlotinib/farmacocinética , Linhagem Celular Tumoral , Feminino , Lipídeos/química , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Portadores de Fármacos/química , Sobrevivência Celular/efeitos dos fármacos , Ácido Fólico/química , Lipossomos
2.
Drug Dev Res ; 85(5): e22231, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38956926

RESUMO

The close association between inflammation and cancer inspired the synthesis of a series of 1,3,4-oxadiazole derivatives (compounds H4-A-F) of 6-methoxynaphtalene. The chemical structures of the new compounds were validated utilizing Fourier-transform infrared, proton nuclear magnetic resonance, and carbon-13 nuclear magnetic resonance spectroscopic techniques and CHN analysis. Computer-aided drug design methods were used to predict the compounds biological target, ADMET properties, toxicity, and to evaluate the molecular similarities between the design compounds and erlotinib, a standard epidermal growth factor receptor (EGFR) inhibitor. The antiproliferative effects of the new compounds were evaluated by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay, cell cycle analysis, apoptosis detection by microscopy, quantitative reverse transcription-polymerase chain reaction, and immunoblotting, and EGFR enzyme inhibition assay. In silico analysis of the new oxadiazole derivatives indicated that these compounds target EGFR, and that compounds H4-A, H4-B, H4-C, and H4-E show similar molecular properties to erlotinib. Additionally, the results indicated that none of the synthesized compounds are carcinogenic, and that compounds H4-A, H4-C, and H4-F are nontoxic. Compound H4-A showed the best-fit score against EGFR pharmacophore model, however, the in vitro studies indicated that compound H4-C was the most cytotoxic. Compound H4-C caused cytotoxicity in HCT-116 colorectal cancer cells by inducing both apoptosis and necrosis. Furthermore, compounds H4-D, H4-C, and H4-B had potent inhibitory effect on EGFR tyrosine kinase that was comparable to erlotinib. The findings of this inquiry offer a basis for further investigation into the differences between the synthesized compounds and erlotinib. However, additional testing will be needed to assess all of these differences and to identify the most promising compound for further research.


Assuntos
Antineoplásicos , Receptores ErbB , Simulação de Acoplamento Molecular , Naproxeno , Oxidiazóis , Receptores ErbB/antagonistas & inibidores , Humanos , Oxidiazóis/farmacologia , Oxidiazóis/química , Oxidiazóis/síntese química , Naproxeno/farmacologia , Naproxeno/análogos & derivados , Naproxeno/química , Naproxeno/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Cloridrato de Erlotinib/farmacologia , Cloridrato de Erlotinib/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Proliferação de Células/efeitos dos fármacos
3.
JMIR Res Protoc ; 13: e51381, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38954434

RESUMO

BACKGROUND: Starting in 2010, the epidermal growth factor receptor (EGFR) kinase inhibitors erlotinib and gefitinib were introduced into routine use in Aotearoa New Zealand (NZ) for treating advanced lung cancer, but their impact in this setting is unknown. OBJECTIVE: The study described in this protocol aims to understand the effectiveness and safety of these new personalized lung cancer treatments and the contributions made by concomitant medicines and other factors to adverse outcomes in the general NZ patient population. A substudy aimed to validate national electronic health databases as the data source and the methods for determining patient eligibility and identifying outcomes and variables. METHODS: This study will include all NZ patients with advanced EGFR mutation-positive lung cancer who were first dispensed erlotinib or gefitinib before October 1, 2020, and followed until death or for at least 1 year. Routinely collected health administrative and clinical data will be collated from national electronic cancer registration, hospital discharge, mortality registration, and pharmaceutical dispensing databases by deterministic data linkage using National Health Index numbers. The primary effectiveness and safety outcomes will be time to treatment discontinuation and serious adverse events, respectively. The primary variable will be high-risk concomitant medicines use with erlotinib or gefitinib. For the validation substudy (n=100), data from clinical records were compared to those from national electronic health databases and analyzed by agreement analysis for categorical data and by paired 2-tailed t tests for numerical data. RESULTS: In the validation substudy, national electronic health databases and clinical records agreed in determining patient eligibility and for identifying serious adverse events, high-risk concomitant medicines use, and other categorical data with overall agreement and κ statistic of >90% and >0.8000, respectively; for example, for the determination of patient eligibility, the comparison of proxy and standard eligibility criteria applied to national electronic health databases and clinical records, respectively, showed overall agreement and κ statistic of 96% and 0.8936, respectively. Dates for estimating time to treatment discontinuation and other numerical variables and outcomes showed small differences, mostly with nonsignificant P values and 95% CIs overlapping with zero difference; for example, for the dates of the first dispensing of erlotinib or gefitinib, national electronic health databases and clinical records differed on average by approximately 4 days with a nonsignificant P value of .33 and 95% CIs overlapping with zero difference. As of May 2024, the main study is ongoing. CONCLUSIONS: A protocol is presented for a national whole-of-patient-population retrospective cohort study designed to describe the safety and effectiveness of erlotinib and gefitinib during their first decade of routine use in NZ for treating EGFR mutation-positive lung cancer. The validation substudy demonstrated the feasibility and validity of using national electronic health databases and the methods for determining patient eligibility and identifying the study outcomes and variables proposed in the study protocol. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12615000998549; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368928. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51381.


Assuntos
Receptores ErbB , Cloridrato de Erlotinib , Gefitinibe , Neoplasias Pulmonares , Mutação , Humanos , Cloridrato de Erlotinib/uso terapêutico , Cloridrato de Erlotinib/efeitos adversos , Gefitinibe/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Receptores ErbB/genética , Receptores ErbB/antagonistas & inibidores , Estudos Retrospectivos , Nova Zelândia , Feminino , Masculino , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , Estudos de Coortes , Pessoa de Meia-Idade , Idoso
4.
Int J Mol Sci ; 25(12)2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38928126

RESUMO

Photodynamic Therapy (PDT) is recognized for its exceptional effectiveness as a promising cancer treatment method. However, it is noted that overexposure to the dosage and sunlight in traditional PDT can result in damage to healthy tissues, due to the low tumor selectivity of currently available photosensitizers (PSs). To address this challenge, we introduce herein a new strategy where the small molecule-targeted agent, erlotinib, is integrated into a boron dipyrromethene (BODIPY)-based PS to form conjugate 6 to enhance the precision of PDT. This conjugate demonstrates optical absorption, fluorescence emission, and singlet oxygen generation efficiency comparable to the reference compound 7, which lacks erlotinib. In vitro studies reveal that, after internalization, conjugate 6 predominantly accumulates in the lysosomes of HepG2 cells, exhibiting significant photocytotoxicity with an IC50 value of 3.01 µM. A distinct preference for HepG2 cells over HELF cells is observed with conjugate 6 but not with compound 7. In vivo experiments further confirm that conjugate 6 has a specific affinity for tumor tissues, and the combination treatment of conjugate 6 with laser illumination can effectively eradicate H22 tumors in mice with outstanding biosafety. This study presents a novel and potential PS for achieving precise PDT against cancer.


Assuntos
Cloridrato de Erlotinib , Neoplasias Hepáticas , Fotoquimioterapia , Fármacos Fotossensibilizantes , Porfobilinogênio , Humanos , Fotoquimioterapia/métodos , Animais , Camundongos , Porfobilinogênio/análogos & derivados , Porfobilinogênio/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Células Hep G2 , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Cloridrato de Erlotinib/farmacologia , Cloridrato de Erlotinib/química , Compostos de Boro/química , Compostos de Boro/farmacologia
5.
Life Sci ; 351: 122849, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-38897346

RESUMO

EGFR tyrosine kinase inhibitor (TKI) resistance is a major challenge for EGFR-mutant non-small cell lung cancer (NSCLC) treatment. Our previous work revealed that overexpression of AXL promoted EGFR-TKI resistance through epithelial-mesenchymal transition (EMT) in a subset of NSCLC patients. Compared with erlotinib resistant and sensitive cells, RP11-874 J12.4 was upregulated in erlotinib-resistant NSCLC cells (HCC827-ER3). Interestingly, the expression of RP11-874 J12.4 positively correlated with AXL. Besides, RP11-874 J12.4 promotes NSCLC cell proliferation and metastasis in vitro. Mechanistically, RP11-874 J12.4 promoted AXL expression through sponge with miR-34a-5p, which was reported to inhibit the translation of AXL mRNA. Meanwhile, the expression of RP11-874 J12.4 in lung cancer tumors were higher than the adjacent tissue, and those patients with high expression of RP11-874 J12.4 showed a poor prognosis in clinical. High expression of RP11-874 J12.4 might be a biomarker for NSCLC patients with erlotinib resistance. These findings reveal a novel insight into the mechanism of erlotinib resistance in NSCLC, and it might be a promising target for the diagnosis and treatment of NSCLC.


Assuntos
Receptor Tirosina Quinase Axl , Carcinoma Pulmonar de Células não Pequenas , Resistencia a Medicamentos Antineoplásicos , Cloridrato de Erlotinib , Neoplasias Pulmonares , Proteínas Proto-Oncogênicas , Receptores Proteína Tirosina Quinases , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Humanos , Cloridrato de Erlotinib/farmacologia , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , MicroRNAs/genética , MicroRNAs/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Animais , Camundongos
6.
J Med Chem ; 67(13): 11152-11167, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38896797

RESUMO

Radionuclide-drug conjugates (RDCs) designed from small molecule or nanoplatform shows complementary characteristics. We constructed a new RDC system with integrated merits of small molecule and nanoplatform-based RDCs. Erlotinib was labeled with 131I to construct the bulk of RDC (131I-ER). Floxuridine was mixed with 131I-ER to develop a hydrogen bond-driving supermolecular RDC system (131I-ER-Fu NPs). The carrier-free 131I-ER-Fu NPs supermolecule not only demonstrated integrated merits of small molecule and nanoplatform-based RDC, including clear structure definition, stable quality control, prolonged circulation lifetime, enhanced tumor specificity and retention, and rapidly nontarget clearance, but also exhibited low biological toxicity and stronger antitumor effects. In vivo imaging also revealed its application for tumor localization of nonsmall cell lung cancer (NSCLC) and screening of patients suitable for epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. We considered that 131I-ER-Fu NPs showed potentials as an integrated platform for the radiotheranostics of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Humanos , Animais , Camundongos , Floxuridina/química , Floxuridina/farmacologia , Radioisótopos do Iodo/química , Cloridrato de Erlotinib/química , Cloridrato de Erlotinib/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacologia , Linhagem Celular Tumoral , Distribuição Tecidual , Camundongos Nus , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Camundongos Endogâmicos BALB C , Feminino
7.
Med Oncol ; 41(7): 173, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38864966

RESUMO

Erlotinib (ELB) is a tyrosine kinase inhibitor that targets the activity of Epidermal Growth Factor Receptor (EGFR) protein found in both healthy and cancerous cells. It binds reversibly to the ATP-binding site of the EGFR tyrosine kinase. ELB was approved by the US Food and Drug Administration (FDA) in 2004 for advanced non-small cell lung cancer (NSCLC) treatment in patients who relapsed after at least one other therapy. It was authorized for use with gemcitabine in 2005 for the treatment of advanced pancreatic cancer. In addition to lung cancer, ELB has shown promising results in the treatment of other cancers, including breast, prostate, colon, pancreatic, cervical, ovarian, and head and neck cancers. However, its limited water solubility, as a BCS class II drug, presents biopharmaceutical problems. Nanoformulations have been developed to overcome these issues, including increased solubility, controlled release, enhanced stability, tumor accumulation, reduced toxicity, and overcoming drug resistance. In older patients, ELB management should involve individualized dosing based on age-related changes in drug metabolism and close monitoring for adverse effects. Regular assessments of renal and hepatic functions are essential. This review provides an overview of ELB's role of ELB in treating various cancers, its associated biopharmaceutical issues, and the latest developments in ELB-related nanotechnology interventions. It also covers ELB patents granted in previous years and the ongoing clinical trials.


Assuntos
Ensaios Clínicos como Assunto , Cloridrato de Erlotinib , Neoplasias , Inibidores de Proteínas Quinases , Humanos , Cloridrato de Erlotinib/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Antineoplásicos/uso terapêutico , Nanotecnologia/métodos , Patentes como Assunto , Receptores ErbB/antagonistas & inibidores
8.
Sci Rep ; 14(1): 14955, 2024 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-38942802

RESUMO

The size of the drug particles is one of the essential factors for the proper absorption of the drug compared to the dose of the drug. When particle size is decreased, drug uptake into the body increases. Recent studies have revealed that the rapid expansion of supercritical solution with cosolvent plays a significant role in preparing micron and submicron particles. This paper examines the preparation of Erlotinib hydrochloride nanoparticles using a supercritical solution through the cosolvent method for the first time. An examination of the parameters of temperature (318-338 K), pressures (15-25 MPa) and nozzle diameter (300-700 µm) was investigated by Box-Behnken design, and their respective effects on particle size revealed that the nozzle diameter has a more significant impact on particle size than the other parameters. The smallest particles were produced at temperature 338 K, pressure 20 MPa, and nozzle diameter 700 µm. Besides, the ERL nanoparticles were characterized using SEM, DLS, XRD, FTIR, and DSC analyses. Finally, the results showed that the average size of the ERL particles decreased from 31.6 µm to 200-1100 nm.


Assuntos
Antineoplásicos , Cloridrato de Erlotinib , Nanopartículas , Tamanho da Partícula , Cloridrato de Erlotinib/química , Nanopartículas/química , Antineoplásicos/química , Temperatura , Cromatografia com Fluido Supercrítico/métodos , Composição de Medicamentos/métodos , Pressão
9.
Am J Case Rep ; 25: e943466, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38822519

RESUMO

BACKGROUND Various resistance mechanisms of the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) have been reported, and approximately half of the cases show a T790M point mutation as resistance to EGFR-TKI. In addition, 3-14% of cases of non-small cell lung cancer transform into small cell lung carcinoma (SCLC) during treatment. However, there are few reported cases in which 2 mechanisms of resistance have been observed simultaneously. This report describes a 66-year-old man with initial presentation of stage IIA right-sided lung adenocarcinoma with EGFR gene exon 21 L858R mutation and 3 years of stable disease. During treatment with erlotinib, the patient developed SCLC and adenocarcinoma with EGFR exon 21 L858R and exon 20 T790M mutation. CASE REPORT A 66-year-old man underwent right pneumonectomy plus nodal dissection 2a for right hilar lung cancer and was diagnosed with an EGFR exon21 L858R mutated lung adenocarcinoma. Three years later, pleural dissemination was observed in the right chest wall. Although erlotinib was continued for 52 months, new metastases to the right ribs were detected. Chest wall tumor resection was performed. Based on the World Health Organization classification, the patient was diagnosed with combined SCLC, with EGFR exon21 L858R and exon20 T790M mutation. The patient received 4 cycles of carboplatin plus etoposide, 14 cycles of amrubicin, and 2 cycles of irinotecan. Chemotherapy continued for 25 months. CONCLUSIONS Long-term survival was achieved by chemotherapy after transformation. Since EGFR mutation-positive lung cancer shows a variety of acquired resistances, it is important to consider the treatment strategy of performing re-biopsy.


Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Receptores ErbB , Cloridrato de Erlotinib , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Idoso , Humanos , Masculino , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/patologia , /uso terapêutico
10.
Artigo em Inglês | MEDLINE | ID: mdl-38851151

RESUMO

In this study, a magnetic three-dimensional nano-composite based on Rubber-Fe3O4@Ni-Co Layered double hydroxide derived from ZIF-67 template was synthesized by a hydrothermal method. The proposed nano-composite was used as a sorbent for the enrichment of trace amounts of anti-cancer drugs (dasatinib and erlotinib hydrochloride) from plasma samples followed by determination using high-performance liquid chromatographic analysis (HPLC-UV). The synthesized nano-sorbent was characterized by X-ray diffraction, field emission scanning electron microscopy, Fourier transform infrared spectroscopy, vibrating-sample magnetometer, Brunauer-Emmett-Teller surface analysis, Barrett-Joyner-Halenda pore size analysis and energy dispersive X-ray spectroscopy. Under optimal experimental conditions, factors affecting on extraction efficiency such as pH, ionic strength, extraction temperature and time, desorption solvent and time, the limit of detection (LODs) and the limit of quantification (LOQs) were obtained as 0.6, 2 µg/L for both of dasatinib and erlotinib, respectively. Also, linear range of the method were 2-500 and 2-1000 µg/L for dasatinib and erlotinib, respectively. Relative standard deviations (RSD%) for the repeatability of extraction on sorbent to sorbent were obtained as 3.59, 1.97 %, and one sorbent reusability were investigated and relative standard deviation values were obtained 5.35, 3.30 % for dasatinib and erlotinib, respectively.


Assuntos
Antineoplásicos , Cloridrato de Erlotinib , Limite de Detecção , Borracha , Borracha/química , Antineoplásicos/sangue , Antineoplásicos/química , Cromatografia Líquida de Alta Pressão/métodos , Reprodutibilidade dos Testes , Humanos , Cloridrato de Erlotinib/sangue , Cloridrato de Erlotinib/química , Modelos Lineares , Dasatinibe/sangue , Dasatinibe/química , Hidróxidos/química , Imidazóis/química , Imidazóis/sangue , Adsorção , Extração em Fase Sólida/métodos , Cobalto/química , Cobalto/sangue , Nanoestruturas/química , Zeolitas
11.
Theranostics ; 14(7): 2816-2834, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38773974

RESUMO

Purpose: Small molecule drugs such as tyrosine kinase inhibitors (TKIs) targeting tumoral molecular dependencies have become standard of care for numerous cancer types. Notably, epidermal growth factor receptor (EGFR) TKIs (e.g., erlotinib, afatinib, osimertinib) are the current first-line treatment for non-small cell lung cancer (NSCLC) due to their improved therapeutic outcomes for EGFR mutated and overexpressing disease over traditional platinum-based chemotherapy. However, many NSCLC tumors develop resistance to EGFR TKI therapy causing disease progression. Currently, the relationship between in situ drug target availability (DTA), local protein expression and therapeutic response cannot be accurately assessed using existing analytical tools despite being crucial to understanding the mechanism of therapeutic efficacy. Procedure: We have previously reported development of our fluorescence imaging platform termed TRIPODD (Therapeutic Response Imaging through Proteomic and Optical Drug Distribution) that is capable of simultaneous quantification of single-cell DTA and protein expression with preserved spatial context within a tumor. TRIPODD combines two complementary fluorescence imaging techniques: intracellular paired agent imaging (iPAI) to measure DTA and cyclic immunofluorescence (cyCIF), which utilizes oligonucleotide conjugated antibodies (Ab-oligos) for spatial proteomic expression profiling on tissue samples. Herein, TRIPODD was modified and optimized to provide a downstream analysis of therapeutic response through single-cell DTA and proteomic response imaging. Results: We successfully performed sequential imaging of iPAI and cyCIF resulting in high dimensional imaging and biomarker assessment to quantify single-cell DTA and local protein expression on erlotinib treated NSCLC models. Pharmacodynamic and pharmacokinetic studies of the erlotinib iPAI probes revealed that administration of 2.5 mg/kg each of the targeted and untargeted probe 4 h prior to tumor collection enabled calculation of DTA values with high Pearson correlation to EGFR, the erlotinib molecular target, expression in the tumors. Analysis of single-cell biomarker expression revealed that a single erlotinib dose was insufficient to enact a measurable decrease in the EGFR signaling cascade protein expression, where only the DTA metric detected the presence of bound erlotinib. Conclusion: We demonstrated the capability of TRIPODD to evaluate therapeutic response imaging to erlotinib treatment as it relates to signaling inhibition, DTA, proliferation, and apoptosis with preserved spatial context.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB , Neoplasias Pulmonares , Imagem Óptica , Análise de Célula Única , Humanos , Imagem Óptica/métodos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Análise de Célula Única/métodos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Animais , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inibidores , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Cloridrato de Erlotinib/farmacologia , Cloridrato de Erlotinib/uso terapêutico , Feminino
12.
Proc Natl Acad Sci U S A ; 121(23): e2317790121, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38814866

RESUMO

The transformation of lung adenocarcinoma to small cell lung cancer (SCLC) is a recognized resistance mechanism and a hindrance to therapies using epidermal growth factor receptor tyrosine kinase inhibitors (TKIs). The paucity of pretranslational/posttranslational clinical samples limits the deeper understanding of resistance mechanisms and the exploration of effective therapeutic strategies. Here, we developed preclinical neuroendocrine (NE) transformation models. Next, we identified a transcriptional reprogramming mechanism that drives resistance to erlotinib in NE transformation cell lines and cell-derived xenograft mice. We observed the enhanced expression of genes involved in the EHMT2 and WNT/ß-catenin pathways. In addition, we demonstrated that EHMT2 increases methylation of the SFRP1 promoter region to reduce SFRP1 expression, followed by activation of the WNT/ß-catenin pathway and TKI-mediated NE transformation. Notably, the similar expression alterations of EHMT2 and SFRP1 were observed in transformed SCLC samples obtained from clinical patients. Importantly, suppression of EHMT2 with selective inhibitors restored the sensitivity of NE transformation cell lines to erlotinib and delayed resistance in cell-derived xenograft mice. We identify a transcriptional reprogramming process in NE transformation and provide a potential therapeutic target for overcoming resistance to erlotinib.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Transformação Celular Neoplásica , Cloridrato de Erlotinib , Neoplasias Pulmonares , Humanos , Animais , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Camundongos , Cloridrato de Erlotinib/farmacologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica , Resistencia a Medicamentos Antineoplásicos/genética , Via de Sinalização Wnt/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/patologia , Transcrição Gênica , Antígenos de Histocompatibilidade , Histona-Lisina N-Metiltransferase
13.
J Pathol Clin Res ; 10(3): e12377, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38750616

RESUMO

Even after decades of research, pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease and responses to conventional treatments remain mostly poor. Subclassification of PDAC into distinct biological subtypes has been proposed by various groups to further improve patient outcome and reduce unnecessary side effects. Recently, an immunohistochemistry (IHC)-based subtyping method using cytokeratin-81 (KRT81) and hepatocyte nuclear factor 1A (HNF1A) could recapitulate some of the previously established molecular subtyping methods, while providing significant prognostic and, to a limited degree, also predictive information. We refined the KRT81/HNF1A subtyping method to classify PDAC into three distinct biological subtypes. The prognostic value of the IHC-based method was investigated in two primary resected cohorts, which include 269 and 286 patients, respectively. In the second cohort, we also assessed the predictive effect for response to erlotinib + gemcitabine. In both PDAC cohorts, the new HNF1A-positive subtype was associated with the best survival, the KRT81-positive subtype with the worst, and the double-negative with an intermediate survival (p < 0.001 and p < 0.001, respectively) in univariate and multivariate analyses. In the second cohort (CONKO-005), the IHC-based subtype was additionally found to have a potential predictive value for the erlotinib-based treatment effect. The revised IHC-based subtyping using KRT81 and HNF1A has prognostic significance for PDAC patients and may be of value in predicting treatment response to specific therapeutic agents.


Assuntos
Biomarcadores Tumorais , Carcinoma Ductal Pancreático , Gencitabina , Fator 1-alfa Nuclear de Hepatócito , Imuno-Histoquímica , Neoplasias Pancreáticas , Valor Preditivo dos Testes , Humanos , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/metabolismo , Feminino , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/metabolismo , Biomarcadores Tumorais/análise , Masculino , Pessoa de Meia-Idade , Idoso , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Prognóstico , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Cloridrato de Erlotinib/uso terapêutico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Idoso de 80 Anos ou mais , Queratinas Específicas do Cabelo/metabolismo , Queratinas Específicas do Cabelo/análise , Estimativa de Kaplan-Meier
14.
Sci Rep ; 14(1): 12218, 2024 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-38806555

RESUMO

Although the use of the tyrosine kinase inhibitors (TKIs) has been proved that it can save live in a cancer treatment, the currently used drugs bring in many undesirable side-effects. Therefore, the search for new drugs and an evaluation of their efficiency are intensively carried out. Recently, a series of eighteen imidazole[1,5-a]pyridine derivatives were synthetized by us, and preliminary analyses pointed out their potential to be an important platform for pharmaceutical development owing to their promising actions as anticancer agents and enzyme (kinase, HIV-protease,…) inhibitors. In the present theoretical study, we further analyzed their efficiency in using a realistic scenario of computational drug design. Our protocol has been developed to not only observe the atomistic interaction between the EGFR protein and our 18 novel compounds using both umbrella sampling and steered molecular dynamics simulations, but also determine their absolute binding free energies. Calculated properties of the 18 novel compounds were in detail compared with those of two known drugs, erlotinib and osimertinib, currently used in cancer treatment. Inspiringly the simulation results promote three imidazole[1,5-a]pyridine derivatives as promising inhibitors into a further step of clinical trials.


Assuntos
Receptores ErbB , Imidazóis , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases , Piridinas , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/química , Receptores ErbB/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Piridinas/química , Piridinas/farmacologia , Humanos , Antineoplásicos/química , Antineoplásicos/farmacologia , Cloridrato de Erlotinib/química , Cloridrato de Erlotinib/farmacologia , Desenho de Fármacos , Simulação de Acoplamento Molecular , Ligação Proteica
15.
Biomed Pharmacother ; 175: 116580, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38723513

RESUMO

Colitis-associated cancer (CAC) in inflammatory bowel diseases exhibits more aggressive behavior than sporadic colorectal cancer; however, the molecular mechanisms remain unclear. No definitive preventative agent against CAC is currently established in the clinical setting. We investigated the molecular mechanisms of CAC in the azoxymethane/dextran sulfate sodium (AOM/DSS) mouse model and assessed the antitumor efficacy of erlotinib, a small molecule inhibitor of the epidermal growth factor receptor (EGFR). Erlotinib premixed with AIN-93 G diet at 70 or 140 parts per million (ppm) inhibited tumor multiplicity significantly by 96%, with ∼60% of the treated mice exhibiting zero polyps at 12 weeks. Bulk RNA-sequencing revealed more than a thousand significant gene alterations in the colons of AOM/DSS-treated mice, with KEGG enrichment analysis highlighting 46 signaling pathways in CAC development. Erlotinib altered several signaling pathways and rescued 40 key genes dysregulated in CAC, including those involved in the Hippo and Wnt signaling. These findings suggest that the clinically-used antitumor agent erlotinib might be repurposed for suppression of CAC, and that further studies are warranted on the crosstalk between dysregulated Wnt and EGFR signaling in the corresponding patient population.


Assuntos
Azoximetano , Neoplasias Associadas a Colite , Sulfato de Dextrana , Modelos Animais de Doenças , Cloridrato de Erlotinib , Animais , Cloridrato de Erlotinib/farmacologia , Neoplasias Associadas a Colite/patologia , Neoplasias Associadas a Colite/tratamento farmacológico , Camundongos , Azoximetano/toxicidade , Receptores ErbB/metabolismo , Receptores ErbB/genética , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Camundongos Endogâmicos C57BL , Masculino , Transdução de Sinais/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Colite/tratamento farmacológico , Colite/induzido quimicamente , Colite/complicações , Colite/patologia
16.
Molecules ; 29(7)2024 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-38611728

RESUMO

The epidermal growth factor receptor (EGFR) plays a pivotal role in cancer therapeutics, with small-molecule EGFR inhibitors emerging as significant agents in combating this disease. This review explores the synthesis and clinical utilization of EGFR inhibitors, starting with the indispensable role of EGFR in oncogenesis and emphasizing the intricate molecular aspects of the EGFR-signaling pathway. It subsequently provides information on the structural characteristics of representative small-molecule EGFR inhibitors in the clinic. The synthetic methods and associated challenges pertaining to these compounds are thoroughly examined, along with innovative strategies to overcome these obstacles. Furthermore, the review discusses the clinical applications of FDA-approved EGFR inhibitors such as erlotinib, gefitinib, afatinib, and osimertinib across various cancer types and their corresponding clinical outcomes. Additionally, it addresses the emergence of resistance mechanisms and potential counterstrategies. Taken together, this review aims to provide valuable insights for researchers, clinicians, and pharmaceutical scientists interested in comprehending the current landscape of small-molecule EGFR inhibitors.


Assuntos
Carcinogênese , Transformação Celular Neoplásica , Humanos , Afatinib , Receptores ErbB , Cloridrato de Erlotinib
17.
Cell Death Dis ; 15(3): 199, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38604999

RESUMO

Epidermal growth factor receptor (EGFR)-targeted drugs (erlotinib, etc.) are used to treat multiple types of tumours. EGFR is highly expressed in most triple-negative breast cancer (TNBC) patients. However, only a small proportion of TNBC patients benefit from EGFR-targeted drugs in clinical trials, and the resistance mechanism is unclear. Here, we found that PDZ domain containing 1 (PDZK1) is downregulated in erlotinib-resistant TNBC cells, suggesting that PDZK1 downregulation is related to erlotinib resistance in TNBC. PDZK1 binds to EGFR. Through this interaction, PDZK1 promotes EGFR degradation by enhancing the binding of EGFR to c-Cbl and inhibits EGFR phosphorylation by hindering EGFR dimerisation. We also found that PDZK1 is specifically downregulated in TNBC tissues and correlated with a poor prognosis in TNBC patients. In vitro and in vivo functional assays showed that PDZK1 suppressed TNBC development. Restoration of EGFR expression or kinase inhibitor treatment reversed the degree of cell malignancy induced by PDZK1 overexpression or knockdown, respectively. PDZK1 overexpression sensitised TNBC cells to erlotinib both in vitro and in vivo. In conclusion, PDZK1 is a significant prognostic factor for TNBC and a potential molecular therapeutic target for reversing erlotinib resistance in TNBC cells.


Assuntos
Antineoplásicos , Receptores ErbB , Proteínas de Membrana , Neoplasias de Mama Triplo Negativas , Humanos , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/farmacologia , Cloridrato de Erlotinib/uso terapêutico , Proteínas de Membrana/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo
18.
J Cell Mol Med ; 28(9): e18263, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38685671

RESUMO

In the quest for effective lung cancer treatments, the potential of 3,6-diaminoacridine-9-carbonitrile (DAC) has emerged as a game changer. While DAC's efficacy against glioblastoma is well documented, its role in combating lung cancer has remained largely untapped. This study focuses on CTX-1, exploring its interaction with the pivotal EGFR-TKD protein, a crucial target in lung cancer therapeutics. A meticulous molecular docking analysis revealed that CTX-1 exhibits a noteworthy binding affinity of -7.9 kcal/mol, challenging Erlotinib, a conventional lung cancer medication, which displayed a binding affinity of -7.3 kcal/mol. For a deeper understanding of CTX-1's molecular mechanics, this study employed rigorous 100-ns molecular dynamics simulations, demonstrating CTX-1's remarkable stability in comparison with erlotinib. The Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) method further corroborated these results, with CTX-1 showing a free binding energy of -105.976 ± 1.916 kJ/mol. The true prowess of CTX-1 was tested against diverse lung cancer cell lines, including A549, Hop-62 and H-1299. CTX-1 not only significantly outperformed erlotinib in anticancer activity but also exhibited a spectrum of therapeutic effects. It effectively diminished cancer cell viability, induced DNA damage, halted cell cycle progression, generated reactive oxygen species (ROS), impaired mitochondrial transmembrane potential, instigated apoptosis and successfully inhibited EGFR-TKD. This study not only underscores the potential of CTX-1 a formidable contender in lung cancer treatment but also marks a paradigm shift in oncological therapeutics, offering new horizons in the fight against this formidable disease.


Assuntos
Receptores ErbB , Neoplasias Pulmonares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Humanos , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Melanoma/patologia , Ligação Proteica , Cloridrato de Erlotinib/farmacologia , Cloridrato de Erlotinib/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos
19.
Cancer Res Commun ; 4(5): 1227-1239, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38639476

RESUMO

The most common oncogenic driver mutations for non-small cell lung cancer (NSCLC) activate EGFR or KRAS. Clinical trials exploring treatments for EGFR- or KRAS-mutated (EGFRmut or KRASmut) cancers have focused on small-molecule inhibitors targeting the driver mutations. Typically, these inhibitors perform more effectively based on combination with either chemotherapies, or other targeted therapies. For EGFRmut NSCLC, a combination of inhibitors of EGFR and Aurora-A kinase (AURKA), an oncogene commonly overexpressed in solid tumors, has shown promising activity in clinical trials. Interestingly, a number of recent studies have indicated that EGFR activity supports overall viability of tumors lacking EGFR mutations, and AURKA expression is abundant in KRASmut cell lines. In this study, we have evaluated dual inhibition of EGFR and AURKA in KRASmut NSCLC models. These data demonstrate synergy between the EGFR inhibitor erlotinib and the AURKA inhibitor alisertib in reducing cell viability and clonogenic capacity in vitro, associated with reduced activity of EGFR pathway effectors, accumulation of enhanced aneuploid cell populations, and elevated cell death. Importantly, the erlotinib-alisertib combination also synergistically reduces xenograft growth in vivo. Analysis of signaling pathways demonstrated that the combination of erlotinib and alisertib was more effective than single-agent treatments at reducing activity of EGFR and pathway effectors following either brief or extended administration of the drugs. In sum, this study indicates value of inhibiting EGFR in KRASmut NSCLC, and suggests the specific value of dual inhibition of AURKA and EGFR in these tumors. SIGNIFICANCE: The introduction of specific KRAS G12C inhibitors to the clinical practice in lung cancer has opened up opportunities that did not exist before. However, G12C alterations are only a subtype of all KRAS mutations observed. Given the high expression of AURKA in KRASmut NSCLC, our study could point to a potential therapeutic option for this subgroup of patients.


Assuntos
Aurora Quinase A , Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB , Cloridrato de Erlotinib , Neoplasias Pulmonares , Mutação , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas p21(ras) , Ensaios Antitumorais Modelo de Xenoenxerto , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Aurora Quinase A/antagonistas & inibidores , Aurora Quinase A/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Animais , Cloridrato de Erlotinib/farmacologia , Cloridrato de Erlotinib/uso terapêutico , Camundongos , Linhagem Celular Tumoral , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Sinergismo Farmacológico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Azepinas/farmacologia , Azepinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
20.
Ocul Surf ; 33: 23-30, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38508390

RESUMO

PURPOSE: To determine the risk and incidence of keratitis following treatment with epidermal growth factor receptor inhibitors (EGFRi) and subtypes of EGFRi-associated keratitis. METHODS: This multi-center cohort study included EGFRi-treated patients and non-users with lung cancer between 2010 and 2023. EGFRi included first-generation agent gefitinib and erlotinib, second-generation agent afatinib, and third-generation agent osimertinib. The primary outcome was new-onset keratitis. Cox proportional hazard models with multivariable adjustment were applied to determine the effect of EGFRi on keratitis over time. Subgroup analyses were conducted, stratified by agents of EGFRi. Sub-outcome analyses were performed to identify the subtypes of EGFRi-associated keratitis. RESULTS: A total of 1549 EGFRi-treated patients and 6146 non-users were included. 38 (2.5%) EGFRi-treated patients developed keratitis. The incidence of keratitis in EGFRi-treated patients was significantly higher than that in controls (incidence rate, IR, per 1000 person-years = 14.7 vs 4.49, p < 0.0001). EGFRi-treated patients presented with an increased risk for keratitis (adjusted hazard ratio, aHR = 3.14, 95% CI = 1.85-5.35, p < 0.001). Erlotinib (aHR = 2.64, 95% CI = 1.35-5.15, p = 0.004), afatinib (aHR = 4.42, 95% CI = 2.17-9.02, p < 0.001), and osimertinib (aHR = 4.67, 95% CI = 1.60-13.64, p = 0.005), but not gefitinib (aHR = 2.30, 95% CI = 0.96-5.55, p = 0.063), significantly contributed to the risk of keratitis. Subtypes of EGFRi-associated keratitis included corneal ulcer (IR = 2.31 vs 0.166, p < 0.0001) and keratoconjunctivitis (IR = 9.27 vs 2.91, p < 0.0001). None of the EGFRi-treated patients developed perforated corneal ulcer, interstitial and deep keratitis, or corneal neovascularization. CONCLUSION: Treatment with EGFRi was associated with an increased risk of keratitis. Ocular toxicity of EGFRi was highest for third-generation agents, followed by second-generation agents, and then first-generation agents.


Assuntos
Receptores ErbB , Ceratite , Neoplasias Pulmonares , Humanos , Masculino , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Pessoa de Meia-Idade , Incidência , Ceratite/epidemiologia , Ceratite/tratamento farmacológico , Idoso , Estudos Retrospectivos , China/epidemiologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Gefitinibe/uso terapêutico , Gefitinibe/efeitos adversos , Acrilamidas/uso terapêutico , Acrilamidas/efeitos adversos , Seguimentos , Fatores de Risco , Cloridrato de Erlotinib/uso terapêutico , Cloridrato de Erlotinib/efeitos adversos , Povo Asiático , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , População do Leste Asiático
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