RESUMO
Tyrosine kinase inhibitors (TKIs) have drastically improved the outcomes of pCML (paediatric CML) but data on long-term off-target toxicities of TKIs in children are scarce. In this single-centre, retrospective cum prospective study of pCML in chronic phase, we report our experience of treating 173 children with imatinib and following them for long-term toxicities. Mean (SD) time to attain CHR, CCyR and MMR were 3.05 (2.1), 10.6 (8.4) and 43.4 (31.8) months respectively. DMR was not attained in 59 (34%) patients at last follow-up. Ten patients were switched to second-generation TKIs (2G-TKIs; nilotinib = 1/dasatinib = 9) due to poor/loss in response, of which seven had kinase domain mutations. Three patients progressed to the blastic phase. At a median follow-up of 84 (3-261) months, the 5-year EFS and OS for the entire cohort were 96.9% (95% CI: 93.4-100) and 98.7% (95% CI: 96.9-100) respectively. Screening for long-term toxicities revealed low bone density and hypovitaminosis D in 70% and 80% respectively. Other late effects included short stature (27%), delayed puberty (15%), poor sperm quality (43%) and miscellaneous endocrinopathies (8%). Children younger than 5 years at diagnosis were more susceptible to growth and endocrine toxicities (p = 0.009). Regular monitoring for long-term toxicities, timely intervention and trial of discontinuation whenever feasible are likely to improve the long-term outlook of pCML.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Criança , Humanos , Masculino , Dasatinibe , Seguimentos , Hospitais , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Estudos Prospectivos , Inibidores de Proteínas Quinases/efeitos adversos , Estudos Retrospectivos , Sêmen , Resultado do Tratamento , Pré-EscolarRESUMO
BACKGROUND: The patient selection for optimal adjuvant therapy in gastrointestinal stromal tumors (GISTs) is provided by nomogram based on tumor size, mitotic index, tumor location, and tumor rupture. Although mutational status is not currently used to risk assessment, tumor genotype showed a prognostic influence on natural history and tumor relapse. Innovative measures, such as KIT/PDGFRA-mutant-specific variant allele frequency (VAF) levels detection from next-generation sequencing (NGS), may act as a surrogate of tumor burden and correlate with prognosis and overall survival of patients with GIST, helping the choice for adjuvant treatment. PATIENTS AND METHODS: This was a multicenter, hospital-based, retrospective/prospective cohort study to investigate the prognostic role of KIT or PDGFRA-VAF of GIST in patients with radically resected localized disease. In the current manuscript, we present the results from the retrospective phase of the study. RESULTS: Two-hundred (200) patients with GIST between 2015 and 2022 afferent to 6 Italian Oncologic Centers in the EURACAN Network were included in the study. The receiver operating characteristic (ROC) curves analysis was used to classify "low" vs. "high" VAF values, further normalized on neoplastic cellularity (nVAF). When RFS between the low and high nVAF groups were compared, patients with GIST with KIT/PDGFRA nVAF > 50% showed less favorable RFS than patients in the group of nVAF ≤ 50% (2-year RFS, 72.6% vs. 93%, respectively; P = .003). The multivariable Cox regression model confirmed these results. In the homogeneous sub-population of intermediate-risk, patients with KIT-mutated GIST, the presence of nVAF >50% was statistically associated with higher disease recurrence. CONCLUSION: In our study, we demonstrated that higher nVAF levels were independent predictors of GIST prognosis and survival in localized GIST patients with tumors harboring KIT or PDGFRA mutations. In the cohort of intermediate-risk patients, nVAF could be helpful to improve prognostication and the use of adjuvant imatinib.
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Antineoplásicos , Tumores do Estroma Gastrointestinal , Humanos , Antineoplásicos/uso terapêutico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Prognóstico , Estudos Retrospectivos , Estudos Prospectivos , Proteínas Proto-Oncogênicas c-kit/genética , Recidiva Local de Neoplasia , Receptores Proteína Tirosina Quinases/genética , Mutação , Frequência do GeneRESUMO
Gastrointestinal stromal tumors (GISTs) are predominately induced by KIT mutants. In this study, we found that four and a half LIM domains 2 (FHL2) was highly expressed in GISTs and KIT signaling dramatically increased FHL2 transcription while FHL2 inhibited KIT transcription. In addition, our results showed that FHL2 associated with KIT and increased the ubiquitination of both wild-type KIT and primary KIT mutants in GISTs, leading to decreased expression and activation of KIT although primary KIT mutants were less inhibited by FHL2 than wild-type KIT. In the animal experiments, loss of FHL2 expression in mice carrying germline KIT/V558A mutation which can develop GISTs resulted in increased tumor growth, but increased sensitivity of GISTs to imatinib treatment which is used as the first-line targeted therapy of GISTs, suggesting that FHL2 plays a role in the response of GISTs to KIT inhibitor. Unlike wild-type KIT and primary KIT mutants, we further found that FHL2 didn't alter the expression and activation of drug-resistant secondary KIT mutants. Taken together, our results indicated that FHL2 acts as the negative feedback of KIT signaling in GISTs while primary KIT mutants are less sensitive and secondary KIT mutants are resistant to the inhibition of FHL2.
Assuntos
Tumores do Estroma Gastrointestinal , Proteínas com Homeodomínio LIM , Proteínas Musculares , Proteínas Proto-Oncogênicas c-kit , Transdução de Sinais , Fatores de Transcrição , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Tumores do Estroma Gastrointestinal/metabolismo , Animais , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Proteínas com Homeodomínio LIM/genética , Proteínas com Homeodomínio LIM/metabolismo , Humanos , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Camundongos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Mutação , Carcinogênese/genética , Regulação Neoplásica da Expressão Gênica , Mesilato de Imatinib/farmacologia , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Neoplasias Gastrointestinais/metabolismo , Linhagem Celular Tumoral , UbiquitinaçãoRESUMO
BACKGROUND: Excessive pericyte coverage promotes tumor growth, and a downregulation may solve this dilemma. Due to the double-edged sword role of vascular pericytes in tumor microenvironment (TME), indiscriminately decreasing pericyte coverage by imatinib causes poor treatment outcomes. Here, we optimized the use of imatinib in a colorectal cancer (CRC) model in high pericyte-coverage status, and revealed the value of multiparametric magnetic resonance imaging (mpMRI) at 9.4T in monitoring treatment-related changes in pericyte coverage and the TME. METHODS: CRC xenograft models were evaluated by histological vascular characterizations and mpMRI. Mice with the highest pericyte coverage were treated with imatinib or saline; then, vascular characterizations, tumor apoptosis and HIF-1α level were analyzed histologically, and alterations in the expression of Bcl-2/bax pathway were assessed through qPCR. The effects of imatinib were monitored by dynamic contrast-enhanced (DCE)-, diffusion-weighted imaging (DWI)- and amide proton transfer chemical exchange saturation transfer (APT CEST)-MRI at 9.4T. RESULTS: The DCE- parameters provided a good histologic match the tumor vascular characterizations. In the high pericyte coverage status, imatinib exhibited significant tumor growth inhibition, necrosis increase and pericyte coverage downregulation, and these changes were accompanied by increased vessel permeability, decreased microvessel density (MVD), increased tumor apoptosis and altered gene expression of apoptosis-related Bcl-2/bax pathway. Strategically, a 4-day imatinib effectively decreased pericyte coverage and HIF-1α level, and continuous treatment led to a less marked decrease in pericyte coverage and re-elevated HIF-1α level. Correlation analysis confirmed the feasibility of using mpMRI parameters to monitor imatinib treatment, with DCE-derived Ve and Ktrans being most correlated with pericyte coverage, Ve with vessel permeability, AUC with microvessel density (MVD), DWI-derived ADC with tumor apoptosis, and APT CEST-derived MTRasym at 1 µT with HIF-1α. CONCLUSIONS: These results provided an optimized imatinib regimen to achieve decreasing pericyte coverage and HIF-1α level in the high pericyte-coverage CRC model, and offered an ultrahigh-field multiparametric MRI approach for monitoring pericyte coverage and dynamics response of the TME to treatment.
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Apoptose , Neoplasias Colorretais , Subunidade alfa do Fator 1 Induzível por Hipóxia , Mesilato de Imatinib , Imageamento por Ressonância Magnética Multiparamétrica , Pericitos , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Animais , Pericitos/metabolismo , Pericitos/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/diagnóstico por imagem , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Humanos , Camundongos Nus , Microambiente Tumoral/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
AIM: Patients with advanced gastrointestinal stromal tumors (GISTs) exhibiting an imatinib plasma trough concentration (IM Cmin) under 1100 ng/ml may show a reduced drug response rate, leading to the suggestion of monitoring for IM Cmin. Consequently, the objective of this research was to create a customized IM Cmin classification model for patients with advanced GISTs from China. METHODS: Initial data and laboratory indicators from patients with advanced GISTs were gathered, and the above information was segmented into a training set, validation set, and testing set in a 6:2:2 ratio. Key variables associated with IM Cmin were identified to construct the classification model using the least absolute shrinkage and selection operator (LASSO) regression and forward stepwise binary logistic regression. Within the training and validation sets, nine ML classification models were constructed via the resampling method and underwent comparison through the Brier scores, the areas under the receiver-operating characteristic curve (AUROC), the decision curve, and the precision-recall (AUPR) curve to determine the most suitable model for this dataset. Two methods of internal validation were used to assess the most suitable model's classification performance: tenfold cross-validation and random split-sample validation (test set), and the value of the test set AUROC was used to evaluate the model's classification performance. RESULTS: Six key variables (gender, daily IM dose, metastatic site, red blood cell count, platelet count, and percentage of neutrophils) were ultimately selected to construct the classification model. In the validation set, it is found by comparison that the Extreme Gradient Boosting (XGBoost) model has the largest AUROC, the lowest Brier score, the largest area under the decision curve, and the largest AUPR value. Furthermore, as evaluated via internal verification, it also performed well in the test set (AUROC = 0.725). CONCLUSION: For patients with advanced GISTs who receive IM, initial data and laboratory indicators could be used to accurately estimate whether the IM Cmin is below 1100 ng/ml. The XGBoost model may stand a chance to assist clinicians in directing the administration of IM.
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Tumores do Estroma Gastrointestinal , Humanos , Área Sob a Curva , China , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Mesilato de Imatinib/sangue , Aprendizado de Máquina , Masculino , FemininoRESUMO
Gastrointestinal stromal tumor (GIST) is the most common sarcoma located in gastrointestinal tract and derived from the interstitial cell of Cajal (ICC) lineage. Both ICC and GIST cells highly rely on KIT signal pathway. Clinically, about 80-90% of treatment-naive GIST patients harbor primary KIT mutations, and special KIT-targeted TKI, imatinib (IM) showing dramatic efficacy but resistance invariably occur, 90% of them was due to the second resistance mutations emerging within the KIT gene. Although there are multiple variants of KIT mutant which did not show complete uniform biologic characteristics, most of them have high KIT expression level. Notably, the high expression level of KIT gene is not correlated to its gene amplification. Recently, accumulating evidences strongly indicated that the gene coding, epigenetic regulation, and pre- or post- protein translation of KIT mutants in GIST were quite different from that of wild type (WT) KIT. In this review, we elucidate the biologic mechanism of KIT variants and update the underlying mechanism of the expression of KIT gene, which are exclusively regulated in GIST, providing a promising yet evidence-based therapeutic landscape and possible target for the conquer of IM resistance. Video Abstract.
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Antineoplásicos , Produtos Biológicos , Tumores do Estroma Gastrointestinal , Humanos , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Epigênese Genética , Pirimidinas , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Mutação/genética , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores de Proteínas Quinases/farmacologiaRESUMO
α1-Acid glycoprotein (AGP) is a primary binding protein for many basic drugs in plasma. The number of drugs that bind to AGP, such as molecular target anticancer drugs, has been continuously increasing. Since the plasma level of AGP fluctuates under various pathological conditions such as inflammation, it is important to evaluate the contribution of AGP to drug pharmacokinetics. Here, we generated conventional AGP-knockout (AGP-KO) mice and used them to evaluate the contribution of AGP. The pharmacokinetics of drugs that bind to two AGP variants (F1*S or A variants) or albumin were evaluated. Imatinib (a F1*S-binding drug) and disopyramide (an A-binding drug) or ibuprofen (an albumin-binding drug) were administered to wild-type (WT) and AGP-KO. The plasma level of imatinib and disopyramide decreased rapidly in AGP-KO as compared to WT. In AGP-KO, AUC and t1/2 were decreased, then CLtot was increased. Compared with disopyramide, imatinib pharmacokinetics showed more marked changes in AGP-KO as compared to WT. The results seemed to be due to the difference in plasma level of each AGP variant (F1*S:A = 2-3:1). No differences were observed in ibuprofen pharmacokinetics between the WT and AGP-KO mice. In vitro experiments using plasma from WT and AGP-KO showed that unbound fractions of imatinib and disopyramide were higher in AGP-KO. These results suggest that the rapid elimination of imatinib and disopyramide in AGP-KO could be due to decreased protein binding to AGP. Taken together, the AGP-KO mouse could be a potential animal model for evaluating the contribution of AGP to the pharmacokinetics of various drugs.
Assuntos
Ibuprofeno , Mesilato de Imatinib , Camundongos Knockout , Orosomucoide , Animais , Orosomucoide/metabolismo , Orosomucoide/genética , Camundongos , Mesilato de Imatinib/farmacocinética , Mesilato de Imatinib/sangue , Ibuprofeno/farmacocinética , Ibuprofeno/administração & dosagem , Masculino , Ligação Proteica , Camundongos Endogâmicos C57BLRESUMO
Because genetic alterations including mutations, overexpression, translocations, and dysregulation of protein kinases are involved in the pathogenesis of many illnesses, this enzyme family is the target of many drug discovery programs worldwide. The FDA has approved 80 small molecule protein kinase inhibitors with 77 drugs orally bioavailable. The data indicate that 69 of these medicinals are approved for the management of neoplasms including solid tumors such as breast and lung cancer as well as non-solid tumors such as leukemia. Moreover, the remaining 11 drugs target non-neoplastic diseases including psoriasis, rheumatoid arthritis, and ulcerative colitis. The cost of drugs was obtained from www.pharmacychecker.com using the FDA label to determine the dosage and number of tablets required per day. This methodology excludes any private or governmental insurance coverage, which would cover the entire cost or more likely a fraction of the stated price. The average monthly cost for the treatment of neoplastic diseases was $17,900 with a price of $44,000 for futibatinib (used to treat cholangiocarcinomas with FGFR2 fusions) and minimum of $5100 for binimetinib (melanoma). The average monthly cost for the treatment of non-neoplastic diseases was $6800 with a maximum of $17,000 for belumosudil (graft vs. host disease) and a minimum of $200 for netarsudil eye drops (glaucoma). There is a negative correlation of the cost of the drugs and the incidence of the targeted disease. Many of these agents are or were designated as orphan drugs meaning that there are fewer than 200,000 potential patients in the United States.
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Neoplasias , Inibidores de Proteínas Quinases , Humanos , Estados Unidos , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismoRESUMO
BACKGROUND: Barely two per million Belgian children/adolescents are diagnosed with chronic myeloid leukemia (CML) annually. In this retrospective study, we aimed to investigate the diagnostic features, clinical and laboratory characteristics, and treatment outcome of this rare entity. METHODS: Medical records of all pediatric CML patients (age ≤ 17 years) diagnosed at the University Hospitals Leuven between 1986 and 2021 were reviewed. RESULTS: Fourteen patients (median age at diagnosis 12.5 years) were included, all presenting in chronic phase. Five patients were diagnosed before 2003; main therapy included hydroxyurea (n = 5/5), interferon-alfa (n = 3/5) and allogeneic hematopoietic stem cell transplantation (allo-Tx) (n = 3/5). Complete hematologic response (CHR), complete cytogenetic response (CCyR) and major molecular response (MMR) was reached in resp. 4/5, 4/5 and in 2/3 of evaluable patients. Three patients progressed to accelerated/blast phase (median time 19 months) and 1/5 is alive and disease-free at last follow-up. Nine patients were diagnosed after 2003 and were treated with first generation (1°G) tyrosine kinase inhibitors (TKI): 3/9 subsequently underwent an allo-Tx, 4/9 were switched to 2°G TKI, one patient was additionally switched to 3°G TKI. CHR, CCyR and MMR was reached in 9/9, 9/9 and 8/9 of these patients. No progression to accelerated/blast phase was observed and none of these patients deceased. At last follow-up, 7/9 patients were in MMR or disease free, the two remaining patients did not reach or lost MMR, both related to compliance issues. CONCLUSION: Our study confirmed that TKI significantly improved the prognosis of pediatric CML. However, drug compliance poses a considerable challenge.
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Crise Blástica , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Adolescente , Criança , Crise Blástica/tratamento farmacológico , Mesilato de Imatinib/uso terapêutico , Estudos Retrospectivos , Inibidores de Proteínas Quinases/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Resultado do Tratamento , Resposta Patológica CompletaRESUMO
OBJECTIVES: This study aimed to evaluate the clinical and prognostic characteristics of primary gastric gastrointestinal stromal tumors (GIST). METHODS: Patients who underwent resection for primary gastric GIST between January 2002 and December 2017 were included. Recurrence-free survival (RFS) was calculated by Kaplan-Meier analysis, and Cox proportional hazards model was used to identify independent prognostic factors. RESULTS: Altogether, 653 patients were enrolled. The median patient age was 59 years (range 15-86 years). Open, laparoscopic, and endoscopic resections were performed in 394 (60.3%), 105 (16.1%), and 154 (23.6%) patients, respectively. According to the modified NIH consensus classification, 132 (20.2%), 245 (37.5%), 166 (25.4%), and 88 (13.5%) patients were categorized into very low-, low-, intermediate-, and high-risk, respectively. A total of 136 (20.8%) patients received adjuvant imatinib treatment. The median follow-up time was 78 months (range 4-219 months), and the estimated 5-year RFS rate was 93.0%. In all patients, tumor size and rupture, mitotic counts, and adjuvant imatinib treatment were independent prognostic factors. The prognosis of gastric GIST treated with endoscopic resection was not significantly different from that of laparoscopic or open resection after adjusting for covariates using propensity score matching (log-rank p = .558). Adjuvant imatinib treatment (HR = 0.151, 95%CI 0.055-0.417, p < .001) was a favorable prognostic factor for high-risk patients, but was not associated with prognosis in intermediate-risk patients. CONCLUSION: Patients with small gastric GISTs who successfully underwent endoscopic resection may have a favorable prognosis. Adjuvant imatinib treatment improve the prognosis of high-risk gastric GISTs, however, its use in intermediate-risk patients remains controversial.
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Antineoplásicos , Tumores do Estroma Gastrointestinal , Neoplasias Gástricas , Humanos , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Mesilato de Imatinib/uso terapêutico , Tumores do Estroma Gastrointestinal/cirurgia , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Antineoplásicos/uso terapêutico , Estudos Retrospectivos , Prognóstico , Neoplasias Gástricas/cirurgiaRESUMO
INTRODUCTION: Contour maps enable risk classification of GIST recurrence in individual patients within 10 postoperative years. Although contour maps have been referred to in Japanese guidelines, their usefulness and role in determining indications for adjuvant therapy is still unclear in Japanese patients. The aims of this study are to investigate the validity of contour maps in Japanese patients with GIST and explore the new strategy for adjuvant therapy. MATERIALS AND METHODS: A total of 1426 Japanese GIST patients who were registered to the registry by the Kinki GIST Study Group between 2003 and 2012 were analyzed. Patients who had R0 surgery without perioperative therapy were included in this study. The accuracy of contour maps was validated. RESULTS: Overall, 994 patients have concluded this study. Using contour maps, we validated the patients. The 5-year recurrence-free survival rates of patients within the GIST classification groups of 0-10%, 10-20%, 20-40%, 40-60%, 60-80%, 80-90%, and 90-100% were 98.1%, 96.6%, 92.3%, 48.0%, 37.3%, 41.0% and 42.4%, respectively. We confirmed that this classification by contour maps was well reflected recurrence prediction. Further, in the high-risk group stratified by the modified National Institutes of Health consensus criteria (m-NIHC), the 10-year RFS rate was remarkably changed at a cutoff of 40% (0-40% group vs. 40-100% group: 88.7% vs. 50.3%, p < 0.001). CONCLUSION: Contour maps are effective in predicting individual recurrence rates. And it may be useful for the decision of individual strategy for high-risk patients combined with m-NIHC.
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Antineoplásicos , Tumores do Estroma Gastrointestinal , Neoplasias Gástricas , Humanos , Mesilato de Imatinib/uso terapêutico , Antineoplásicos/uso terapêutico , Tumores do Estroma Gastrointestinal/patologia , Recidiva Local de Neoplasia/patologia , Neoplasias Gástricas/tratamento farmacológico , Sistema de Registros , Quimioterapia Adjuvante , Estudos RetrospectivosRESUMO
BACKGROUND: Imatinib contributes to improving prognosis of high-risk or unresectable gastrointestinal stromal tumors (GISTs). As therapeutic efficacy is limited by imatinib resistance and toxicity, the exploration of predictive markers of imatinib therapeutic efficacy that enables patients to utilize more effective therapeutic strategies remains urgent. METHODS: The correlation between FBXW7 and imatinib resistance via FBXW7-MCL1 axis was evaluated in vitro and in vivo experiments. The significance of FBXW7 as a predictor of imatinib treatment efficacy was examined in 140 high-risk patients with GISTs. RESULTS: The ability of FBXW7 to predict therapeutic efficacy of adjuvant imatinib in high-risk GIST patients was determined through 5-year recurrence-free survival (RFS) rates analysis and multivariate analysis. FBXW7 affects imatinib sensitivity by regulating apoptosis in GIST-T1 cells. FBXW7 targets MCL1 to regulate apoptosis. MCL1 involves in the regulation of imatinib sensitivity through inhibiting apoptosis in GIST-T1 cells. FBXW7 regulates imatinib sensitivity by down-regulating MCL1 to enhance imatinib-induced apoptosis in vitro. FBXW7 regulates imatinib sensitivity of GIST cells by targeting MCL1 to predict efficacy of imatinib treatment in vivo. CONCLUSIONS: FBXW7 regulates imatinib sensitivity by inhibiting MCL1 to enhance imatinib-induced apoptosis in GIST, and predicts efficacy of imatinib treatment in high-risk GIST patients treated with imatinib.
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Antineoplásicos , Proteína 7 com Repetições F-Box-WD , Neoplasias Gastrointestinais , Tumores do Estroma Gastrointestinal , Mesilato de Imatinib , Neoplasias Gástricas , Humanos , Antineoplásicos/uso terapêutico , Proteína 7 com Repetições F-Box-WD/metabolismo , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/patologia , Mesilato de Imatinib/uso terapêutico , Proteína de Sequência 1 de Leucemia de Células Mieloides/uso terapêutico , Neoplasias Gástricas/tratamento farmacológicoRESUMO
BACKGROUND: Imatinib resistance remains a major obstacle in the treatment of chronic myelogenous leukemia (CML). Crocin (CRC) and astaxanthin (ATX) are phytochemicals with anti-cancer properties. AIMS: This study aimed to explore the effects of combination treatment of Imatinib with CRC and ATX on Imatinib-resistant K562 (IR-K562) cells. METHODS AND RESULTS: After the establishment of IR-K562 cells, growth inhibitory activity was determined by the MTT assay. To test the regeneration potential, a colony formation assay was performed. Cell cycle analyses were examined by flow cytometry. Cell injury was evaluated by lactate dehydrogenase (LDH) leakage. Real-time PCR was applied to assess the expression of IL6, TNF-α, STAT3, BAD, CASP3, TP53, and Bcl-2 genes. Caspase-3 activity was determined by a colorimetric assay. Antioxidant activity was measured using a diphenylpicrylhydrazyl (DPPH) assay. After 48 h of treatment, ATX (IC50 = 30µM) and CRC (IC50 = 190µM) significantly inhibited cell proliferation and colony formation ability, induced G1 cell cycle arrest and cell injury, upregulated the expression of apoptosis-associated genes, and downregulated the expression of anti-apoptotic and inflammatory genes. The combination of IM with ATX and/or CRC synergistically reduced cell viability (combination index [CI] < 1). CONCLUSION: Our data suggest that IM shows better therapeutic efficacy at lower doses when combined with ATX and/or CRC.
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Carotenoides , Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide , Humanos , Antioxidantes/farmacologia , Mesilato de Imatinib/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Morte Celular , Inflamação , XantofilasRESUMO
An analytical method for the determination of imatinib (IMA, the primary treatment for chronic myeloid leukemia), based on the fluorescence properties of graphene quantum dots (GQDs), is reported in this work. The method is addressed to the analytical control of IMA in biological and pharmaceutical samples, due to the present interest in the control of the doses of this anticancer drug, as well as the therapeutic monitoring. The whole method involves the use of a solid-phase extraction (SPE) procedure, followed by an evaporation step, for the treatment of biological samples. For that, tC18 sorbent cartridges were used. After the sample treatment, the solution containing the analyte was mixed with an aqueous solution of GQDs at pH 7.2, and the fluorescent quenching of GQDs was measured. IMA was determined in the 10-250 µg L-1 range, with a limit of detection of 21 µg L-1 and a precision of 1.5% as relative standard deviation, measured in terms of reproducibility. The recovery for biological samples was in the 84-113% range.
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BACKGROUND: Imatinib treatment for certain cancers can lead to elevated creatine kinase (CK) levels, potentially indicating muscle injury, and ongoing research aims to understand the correlation between imatinib levels and creatine kinase to assess its impact on treatment response. METHODS: This single-center observational study involved 76 chronic myeloid leukemia (CML) patients receiving imatinib treatment, focusing on evaluating drug and metabolite levels using liquid chromatography-mass spectrometry (LC-MS-MS) instrumentation. Serum CK and creatine kinase-MB (CK-MB) levels were assessed using Colorimetric kits. RESULTS: CK and CK-MB levels were measured, CK showed a median value of 211.5 IU/l and CK-MB showed a median value of 4.4 IU/l. Comparing low and high CK groups, significant differences were found in peak and trough plasma concentrations of imatinib and its metabolites. Correlations between CK levels and pharmacokinetic parameters were explored, with notable associations identified. Binary logistic regression revealed predictors influencing the therapeutic response to imatinib and categorized expected CK levels into high or low, with peak levels of imatinib emerging as a significant predictor for CK level categorization. CONCLUSION: The study highlights the link between imatinib's pharmacokinetics and elevated CK levels, indicating a possible correlation between specific metabolites and improved treatment response. Individualized monitoring of CK levels and imatinib pharmacokinetics could enhance care for CML patients.
Assuntos
Antineoplásicos , Creatina Quinase , Monitoramento de Medicamentos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Mesilato de Imatinib/farmacocinética , Mesilato de Imatinib/uso terapêutico , Mesilato de Imatinib/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Antineoplásicos/sangue , Creatina Quinase/sangue , Idoso , Monitoramento de Medicamentos/métodos , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/sangue , Adulto Jovem , Resultado do Tratamento , Creatina Quinase Forma MB/sangue , Espectrometria de Massas em Tandem , Idoso de 80 Anos ou mais , Cromatografia LíquidaRESUMO
Lung cancer is known as the most common cancer. Although the Ramucirumab antibody is a second-line treatment for lung cancer, the high interstitial fluid pressure limits the antibody's performance. In this way, Imatinib is a chemotherapeutic drug to reduce the interstitial fluid pressure. Up to now, unfortunately, both Ramucirumab and imatinib have not been reported in one nanosystem for cancer therapy. To fulfill this shortcoming, this paper aims to design a chitosan nanocarrier that loads imatinib and attaches to Ramucirumab for selective bonding to A549. Therefore, this paper aims to develop a polymeric nanosystem for non-small cell lung cancer (NSCLC) treatment. In first, the chitosan polyethylene glycol nanoparticle is synthesized, loaded with imatinib, and then targeted using Ramucirumab. Afterwards, the CS-PEG-Ab-Im by FTIR, TEM, DLS, zeta potential, and TGA techniques are characterized. The size of CS-PEG-Ab-Im was 25-30 nm, its surface charge was 13.1 mV, and the shape of CS-PEG-Ab-Im was nearly spherical and cylindrical. The therapeutic potential of CS-PEG-Ab-Im was assessed using the A549 cell line. According to the obtained results, the cell viability was 48% after 48 h of treatment of A549 cells using the IC50 concentration of CS-PEG-Ab-Im (100 nanomolar). Moreover, the apoptosis and cell cycle arrest percentages were increased by 3 and 6 times, respectively, as compared to free imatinib. Furthermore, the release rate of imatinib from CS-PEG-Ab-Im in an acidic medium was 17% during 1 h, indicating five times the imatinib release in the natural medium. Eventually, the result of flow cytometry indicates the more apoptotic effect of nanosystem to free imatinib and CS-PEG-Ab. Besides, cell arresting result exhibits the CS-PEG-Ab-Im and causes cell arrested at G1 by %8.17. Thus, it can be concluded that CS-PEG-Ab-Im can be an ideal nanosystem in NSCLC treatment.
Assuntos
Quitosana , Mesilato de Imatinib , Neoplasias Pulmonares , Polietilenoglicóis , Humanos , Mesilato de Imatinib/farmacologia , Quitosana/química , Polietilenoglicóis/química , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Células A549 , Apoptose/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/química , Portadores de Fármacos/química , Linhagem Celular Tumoral , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismoRESUMO
Pityriasis rosea is an acute, self-limited exanthem that typically occurs in adolescence and young adulthood, classically featuring ovoid erythematous and scaly lesions on the trunk and proximal extremities. While its cause is not definitively known, the classic form of pityriasis rosea may result from the reactivation of latent human herpesvirus (HHV) infections (HHV-6 and HHV-7). Interestingly, drug eruptions that clinically and/or histopathologically resemble pityriasis rosea have also been reported. These pityriasis rosea-like drug eruptions tend to occur at an older age and have a shorter duration than the classic type. As there are different management paradigms, the distinction between classic pityriasis rosea and the mimicking drug eruption is important to recognize. Herein, we report a case of a pityriasis rosea-like drug eruption that occurred in association with imatinib mesylate treatment for chronic myeloid leukemia. We also review the clinicopathologic features of reported cases of pityriasis rosea-like drug eruption, including those due to imatinib. While the clinical morphology of the cutaneous drug-related eruption mimics the lesions seen in classic pityriasis rosea, the presence of unique histopathologic findings, including necrotic keratinocytes, interface dermatitis, and eosinophils, may aid in distinction.
RESUMO
BACKGROUND: Several doubts remain regarding the optimal use of neoadjuvant imatinib in gastrointestinal stromal tumors (GISTs), such as ideal treatment duration, patient selection, and long-term survival outcomes. This manuscript provides a comprehensive review on neoadjuvant imatinib treatment outcomes and facilitate evidence-based decision-making for the use of imatinib therapy in GISTs. METHODS: Four databases (PubMed, EMBASE, Scopus, and Cochrane Library) were searched from inception to September 9, 2023. Meta-analyses of proportions were performed for the outcomes of R0 resection, disease responses, and 1-year, 3-year, and 5-year overall survival (OS) as well as 1-year, 3-year, and 5-year disease free survival (DFS). Sensitivity analyses in the form of leave-one-out analyses, meta-regression, and subgroup analyses were performed for outcomes with substantial statistical heterogeneity. RESULTS: The search yielded 1254 articles, and 36 studies were included in our analysis. Meta-analysis of proportions revealed that 1-year, 3-year, and 5-year OS was 100%, 94%, and 88%, while 1-year, 3-year and 5-year DFS was 99%, 89%, and 79%, respectively. An R0 resection rate of 89% and a disease response rate of 67% was achieved after a mean duration of treatment of 8.41 ± 0.367 months. KIT exon 9 mutation was significantly associated with poorer 5-year DFS. CONCLUSION: This study quantified key outcomes for neoadjuvant imatinib in locally advanced and metastatic or recurrent GIST. Patients with gastric and rectal tumous stand to benefit from neoadjuvant imatinib with an optimal treatment duration of 8 months. Furthermore, the potential utility of mutational analysis in guiding treatment with neoadjuvant imatinib was demonstrated.
Assuntos
Antineoplásicos , Neoplasias Gastrointestinais , Tumores do Estroma Gastrointestinal , Mesilato de Imatinib , Terapia Neoadjuvante , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/mortalidade , Tumores do Estroma Gastrointestinal/patologia , Tumores do Estroma Gastrointestinal/genética , Mesilato de Imatinib/uso terapêutico , Humanos , Terapia Neoadjuvante/métodos , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/patologia , Neoplasias Gastrointestinais/mortalidade , Neoplasias Gastrointestinais/genética , Antineoplásicos/uso terapêutico , Resultado do TratamentoRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with poor prognosis. Gemcitabine-based chemotherapy has become one of the main modalities of its management. However, gemcitabine resistance frequently occurs, leading to failure of PDAC therapy. Platelet-derived growth factors (PDGFs) and their receptors play important roles in cancer progression and chemoresistance. We aimed to investigate the biological function and therapeutic significance of platelet-derived growth factor C (PDGFC) in drug-resistant PDAC. Our study showed that PDGFC was abnormally highly expressed in gemcitabine-resistant PDAC. Silencing PDGFC expression can enhance the therapeutic effect of gemcitabine on PDAC. Mechanistically, the transcription of PDGFC is mediated by H3K27 acetylation, and PDGFC promotes gemcitabine resistance by activating the PDGFR-PI3K-AKT signaling pathway. The PDGFR inhibitor imatinib inhibits the PDGFR pathway. Imatinib and gemcitabine have a synergistic effect on the treatment of PDAC, and imatinib can significantly enhance the anti-tumor effect of gemcitabine in a drug-resistant PDAC patient-derived xenograft model. In conclusion, PDGFC is a potential predictor of gemcitabine-resistant PDAC. Imatinib inhibits PDGFR activation to promote gemcitabine sensitivity in PDAC. Combined modality regimen of imatinib and gemcitabine is likely to translate into clinical trial for the treatment of PDGFC-associated gemcitabine-resistant patients.
Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Gencitabina , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Desoxicitidina/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Linhagem Celular Tumoral , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Transdução de Sinais , Resistencia a Medicamentos Antineoplásicos/genéticaRESUMO
The formation of the BCR-ABL fusion gene drives human chronic myeloid leukemia (CML). The last 2 decades have witnessed that specific tyrosine kinase inhibitors (TKIs, e.g., imatinib mesylate, IM) against ABL1 improve disease treatment, although some patients still suffer from relapse and TKI resistance. Therefore, a better understanding of the molecular pathology of CML is still urgently needed. miR-181a-5p (miR-181a) acts as a tumor suppressor in CML; however, the molecular mechanism of miR-181a in CML stem/progenitor cells remains elusive. Herein, we showed that miR-181a inhibited the growth of CML CD34+ cells, including the quiescent subset, and sensitized them to IM treatment, while miR-181a inhibition by a sponge sequence collaborated with BCR-ABL to enhance the growth of normal CD34+ cells. Transcriptome data and biochemical analysis revealed that SERPINE1 was a bona fide and critical target of miR-181a, which deepened the understanding of the regulatory mechanism of SERPINE1. Genetic and pharmacological inhibition of SERPINE1 led to apoptosis mainly mediated by caspase-9 activation. The dual inhibition of SERPINE1 and BCR-ABL exhibited a significantly stronger inhibitory effect than a single agent. Taken together, this study demonstrates that a novel miR-181a/SERPINE1 axis modulates CML stem/progenitor cells, which likely provides an important approach to override TKI resistance.