RESUMO
Tyrosine kinase inhibitors (TKIs) offer targeted therapy for cancers but can cause severe cardiotoxicities. Determining their dosedependent impact on cardiac function is required to optimize therapy and minimize adverse effects. The dosedependent cardiotoxic effects of two TKIs, imatinib and ponatinib, were assessed in vitro using H9c2 cardiomyoblasts and in vivo using zebrafish embryos. In vitro, H9c2 cardiomyocyte viability, apoptosis, size, and surface area were evaluated to assess the impact on cellular health. In vivo, zebrafish embryos were analyzed for heart rate, blood flow velocity, and morphological malformations to determine functional and structural changes. Additionally, reverse transcriptionquantitative PCR (RTqPCR) was employed to measure the gene expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), established markers of cardiac injury. This comprehensive approach, utilizing both in vitro and in vivo models alongside functional and molecular analyses, provides a robust assessment of the potential cardiotoxic effects. TKI exposure decreased viability and surface area in H9c2 cells in a dosedependent manner. Similarly, zebrafish embryos exposed to TKIs exhibited dosedependent heart malformation. Both TKIs upregulated ANP and BNP expression, indicating heart injury. The present study demonstrated dosedependent cardiotoxic effects of imatinib and ponatinib in H9c2 cells and zebrafish models. These findings emphasize the importance of tailoring TKI dosage to minimize cardiac risks while maintaining therapeutic efficacy. Future research should explore the underlying mechanisms and potential mitigation strategies of TKIinduced cardiotoxicities.
Assuntos
Cardiotoxicidade , Mesilato de Imatinib , Imidazóis , Miócitos Cardíacos , Piridazinas , Peixe-Zebra , Animais , Peixe-Zebra/embriologia , Imidazóis/toxicidade , Piridazinas/efeitos adversos , Piridazinas/farmacologia , Piridazinas/toxicidade , Mesilato de Imatinib/toxicidade , Mesilato de Imatinib/efeitos adversos , Mesilato de Imatinib/farmacologia , Cardiotoxicidade/etiologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/toxicidade , Inibidores de Proteínas Quinases/farmacologia , Linhagem Celular , Peptídeo Natriurético Encefálico/metabolismo , Peptídeo Natriurético Encefálico/genética , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Mioblastos Cardíacos/efeitos dos fármacos , Mioblastos Cardíacos/metabolismo , RatosRESUMO
BACKGROUND: In Nigeria, since 2002, Imatinib mesylate (glivec®) has been available freely to chronic myeloid leukaemia (CML) patients but only at a tertiary health care centre in the southwestern part of the country. Despite this, it is not readily accessible to many patients due to the distance and other challenges including low socioeconomic status and political problems, preventing timely access to specialist care. This study evaluated the effect of the baseline characteristics on the prognostic implication and treatment outcome of CML patients in Nigeria. METHOD: This study retrospectively evaluated the baseline characteristics, clinical presentations and treatment outcomes of 889 CML patients over 18 years (2002-2020). Of these, 576 (65%) patients had complete information with up-to-date BCR::ABL1 records. These 576 patients were categorized based on their responses to Imatinib therapy into three groups viz.; Optimal response (OR) defined as BCR::ABL1 ratio of < 0.1% or major molecular remission (≥ 3-log reduction of BCR::ABL1 mRNA or BCR::ABL1 ratio of < 0.1% on the International Scale), Suboptimal response (SR) with BCR::ABL ratio of 0.1-1%, and Treatment failure (TF) when MMR has not been achieved at 12 months. The variables were analyzed using descriptive and inferential statistics and a p-value < 0.05 was considered statistically significant. RESULTS: The result revealed a median age of 37 years at diagnosis with a male-to-female ratio of 1.5:1. The majority (96.8%) of the patients presented with one or more symptoms at diagnosis with a mean symptom duration of 12 ± 10.6 months. The mean Sokal and EUTOS scores were 1.3 ± 0.8 and 73.90 ± 49.09 respectively. About half of the patients presented with high-risk Sokal (49%) and EUTOS (47%) scores. Interestingly, both the Sokal (r = 0.733, p = 0.011) and EUTOS (r = 0.102, p = 0.003) scores correlated positively and significantly with the duration of symptoms at presentation. Based on response categorization, 40.3% had OR while 27.1% and 32.6% had SR and TF respectively. CONCLUSION: This study observed a low optimal response rate of 40.3% and treatment failure rate of 32.6% in our CML cohort while on first-line Imatinib therapy. This treatment response is strongly attributable to the long duration of symptoms of 12 months or more and high Sokal and EUTOS scores at presentation. We advocate prompt and improved access to specialist care with optimization of tyrosine kinase inhibitor therapy in Nigeria.
Assuntos
Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Estudos Retrospectivos , Mesilato de Imatinib/uso terapêutico , Nigéria , Prognóstico , Resultado do Tratamento , Idoso , Adulto Jovem , Antineoplásicos/uso terapêutico , Adolescente , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/antagonistas & inibidores , PobrezaRESUMO
Recent studies have emphasized the critical role of alteration in cellular plasticity in the development of fibrotic disorders, particularly pulmonary fibrosis, prompting further investigation into molecular mechanisms and therapeutic approaches. In this context, Precision Cut Lung Slices (PCLSs) emerge as a valuable ex vivo research tool. The process of PCLSs generation preserves most features of the naïve lung tissue, such as its architecture and complex cellular composition. We previously stimulated normal lung PCLSs with two different stimuli (fibrotic cocktail, composed by platelet lysate and TGFß, or neutrophil extracellular traps) and we observed a significant elevation of Epithelial-Mesenchymal Transition (EMT) markers from 24 h to 72 h of culture. The aim of our work was to exploit this PCLSs based ex vivo model of EMT, to evaluate the effect of imatinib, an old tyrosine kinase inhibitor with reported anti-remodeling activities in vitro and in animal models. Imatinib treatment significantly decreased α-SMA and collagen expression already starting from 24 h on stimulated PCLS. Imatinib showed a significant toxicity on unstimulated cells (3-fold increase in ACTA2 expression levels at 24 h, 1.5-fold increase in COL1A1 expression levels at 24 h, 2-fold increase in COL3A1 expression levels at 72 h). Further evaluations on specific cell lines pointed out that drug effects were mainly directed towards A549 and LFs. In conclusion, our model confirms the anti-remodeling activity of imatinib but suggests that its direct delivery to alveolar epithelial cells as recently attempted by inhalatory preparation of the drug might be associated with a non-negligible epithelial cell toxicity.
Assuntos
Transição Epitelial-Mesenquimal , Mesilato de Imatinib , Pulmão , Mesilato de Imatinib/farmacologia , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Células A549 , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/patologia , Inibidores de Proteínas Quinases/farmacologia , Actinas/metabolismoRESUMO
Therapeutic drug monitoring (TDM) of imatinib (IM) in cancer therapy offers the potential to improve treatment efficacy while minimizing toxicity. There was a significant correlation between unbound concentration and clinical response and toxicity, compared with total plasma concentrations, and the quantification of unbound IM and its metabolite, N-desmethyl imatinib (NDI) are of interest for TDM. However, traditional unbound drug separation methods have shortcomings, especially are susceptible to non-specific binding (NSB) of drugs to the polymer-constructed components of filter membranes, which are difficult to avoid at present. Hence it is necessary to developed a reliable separation method for the analysis of the unbound fraction of IM and NDI in TDM. We developed and validated an hollow fiber solid phase microextraction (HF-SPME) method coupled with high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) that to measure unbound IM and NDI concentration in human plasma. It used the NSB phenomenon and solve the NSB problem. The preparation procedure only involves a common vortex and ultrasonication without dilution of samples and modification of membrane. A total of 50 chronic myeloid leukemia (CML) patients were enrolled in our study. The relationship between the unbound and total concentrations for IM and NDI, as well as the concentration ratios of NDI to IM in 50 clinical plasma samples were investigated. The extraction recovery is high to 95.5-106â¯% with validation parameters for the methodological results were all excellent. There were both a poor linear relationship between the unbound and total concentrations for IM (r2=0.504) and NDI (r2=0.201) in 50 clinical plasma samples. The unbound concentration ratios of NDI to IM varied widely in CML patients. The determination of unbound IM and NDI concentration is meaningful and necessary. The developed HF-SPME method is simple, accurate and precise that could be used to measure unbound IM and NDI concentration in clinical TDM.
Assuntos
Monitoramento de Medicamentos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva , Microextração em Fase Sólida , Espectrometria de Massas em Tandem , Humanos , Mesilato de Imatinib/sangue , Mesilato de Imatinib/farmacocinética , Microextração em Fase Sólida/métodos , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem/métodos , Monitoramento de Medicamentos/métodos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Reprodutibilidade dos TestesRESUMO
BCR-ABL1-independent resistance to imatinib has no effective treatment due to its complexity and diversity. We previously reported that the CDH13 oncogene was expressed at low levels in BCR-ABL1-independent resistant CML cell lines. However, its effects on CML resistant cells and mechanisms remain unknown. This study investigated the effects of saRNA-based CDH13 activation on BCR-ABL1-independent imatinib resistance in CML and its underlying mechanism, and proposes a unique treatment method to overcome imatinib resistance. Specifically, this study demonstrated that using the DSIR (Designer of Small Interfering RNA) website tool, saRNAs targeting the CDH13 promoter region were generated and validated using qPCR and western blotting. Among the predicted sequences, C2 and C3 efficiently elevated CDH13 mRNA and protein expression, as well as inhibited the relative vitality of cells and the ability to form clones. After promoting CDH13 expression in K562-IMR cells, it inhabited the NF-κB signaling pathway and induced apoptosis in imatinib-resistant CML cells. LNP-saRNA (C3) was also observed to limit the growth of K562-IMR cells in vivo. From the above, the activation of CDH13 expression by saRNA promotes cell apoptosis by inhibiting the NF-κB signaling pathway to overcome to BCR-ABL1-independent resistance to imatinib in patients with CML.
Assuntos
Caderinas , Resistencia a Medicamentos Antineoplásicos , Proteínas de Fusão bcr-abl , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva , Transdução de Sinais , Humanos , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Caderinas/metabolismo , Caderinas/genética , Transdução de Sinais/efeitos dos fármacos , Proteínas de Fusão bcr-abl/metabolismo , Proteínas de Fusão bcr-abl/genética , Células K562 , RNA Interferente Pequeno/metabolismo , Animais , Apoptose/efeitos dos fármacos , Camundongos , NF-kappa B/metabolismo , Camundongos Nus , Linhagem Celular TumoralAssuntos
Antineoplásicos , Tumores do Estroma Gastrointestinal , Mesilato de Imatinib , Humanos , Mesilato de Imatinib/uso terapêutico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/patologia , Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Resultado do Tratamento , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/patologiaRESUMO
BACKGROUND/AIM: Inflammatory bowel disease (IBD) is characterized by dysregulated immune responses and a multifactorial etiology. While imatinib has demonstrated efficacy in the treatment of immune-related diseases, its potential effects in IBD treatment remain underexplored. MATERIALS AND METHODS: This study aimed to investigate the therapeutic effects of imatinib in colitis treatment. A dextran sulfate sodium (DSS)-induced colitis model was used to mimic IBD in mice. Imatinib was administered orally to mice simultaneously with DSS treatment. The effects of imatinib on DSS-induced colitis were evaluated by analyzing colitis-related pathology, including the disease activity index (DAI), histological lesions, inflammatory markers, and tight junction integrity. Additionally, western blot analysis and quantitative real-time polymerase chain reaction were used to assess inflammatory markers, tight-junction proteins, and cell death. RESULTS: In the DSS-induced colitis model, imatinib treatment exerted protective effects by attenuating weight loss, restoring colon length, reducing spleen weight, and improving the DAI score and histological lesions. Additionally, imatinib reduced the level of proinflammatory cytokines, including TNF-α, IL-6, and IL-1ß. Furthermore, imatinib treatment restored tight-junction integrity and decreased the expression of apoptosis marker proteins. CONCLUSION: Overall, imatinib treatment significantly alleviated the symptoms of DSS-induced colitis by influencing the expression of proinflammatory cytokines, tight junction proteins, and apoptotic markers in mice. These findings highlight imatinib as a potential therapeutic candidate for IBD.
Assuntos
Apoptose , Colite , Citocinas , Sulfato de Dextrana , Modelos Animais de Doenças , Mesilato de Imatinib , Animais , Mesilato de Imatinib/farmacologia , Sulfato de Dextrana/efeitos adversos , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/patologia , Colite/metabolismo , Camundongos , Apoptose/efeitos dos fármacos , Citocinas/metabolismo , Inflamação/tratamento farmacológico , Inflamação/patologia , Masculino , Mediadores da Inflamação/metabolismo , BiomarcadoresRESUMO
OBJECTIVE: To investigate the anti- chronic myelogenous leukemia (CML) activity of Nur77-specific agonist Csn-B combined with imatinib by promoting Nur77 expression, and explore the potential role of its signaling pathway. METHODS: Firstly, CCK-8 and Transwell assay were used to detect the inhibitory effects of Csn-B, imatinib, and their combination on the proliferation and migration of K562 cells. Furthermore, the apoptosis rate of K562 cells treated with Csn-B, imatinib, and their combination was detected by flow cytometry. The expression levels of Nur77, Pim-1, Drp1, p-Drp1 S616, Bcl-2 and Bax in K562 cells were detected by Western blot. Finally, the expression levels of reactive oxygen species (ROS) in K562 cells treated with Csn-B, imatinib and their combination were detected by immunofluorescence assay. RESULTS: The level of Nur77 in CML patients decreased significantly compared with normal population in dataset of GSE43754 (P < 0.001). Csn-B combined with imatinib could significantly inhibit the proliferation and migration of K562 cells (both P < 0.001), and induce apoptosis (P < 0.001). Csn-B promoted Nur77 expression in K562 cells, and synergistically enhanced imatinib sensitivity when combined with imatinib. Csn-B combined with imatinib could significantly enhanced ROS levels in K562 cells and mitochondria compared with single-drug treatment (both P < 0.001). CONCLUSION: Csn-B combined with imatinib can enhance ROS expression and induce apoptosis of K562 cells through Nur77/Pim-1/Drp1 pathway.
Assuntos
Apoptose , Proliferação de Células , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares , Proteínas Proto-Oncogênicas c-pim-1 , Humanos , Mesilato de Imatinib/farmacologia , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Apoptose/efeitos dos fármacos , Células K562 , Proliferação de Células/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Dinaminas , Transdução de Sinais , Espécies Reativas de Oxigênio/metabolismo , Movimento CelularRESUMO
Imatinib, a small molecule kinase inhibitor, is used as a cancer growth blocker. However, one of its most serious side effects is congestive cardiac failure. Reducing drug toxicity may be achieved through the use of drug delivery systems. Biocompatible metal-organic framework (MOF) materials, namely FeMIL-100 and FeMIL-101-NH2, were employed as potential imatinib carriers. They efficiently delivered the drug as an anticancer agent while minimizing cardiotoxicity. Notably, the release of imatinib from FeMIL-100 was rapid in acidic conditions and slower in pH-neutral environments, allowing targeted delivery to cancer cells. The carrier's pH-dependent stability governed the drug release mechanism. Two release models-Korsmeyer-Peppas and Weibull-were fitted to the experimental data and discussed in terms of drug release from a rigid microporous matrix. Cytotoxicity tests were conducted on two cell lines: HL60 (a model cell line for acute myeloid leukemia) and H9c2 (a cell line for cardiomyocytes). Overall, the metal-organic framework (MOF) carriers mitigated imatinib's adverse effects without compromising its effectiveness.
Assuntos
Antineoplásicos , Portadores de Fármacos , Mesilato de Imatinib , Estruturas Metalorgânicas , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/química , Humanos , Estruturas Metalorgânicas/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Portadores de Fármacos/química , Cardiotoxicidade/prevenção & controle , Liberação Controlada de Fármacos , Sobrevivência Celular/efeitos dos fármacos , Células HL-60 , Concentração de Íons de Hidrogênio , AnimaisRESUMO
BACKGROUND Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the presence of the Philadelphia (Ph) chromosome, which results from the fusion of the translocation of the ABL1 gene from chromosome 9 to the BCR gene located in chromosome 22, forming the BCR-ABL gene on chromosome number 22, which accounts for approximately 95% of CML cases. Complex translocation involving other chromosomes can occur. CASE REPORT We present a rare case of CML with a variant Ph chromosome, in which chromosome 16 was involved with the usual translocation. A 34-year-old woman presented with a history of left upper quadrant pain and excessive sweating, with no hepatosplenomegaly on examination. She was found to have leukocytosis, with elevated neutrophils (34 000/mm³), basophils (1460/mm³), and eosinophils (2650/mm³). Karyotyping showed a translocation (16;22) (q24,q11.2), and FISH analysis showed BCR-ABL fusion as a result of (9,22) translocation, with a third chromosome (chromosome 16) involved and fused with chromosome 22, with a different breakpoint, which has never been reported in the literature, affecting the long arm of chromosome 16. The patient was treated with a first-generation tyrosine kinase inhibitor (imatinib) and achieved a deep molecular remission. The repeated FISH analysis confirmed the disappearance of both translocations (9,22) and (16,22). CONCLUSIONS The impact of the additional chromosomal aberration in CML is widely heterogeneous, and the outcome is dependent on multiple factors. Larger studies are needed to clarify the outcome in CML with variant Ph chromosomes, as most of the available data come from reported cases.
Assuntos
Cromossomos Humanos Par 16 , Leucemia Mielogênica Crônica BCR-ABL Positiva , Cromossomo Filadélfia , Translocação Genética , Humanos , Feminino , Adulto , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Cromossomos Humanos Par 16/genética , Mesilato de Imatinib/uso terapêutico , Proteínas de Fusão bcr-abl/genéticaRESUMO
Imatinib-induced skin rash poses a significant challenge for patients with gastrointestinal stromal tumor, often resulting in treatment interruption or discontinuation and subsequent treatment failure. However, the underlying mechanism of imatinib-induced skin rashes in gastrointestinal stromal tumor patients remains unclear. A total of 51 patients (27 with rash and 24 without rash) were enrolled in our study. Blood samples were collected concomitantly with the onset of clinical manifestations of rashes, and simultaneously collecting clinical relevant information. The imatinib concentration and untargeted metabolomics were performed by ultra-high-performance liquid chromatography-tandem mass spectrometry. There were no significant differences in age, gender, imatinib concentration and white blood cells count between the rash group and the control group. However, the rash group exhibited a higher eosinophil count (P<0.05) and lower lymphocyte count (P<0.05) compared to the control group. Untargeted metabolomics analysis found that 105 metabolites were significantly differentially abundant. The univariate analysis highlighted erucamide, linoleoylcarnitine, and valine betaine as potential predictive markers (AUC≥0.80). Further enriched pathway analysis revealed primary metabolic pathways, including sphingolipid signaling pathway, sphingolipid metabolism, cysteine and methionine metabolism, biosynthesis of unsaturated fatty acids, arginine and proline metabolism, and biosynthesis of amino acids. These findings suggest that the selected differential metabolites could serve as a foundation for the prediction and management of imatinib-induced skin rash in gastrointestinal stromal tumor patients.
Assuntos
Antineoplásicos , Exantema , Neoplasias Gastrointestinais , Tumores do Estroma Gastrointestinal , Mesilato de Imatinib , Metabolômica , Humanos , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Mesilato de Imatinib/efeitos adversos , Mesilato de Imatinib/uso terapêutico , Feminino , Masculino , Pessoa de Meia-Idade , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Exantema/induzido quimicamente , Neoplasias Gastrointestinais/tratamento farmacológico , Idoso , AdultoRESUMO
Understanding the determinants of long-term liver metastasis (LM) outcomes in gastrointestinal stromal tumor (GIST) patients is crucial. We established the feature selection model of intratumoral microbiome at the surgery, achieving robust predictive accuracies of 0.953 and 0.897 AUCs in discovery (n = 74) and validation (n = 34) cohorts, respectively. Notably, despite the significant reduction in LM occurrence with adjuvant imatinib (AI) treatment, intratumoral microbiome exerted independently stronger effects on post-operative LM. Employing both 16S and full-length rRNA sequencing, we pinpoint intracellular Shewanella algae as a foremost LM risk factor in both AI- and non-AI-treated patients. Experimental validation confirmed S. algae's intratumoral presence in GIST, along with migration/invasion-promoting effects on GIST cells. Furthermore, S. algae promoted LM and impeded AI treatment in metastatic mouse models. Our findings advocate for incorporating intratumoral microbiome evaluation at surgery, and propose S. algae as a therapeutic target for LM suppression in GIST.
Assuntos
Neoplasias Gastrointestinais , Tumores do Estroma Gastrointestinal , Mesilato de Imatinib , Neoplasias Hepáticas , Tumores do Estroma Gastrointestinal/patologia , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/microbiologia , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/microbiologia , Animais , Camundongos , Feminino , Masculino , Neoplasias Gastrointestinais/patologia , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/microbiologia , Quimioterapia Adjuvante/métodos , Pessoa de Meia-Idade , Microbiota/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , IdosoRESUMO
BACKGROUND: The long-term impact of tyrosine kinase inhibitor (TKI) discontinuation on resistance and survival in patients with advanced gastrointestinal stromal tumours (GIST) is unclear. We report the exploratory long-term outcomes of patients with advanced GIST stopping imatinib in the BFR14 trial. METHODS: BFR14, an open-label, randomised, phase 3 trial, was done in 17 comprehensive cancer centres or hospitals across France. Patients with advanced GIST aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-3, no previous treatment with imatinib, and no previous malignancy were eligible. Patients were treated with oral imatinib 400 mg daily. Patients with a complete or partial response, or stable disease, according to Response Evaluation Criteria in Solid Tumours (1.0) at 1 year, 3 years, and 5 years from the start of treatment were randomly assigned (1:1) to treatment discontinuation until progression (interruption group) or treatment continuation until progression (continuation group). Randomisation was done centrally with computer-generated permuted blocks of two and six patients stratified by participating centre and presence or absence of residual disease on CT scan. The primary endpoint was progression-free survival. Secondary endpoints included time to imatinib resistance and overall survival. Analyses were conducted on an intention-to-treat basis in all randomly assigned patients who were not lost to follow-up. This trial is registered with ClinicalTrial.gov, NCT00367861. FINDINGS: Between May 12, 2003, and March 16, 2004, after 1 year of imatinib, 32 patients were randomly assigned to the interruption group and 26 to the continuation group. Between June 13, 2005, and May 30, 2007, after 3 years of imatinib, 25 patients were randomly assigned to the interruption group and 25 to the continuation group. Between Nov 9, 2007, and July 12, 2010, after 5 years of imatinib, 14 patients were randomly assigned to the interruption group and 13 to the continuation group. Median follow-up was 235·2 months (IQR 128·8-236·6) after the 1-year randomisation, 200·9 months (190·2-208·4) after the 3-year randomisation, and 164·5 months (134·4-176·4) after the 5-year randomisation. Median progression-free survival in the interruption group versus the continuation group after 1 year of imatinib was 6·1 months (95% CI 2·5-10·1) versus 27·8 months (19·5-37·9; hazard ratio [HR] 0·36 [95% CI 0·20-0·64], log-rank p=0·0003), after 3 years of imatinib was 7·0 months (3·5-11·7) versus 67·0 months (48·8-85·6; 0·15 [0·07-0·32], log-rank p<0·0001), and after 5 years of imatinib was 12·0 months (9·0-16·6) versus not reached (NR; NR-NR; 0·13 [0·03-0·58], log-rank p=0·0016). The median time to imatinib resistance after 1 year of imatinib was 28·7 months (95% CI 18·1-39·1) versus 90·6 months (25·3-156·1; HR 0·93 [95% CI 0·51-1·71], log-rank p=0·82), after 3 years was 66·2 months (43·0-89·6) versus 127·3 months (15·0-239·7; 0·35 [0·17-0·72, log-rank p=0·0028), and after 5 years was 58·6 months (0·0-167·4) versus NR (NR-NR; 0·24 [0·05-1·12], log-rank p=0·049). Median overall survival after 1 year of imatinib was 56·0 months (95% CI 30·3-82·9) versus 105·0 months (20·6-189·6; HR 0·84 [95% CI 0·46-1·54], log-rank p=0·57), after 3 years was 104·0 months (90·7-118·7) versus 134·0 months (89·7-178·3; 0·40 [0·20-0·82], log-rank p=0·0096), and after 5 years was NR (NR-NR) versus 110·4 months (82·7-154·1; 1·28 [0·41-3·99]; log-rank p=0·67), INTERPRETATION: Imatinib interruption in patients with GIST without progressive disease is not recommended. Imatinib interruption in non-progressing patients with GIST was associated with rapid progression, faster resistance to imatinib, and shorter overall survival in the long-term follow-up when compared with imatinib continuation in patients after 3 years and 5 years of imatinib. FUNDING: Centre Léon Bérard, INCa, CONTICANET, Ligue Contre le Cancer, and Novartis.
Assuntos
Tumores do Estroma Gastrointestinal , Mesilato de Imatinib , Inibidores de Proteínas Quinases , Humanos , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/patologia , Tumores do Estroma Gastrointestinal/mortalidade , Mesilato de Imatinib/administração & dosagem , Mesilato de Imatinib/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Seguimentos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , França , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/patologia , Neoplasias Gastrointestinais/mortalidade , Intervalo Livre de Progressão , Adulto , Fatores de Tempo , Resistencia a Medicamentos Antineoplásicos , Suspensão de Tratamento/estatística & dados numéricos , Esquema de MedicaçãoRESUMO
Chronic myelogenous leukemia (CML) is a hematological malignancy originating from the pluripotent hematopoietic stem cells. Imatinib is the first generation of small molecule tyrosine kinase inhibitors (TKI) that revolutionized the treatment of CML. Flumatinib, as a novel oral TKI that independently developed in China, which can be used as a preferred treatment for CML. Basic researches suggested that the inhibitory effect of flumatinib on CML cell lines is stronger than imatinib. Flumatinib demonstrated that it has better efficacy than imatinib on CML in clinical trials and in real world studies. Flumatinib also showed a higher potency against CML with specific mutations, Ph(+) acute lymphoblastic leukemia and some solid tumors. The adverse events are manageable and tolerable.
Assuntos
Aminopiridinas , Benzamidas , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Benzamidas/farmacologia , Aminopiridinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piperazinas/farmacologia , Mesilato de Imatinib/farmacologia , Pirimidinas/farmacologia , Antineoplásicos/farmacologiaRESUMO
Understanding drug residence times in target proteins is key to improving drug efficacy and understanding target recognition in biochemistry. While drug residence time is just as important as binding affinity, atomic-level understanding of drug residence times through molecular dynamics (MD) simulations has been difficult primarily due to the extremely long time scales. Recent advances in rare event sampling have allowed us to reach these time scales, yet predicting protein-ligand residence times remains a significant challenge. Here we present a semi-automated protocol to calculate the ligand residence times across 12 orders of magnitude of time scales. In our proposed framework, we integrate a deep learning-based method, the state predictive information bottleneck (SPIB), to learn an approximate reaction coordinate (RC) and use it to guide the enhanced sampling method metadynamics. We demonstrate the performance of our algorithm by applying it to six different protein-ligand complexes with available benchmark residence times, including the dissociation of the widely studied anticancer drug Imatinib (Gleevec) from both wild-type Abl kinase and drug-resistant mutants. We show how our protocol can recover quantitatively accurate residence times, potentially opening avenues for deeper insights into drug development possibilities and ligand recognition mechanisms.
Assuntos
Simulação de Dinâmica Molecular , Proteínas , Ligantes , Proteínas/química , Proteínas/metabolismo , Mesilato de Imatinib/química , Algoritmos , Ligação ProteicaRESUMO
INTRODUCTION: We conducted an open-label, single-arm, multi-center phase II trial to evaluate the efficacy and safety of imatinib chemotherapy-refractory or metastatic solid tumor patients with c-KIT mutations and/or amplification. METHODS: c-KIT mutations and amplification were detected using NGS. Imatinib (400 mg daily) was administered continuously in 28-day cycles until disease progression, unacceptable adverse events, or death by any cause. The primary endpoint was the objective response rate (ORR). RESULT: In total, 18 patients were enrolled on this trial. The most common tumor type was melanoma (n = 15, 83.3%), followed by ovarian cancer, breast cancer, and metastasis of unknown origin (MUO) (each n = 1, 5.5%). The total number of evaluable patients was 17, of which one patient had a complete response, six patients had partial response, and two patients had stable disease. The overall response rate (ORR) of 41.2% (95% CI 17.80-64.60) and a disease control rate of 52.9% (95% CI 29.17-76.63). The median progression-free survival was 2.2 months (95% CI 1.29-3.20), and median overall survival was 9.1 months (95% CI 2.10-16.11). The most common adverse events were edema (31.3%), anorexia (25.0%), nausea (18.8%), and skin rash (18.8%). CONCLUSION: Imatinib demonstrated modest anti-tumor activity and a manageable safety profile in chemotherapy-refractory solid tumors with c-KIT mutation, especially in melanoma patients.
Assuntos
Mesilato de Imatinib , Mutação , Neoplasias , Proteínas Proto-Oncogênicas c-kit , Humanos , Proteínas Proto-Oncogênicas c-kit/genética , Mesilato de Imatinib/uso terapêutico , Mesilato de Imatinib/administração & dosagem , Feminino , Pessoa de Meia-Idade , Masculino , Adulto , Idoso , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Neoplasias/mortalidade , Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , República da Coreia , Metástase Neoplásica , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Resultado do TratamentoRESUMO
In the treatment of chronic myeloid leukemia (CML), resistance to BCR-ABL inhibitors makes it difficult to continue treatment and is directly related to life expectancy. Therefore, asciminib was introduced to the market as a useful drug for overcoming drug resistance. While combining molecular targeted drugs is useful to avoid drug resistance, the new BCR-ABL inhibitor asciminib and conventional BCR-ABL inhibitors should be used as monotherapy in principle. Therefore, we investigated the synergistic effect and mechanism of the combination of asciminib and imatinib. We generated imatinib-resistant cells using the human CML cell line K562, examined the effects of imatinib and asciminib exposure on cell survival using the WST-8 assay, and comprehensively analyzed genetic variation related to drug resistance using RNA-seq and real-time PCR. A synergistic effect was observed when imatinib and asciminib were combined with or without imatinib resistance. Three genes, GRRP1, ESPN, and NOXA1, were extracted as the sites of action of asciminib. Asciminib in combination with BCR-ABL inhibitors may improve the therapeutic efficacy of conventional BCR-ABL inhibitors and prevent the development of resistance. Its dosage may be effective even at minimal doses that do not cause side effects. Further verification of this mechanism of action is needed. Additionally, cross-resistance between BCR-ABL inhibitors and asciminib may occur, which needs to be clarified through further validation as soon as possible.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Proteínas de Fusão bcr-abl , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva , Mesilato de Imatinib/farmacologia , Humanos , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Inibidores de Proteínas Quinases/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antineoplásicos/farmacologia , Niacinamida/análogos & derivados , PirazóisRESUMO
OBJECTIVES: We studied the short- and long-term effects of imatinib in hospitalized COVID-19 patients. METHODS: Participants were randomized to receive standard of care (SoC) or SoC with imatinib. Imatinib dosage was 400 mg daily until discharge (max 14 days). Primary outcomes were mortality at 30 days and 1 year. Secondary outcomes included recovery, quality of life and long COVID symptoms at 1 year. We also performed a systematic review and meta-analysis of randomized trials studying imatinib for 30-day mortality in hospitalized COVID-19 patients. RESULTS: We randomized 156 patients (73 in SoC and 83 in imatinib). Among patients on imatinib, 7.2% had died at 30 days and 13.3% at 1 year, and in SoC, 4.1% and 8.2% (adjusted HR 1.35, 95% CI 0.47-3.90). At 1 year, self-reported recovery occurred in 79.0% in imatinib and in 88.5% in SoC (RR 0.91, 0.78-1.06). We found no convincing difference in quality of life or symptoms. Fatigue (24%) and sleep issues (20%) frequently bothered patients at one year. In the meta-analysis, imatinib was associated with a mortality risk ratio of 0.73 (0.32-1.63; low certainty evidence). CONCLUSIONS: The evidence raises doubts regarding benefit of imatinib in reducing mortality, improving recovery and preventing long COVID symptoms in hospitalized COVID-19 patients.
Assuntos
Tratamento Farmacológico da COVID-19 , COVID-19 , Hospitalização , Mesilato de Imatinib , Qualidade de Vida , SARS-CoV-2 , Humanos , Mesilato de Imatinib/uso terapêutico , Feminino , Masculino , Pessoa de Meia-Idade , COVID-19/mortalidade , Hospitalização/estatística & dados numéricos , Idoso , Resultado do Tratamento , AdultoRESUMO
BACKGROUND: Imatinib (IM) is the primary treatment for patients with chronic-phase CML (CML-CP). However, an increasing number of CML-CP patients have developed resistance to IM. Our study aims to explore the expression of miR-629-5p in extracellular vesicles (EVs) from both IM-sensitive (K562) and resistant (K562-Re) CML cell lines and to investigate the impact of regulating miR-629-5p expression on the biological characteristics of K562 and K562-Re cells. METHODS: Assess miR-629-5p expression levels in IM-sensitive and resistant CML cell lines. Separate EVs and verify it. EVs from K562-Re cells were co-cultured with K562 cells to detect the expression level of miR-629-5p. Target genes of miR-629-5p were determined and validated through luciferase experiments. Examined by manipulating miR-629-5p expression in cells using transfection techniques. The expression level of phosphorylated proteins in the PI3K/AKT/mTOR signaling pathway after IM was detected in CML cell lines. In K562-Re cells, the expression level of phosphorylated protein in the PI3K/AKT/mTOR signaling pathway was detected after single transfection of miR-629-5p inhibitor and cotransfection of miR-629-5p inhibitor and siSENP2. RESULTS: Increasing concentrations of EVs from K562-Re cells elevated miR-629-5p expression levels. The expression levels of miR-629-5p in CML cells varied with IM concentration and influenced the biological characteristics of cells. SENP2 was identified as a target gene of miR-629-5p. Furthermore, miR-629-5p was found to modulate the SENP2/PI3K/AKT/mTOR pathway, impacting IM resistance in CML cells. CONCLUSION: EVs from IM-resistant CML cells alter the expression of miR-629-5p in sensitive cells, activating the SENP2/PI3K/AKT/mTOR pathway and leading to IM resistance.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Vesículas Extracelulares , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva , MicroRNAs , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Serina-Treonina Quinases TOR , Humanos , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/genética , Mesilato de Imatinib/farmacologia , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismoRESUMO
BACKGROUND: Current guidelines recommend use of adjuvant imatinib therapy for many patients with gastrointestinal stromal tumours (GISTs); however, its optimal treatment duration is unknown and some patient groups do not benefit from the therapy. We aimed to apply state-of-the-art, interpretable artificial intelligence (ie, predictions or prescription logic that can be easily understood) methods on real-world data to establish which groups of patients with GISTs should receive adjuvant imatinib, its optimal treatment duration, and the benefits conferred by this therapy. METHODS: In this observational cohort study, we considered for inclusion all patients who underwent resection of primary, non-metastatic GISTs at the Memorial Sloan Kettering Cancer Center (MSKCC; New York, NY, USA) between Oct 1, 1982, and Dec 31, 2017, and who were classified as intermediate or high risk according to the Armed Forces Institute of Pathology Miettinen criteria and had complete follow-up data with no missing entries. A counterfactual random forest model, which used predictors of recurrence (mitotic count, tumour size, and tumour site) and imatinib duration to infer the probability of recurrence at 7 years for a given patient under each duration of imatinib treatment, was trained in the MSKCC cohort. Optimal policy trees (OPTs), a state-of-the-art interpretable AI-based method, were used to read the counterfactual random forest model by training a decision tree with the counterfactual predictions. The OPT recommendations were externally validated in two cohorts of patients from Poland (the Polish Clinical GIST Registry), who underwent GIST resection between Dec 1, 1981, and Dec 31, 2011, and from Spain (the Spanish Group for Research in Sarcomas), who underwent resection between Oct 1, 1987, and Jan 30, 2011. FINDINGS: Among 1007 patients who underwent GIST surgery in MSKCC, 117 were included in the internal cohort; for the external cohorts, the Polish cohort comprised 363 patients and the Spanish cohort comprised 239 patients. The OPT did not recommend imatinib for patients with GISTs of gastric origin measuring less than 15·9 cm with a mitotic count of less than 11·5 mitoses per 5 mm2 or for those with small GISTs (<5·4 cm) of any site with a count of less than 11·5 mitoses per 5 mm2. In this cohort, the OPT cutoffs had a sensitivity of 92·7% (95% CI 82·4-98·0) and a specificity of 33·9% (22·3-47·0). The application of these cutoffs in the two external cohorts would have spared 38 (29%) of 131 patients in the Spanish cohort and 44 (35%) of 126 patients in the Polish cohort from unnecessary treatment with imatinib. Meanwhile, the risk of undertreating patients in these cohorts was minimal (sensitivity 95·4% [95% CI 89·5-98·5] in the Spanish cohort and 92·4% [88·3-95·4] in the Polish cohort). The OPT tested 33 different durations of imatinib treatment (<5 years) and found that 5 years of treatment conferred the most benefit. INTERPRETATION: If the identified patient subgroups were applied in clinical practice, as many as a third of the current cohort of candidates who do not benefit from adjuvant imatinib would be encouraged to not receive imatinib, subsequently avoiding unnecessary toxicity on patients and financial strain on health-care systems. Our finding that 5 years is the optimal duration of imatinib treatment could be the best source of evidence to inform clinical practice until 2028, when a randomised controlled trial with the same aims is expected to report its findings. FUNDING: National Cancer Institute.