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1.
Frontiers of Medicine ; (4): 221-231, 2021.
Article in English | WPRIM | ID: wpr-880964

ABSTRACT

The mammalian target of rapamycin (mTOR) critically regulates several essential biological functions, such as cell growth, metabolism, survival, and immune response by forming two important complexes, namely, mTOR complex 1 (mTORC1) and complex 2 (mTORC2). mTOR signaling is often dysregulated in cancers and has been considered an attractive cancer therapeutic target. Great efforts have been made to develop efficacious mTOR inhibitors, particularly mTOR kinase inhibitors, which suppress mTORC1 and mTORC2; however, major success has not been achieved. With the strong scientific rationale, the intriguing question is why cancers are insensitive or not responsive to mTOR-targeted cancer therapy in clinics. Beyond early findings on induced activation of PI3K/Akt, MEK/ERK, and Mnk/eIF4E survival signaling pathways that compromise the efficacy of rapalog-based cancer therapy, recent findings on the essential role of GSK3 in mediating cancer cell response to mTOR inhibitors and mTORC1 inhibition-induced upregulation of PD-L1 in cancer cells may provide some explanations. These new findings may also offer us the opportunity to rationally utilize mTOR inhibitors in cancer therapy. Further elucidation of the biology of complicated mTOR networks may bring us the hope to develop effective therapeutic strategies with mTOR inhibitors against cancer.


Subject(s)
Glycogen Synthase Kinase 3 , Mechanistic Target of Rapamycin Complex 2 , Neoplasms/drug therapy , Phosphatidylinositol 3-Kinases , Protein Kinase Inhibitors , Proto-Oncogene Proteins c-akt , TOR Serine-Threonine Kinases
2.
Article in English | WPRIM | ID: wpr-880693

ABSTRACT

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) can effectively inhibit the growth of EGFR-dependent mutant non-small cell lung cancer (NSCLC). Unfortunately, NSCLC patients often develop severe drug resistance after long-term EGFR-TKI treatment. Studies have shown that the disorder of energy metabolism in tumor cells can induce EGFR-TKI resistance. Due to the drug action, gene mutation and other factors, tumor cells undergo metabolic reprogramming, which increases the metabolic rate and intensity of tumor cells, promotes the intake and synthesis of nutrients (such as sugar, fat and glutamine), forms a microenvironment conducive to tumor growth, enhances the bypass activation, phenotype transformation and abnormal proliferation of tumor cells, and inhibits the activity of immune cells and apoptosis of tumor cells, ultimately leading to drug resistance of tumor cells to EGFR-TKI. Therefore, targeting energy metabolism of NSCLC may be a potential way to alleviate TKI resistance.


Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , Epidermal Growth Factor , ErbB Receptors/genetics , Humans , Lung Neoplasms/genetics , Mutation , Protein Kinase Inhibitors/therapeutic use , Tumor Microenvironment
3.
Article in Chinese | WPRIM | ID: wpr-880028

ABSTRACT

OBJECTIVE@#To analyze the outcomes of the children suffered from philadelphia chromosome positive acute lymphoblastic leukemia (Ph@*METHODS@#21 cases of firstly diagnosed Ph@*RESULTS@#Among 21 patients, 17 were male and 4 were female with a median age of 8 years old (range, 4-12 years), the median follow-up time was 30 moths (range, 10-133 months). All the patients were treated with chemotherapy induced by the high-risk project of CCLG-ALL 2008. Among 14 patients treated with TKI plus chemotherapy, nine patients achieved complete remission. During 3 months after treatment, patients without complete molecular response or with the second complete remission and intensity desire of transplantation were treated with allo-HSCT, among 9 patients with allo-HSCT, six patients achieved long term survival.@*CONCLUSION@#At TKI era, TKI combined with strong chemotherapy can make Ph


Subject(s)
Aged , Child , Female , Hematopoietic Stem Cell Transplantation , Humans , Infant , Male , Philadelphia Chromosome , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Protein Kinase Inhibitors , Retrospective Studies
4.
Clinics ; 76: e2251, 2021. tab, graf
Article in English | LILACS | ID: biblio-1153972

ABSTRACT

OBJECTIVES: Lung cancer is the leading cause of cancer-related deaths worldwide. However, factors associated with the survival of patients with advanced non-small-cell lung cancer (NSCLC) who received only hospice care are largely unclear. In this study, we aimed to determine the prognostic factors correlated with survival in patients with advanced NSCLC who had undergone hospice care only. METHODS: A total of 102 patients with recurrent stage III/IV NSCLC after traditional treatment failure were investigated. Survival was measured from the date of enrollment to December 2019 or the time of death. Tumor tissues were collected, and DNA sequencing was performed to identify somatic mutations. Data on clinical factors of patients were collected and analyzed by univariate and multivariate analyses. Overall survival analysis was conducted using the Kaplan-Meier method. RESULTS: The 6-month, 1-year, and 2-year overall survival rates of the 102 patients with metastatic NSCLC were 17.65%, 3.92%, and 0.98%, respectively. The median overall survival of the 102 patients was 3.15 months. Tumor location in the peripheral lung, epidermal growth factor receptor (EGFR) inhibitor history, low tumor mutation load, adenocarcinoma, and poor performance status score were associated with prolonged survival compared with tumor location in the central lung, no EGFR inhibitor history, high tumor mutation load, squamous cell carcinoma, and good performance status score (p=0.045, p=0.003, p=0.045, p=0.021, and p=0.0003, respectively). CONCLUSIONS: EGFR inhibitor treatment history and tumor mutation load are risk factors for the overall survival of patients with stage III/IV NSCLC who have undergone only hospice care. These results provide a critical clinical basis for further study of nontraditional anti-tumor responses induced by EGFR inhibitors.


Subject(s)
Humans , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Lung Neoplasms/drug therapy , Prognosis , Retrospective Studies , Protein Kinase Inhibitors/therapeutic use , ErbB Receptors/genetics , Mutation , Neoplasm Staging
5.
Chinese Journal of Oncology ; (12): 405-413, 2021.
Article in Chinese | WPRIM | ID: wpr-877505

ABSTRACT

The introduction of cyclin-dependent kinase (CDK) 4/6 inhibitors has revolutionized the clinical management paradigm of hormone receptor (HR) positive/human epidermal growth factor receptor (HER) 2 negative breast cancer. As of today, CDK 4/6 inhibitors including Palbociclib, Ribociclib, and Abemaciclib have been widely approved by regulatory agencies. Randomized clinical trials demonstrated that CDK 4/6 inhibitors in combination with an aromatase inhibitor (AI) or fulvestrant in the first-, second- or later-line setting for HR positive/HER2 negative locally advanced or metastatic breast cancer led to substantial reduction in the risk of disease progression or death. Adverse effects of treatment were manageable and as or better than expected in terms of patient satisfaction. Considering CDK4/6 inhibitors in combination with endocrine therapy being a novel approach in China clinical practice, the panel developed the consensus comprehensively describing the pharmacology properties, monitoring strategy during treatment and adverse events management, to facilitate greater understanding in Chinese oncologists of a whole new therapeutic class of drug, promote accuracy of clinical decision and help reach the ultimate goal of improving survival and quality of life of the target patient population.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , China , Consensus , Cyclin-Dependent Kinase 4 , Cyclin-Dependent Kinase 6 , Humans , Protein Kinase Inhibitors/therapeutic use , Quality of Life , Receptor, ErbB-2
6.
Rev. méd. Chile ; 148(7): 1039-1043, jul. 2020. graf
Article in Spanish | LILACS | ID: biblio-1139408

ABSTRACT

Biological therapy dramatically changed the management of Ulcerative Colitis (UC). However, a significant number of these patients fail to respond or have secondary loss of response to this strategy. In this clinical situation, the options include intensification of anti-TNF therapy, the use of a second anti-TNF or being switched to another drug class. Among the later, tofacitinib, an oral small molecule directed against the JAK/STAT pathway, is safe and effective in inducing and maintaining remission in patients with moderate-severe UC. We report two patients with UC refractory to conventional treatment and biological therapy, who responded successfully to the use of tofacitinib.


Subject(s)
Humans , Male , Middle Aged , Piperidines/therapeutic use , Pyrimidines/therapeutic use , Colitis, Ulcerative/drug therapy , Protein Kinase Inhibitors/therapeutic use , Colitis, Ulcerative/diagnostic imaging , Colonoscopy , Treatment Outcome
7.
Journal of Experimental Hematology ; (6): 1054-1058, 2020.
Article in Chinese | WPRIM | ID: wpr-827162

ABSTRACT

Abstract  Spleen tyrosine kinase (SYK) is not only a key kinase in the B-cell receptor (BCR) signaling pathway, but also a critical component of other signal transduction pathways such as Fc receptor, complement receptor and integrin. Abnormal activation of SYK closely related to the occurrence and development of hematological malignancies, thus targeting SYK has become a research hotspot. Several SYK inhibitors including Fostamatinib, Entospletinib and Cerdulatinib were being evaluated in clincal trials. As a second generation SYK inhibitor, Entospletinib has achieved good efficacy in lymphoid and myeloid hematologic tumors. Furthermore, Entospletinib can significantly relieve hematopoietic stem cell transplantation(HCT) related graft versus host disease (GVHD). In this review the role of SYK inhibitors in treatment of hematological malignancies is summarized brifely.


Subject(s)
Graft vs Host Disease , Hematologic Neoplasms , Humans , Protein Kinase Inhibitors , Spleen , Syk Kinase
8.
Journal of Experimental Hematology ; (6): 1162-1166, 2020.
Article in Chinese | WPRIM | ID: wpr-827146

ABSTRACT

OBJECTIVE@#To investigate the curative efficacy of first generation TKI in the treatment of CML-CP combined with vPh and genetic characteristics.@*METHODS@#60 patients with CML-CP combined with vPh from January 2010 to May 2017 in the First Affiliated Hospital of Kunming Medical University were chosen as CML-CP-vPh group, and 107 patients with CML-CP combined with typical Ph chromosome at the same time were chosen as control group. The patients in two groups were treated with imatinib; The curative efficacy, karyotype and FISH signal type were compared between 2 groups, and the factors influencing long-term survival of patients were analyzed by Cox risk model.@*RESULTS@#There was no significant difference in the demographic and hematological baseline data between 2 groups (P>0.05), and there was no significant difference in the incidence of drug-resistance between 2 groups (P>0.05). The incidence of primary drug-resistance and primary hematological drug-resistance in the CML-CP-vPh group were significantly higher than that in control group (P<0.05). There was no significant difference in the accumulative CCyR rate, accumulative MMR rate, OS and EFS between 2 groups (P>0.05). Multivariate Cox model analysis showed that vPh not correlated with OS and EFS of patients with CML-CP (P>0.05). The factors influencing OS in CML-vPh patients included high risk of Sokal scores, peripheral blood basophils proportion ≥10%, BCR-ABL in 3 months after treatment<10%, achieviag CCyR in 6 months after treatment and achieviag MMR in 12 months after treatment (P<0.05). The factors influencing EFS included BCR-ABL<10% in 3 months after treatment and achieving MMR in 12 months after treatment (P<0.05). The regions with high frequency of heterotopic involvement included 12q1, 12q2 [9 cases (15.00%)] and 1p3 [8 cases (13.33%)]. The percentage of 2G2R1Y, 1G1R2F, 1G2R1Y, 2G1R1Y and 1G1R1Y in FISH signal types were 73.33%, 10.00%, 1.67%, 1.67% and 1.67% respectively.@*CONCLUSION@#Patients with CML-CP combined with vPh possess higher primary drug-resistance rate and primary hematological drug-resistance rate for the first generation TKI, while second-generation TKI can efficiently improve long-term survival, its efficacy is similar to efficacy for patients with typical Ph chromosomes. CML-CP combined with vPh does not display special demographic and hematological characteristics. The main involved regions of heterotopic variants include 12q1, 12q2 and 1p3, while 2G2R1Y type is the most common type of FISH signal.


Subject(s)
Fusion Proteins, bcr-abl , Humans , Imatinib Mesylate , Karyotyping , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Protein Kinase Inhibitors , Treatment Outcome
9.
Journal of Experimental Hematology ; (6): 2093-2096, 2020.
Article in Chinese | WPRIM | ID: wpr-880021

ABSTRACT

Tyrosine kinase inhibitor (TKI) has significantly improved the treatment of chronic myeloid leukemia (CML), however the resistance often resulted in treatment failure. Currently, it is known that the survival of CML cells can be affected by regulating autophagy, oxidative stress and mitochondrial metabolism, among which autophagy is an evolution-conserved catabolism process, and closely related to the pathogenesis of CML, thus playing a dual role in regulating the biological characteristics of cells. On the one hand, autophagy can promote the apoptosis of CML cells, and also can induce the drug resistance of CML cells on the other hand. In this review, the effect of autophagy on CML cells was summarzed briefly, so as to provide a useful idea to explore the combination of TKI with the autophagy inhibitor or inducer to overcome the resistance of CML to TKI.


Subject(s)
Apoptosis , Autophagy , Drug Resistance, Neoplasm , Fusion Proteins, bcr-abl , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Protein Kinase Inhibitors/pharmacology , Research
10.
Clinics ; 75: e1777, 2020. tab, graf
Article in English | LILACS | ID: biblio-1133470

ABSTRACT

OBJECTIVES: To evaluate the molecular testing and treatment patterns in a retrospective cohort of newly diagnosed treatment-naïve patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). METHODS: This is an observational retrospective cohort study conducted across 10 cancer centers in Brazil. Treatment-naïve patients with locally advanced or metastatic NSCLC were enrolled from January to December 2014. The following data were collected from the medical records of patients from diagnosis until the last record (death, loss to follow-up, or the end of the maximum follow-up period): demographics; medical history; smoking status; disease characteristics; previous treatments; and molecular testing patterns and results. The overall survival (OS) was also estimated. Results: A total of 391 patients from 8 different Brazilian states were included, with a median age of 64.1 years (23.7-98.7), with most patients being males (60.1%). The smoking status of 74.2% of patients was a 'former' or 'current smoker'. Stage IV NSCLC at diagnosis was observed in 82.4% of patients, with 269 of them (68.8%) presenting adenocarcinoma (ADC). Among the stage IV ADC patients, 54.0% were referred for molecular testing. Among the patients with an available epidermal growth factor receptor (EGFR) mutation status, 31 (24.0%) were EGFR-positive. The first-line treatment was a platinum-based chemotherapy for 98 patients (25.1%), while non-platinum-based regimens were used in 54 patients (13.8%). OS data were available for 370 patients, with a median OS of 10.8 months. Never smokers had a significantly higher median OS versus current or former smokers (14.6 versus 9.1 months; log-rank p=0.003). Among the patients for whom molecular testing data were available, those with EGFR-positive results had a longer median OS (34.6 versus 12.8 months; log-rank p=0.003). Conclusion: Our findings provide relevant information for prescribers and policy decision-makers by highlighting the unmet needs of patients and the importance of molecular testing in newly diagnosed locally advanced or metastatic lung adenocarcinoma. We also highlight the respective EGFR-tyrosine kinase inhibitor treatment when the result is positive and the areas in which further efforts are required to grant access to effective treatment.


Subject(s)
Humans , Male , Middle Aged , Carcinoma, Non-Small-Cell Lung/diagnosis , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/drug therapy , Brazil , Retrospective Studies , Molecular Diagnostic Techniques , Protein Kinase Inhibitors , Mutation
11.
Clinics ; 75: e2011, 2020. tab, graf
Article in English | LILACS | ID: biblio-1133363

ABSTRACT

OBJECTIVE: The occurrence of cryptic Philadelphia (Ph) chromosome translocation is rare in BCR-ABL1-positive acute lymphoblastic leukemia (BCR-ABL1+ ALL) and is of unknown significance in the tyrosine kinase inhibitor (TKI) era. METHODS: We retrospectively studied a series of adult patients receiving TKI-based therapy to evaluate the prognostic impact of the normal karyotype (NK) (n=22) in BCR-ABL1+ ALL by comparison with the isolated Ph+ karyotype (n=54). RESULTS: There were no statistically significant differences in clinical characteristics and complete remission rate between the two groups. Compared with the isolated Ph+ group, the NK/BCR-ABL1+ group had a higher relapse rate (55.0% versus 29.4%, p=0.044). Overall survival (OS) and disease-free survival (DFS) were significantly shorter in the NK/BCR-ABL1+ group than in the isolated Ph+ group [median OS: 24.5 versus 48.6 (months), p=0.013; median DFS: 11.0 (months) versus undefined, p=0.008]. The five-year OS and DFS for patients with NK/BCR-ABL1+ were 19.2% and 14.5%, respectively; those for patients with isolated Ph+ were 49.5% and 55.7%, respectively. Thirty-four (44.7%) patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in this study. Among the patients who received allo-HSCT, the median OS and DFS in the NK/BCR-ABL+ group (n=9) were 35.5 and 27.5 months, respectively, while those in the isolated Ph+ group (n=25) were undefined. There was a trend of significant statistical difference in the OS between the two subgroups (p=0.066), but no significant difference in the DFS. Multivariate analysis revealed that NK was independently associated with worse OS and DFS in BCR-ABL1+ ALL patients [Hazard ratio (HR) 2.256 (95% confidence interval (CI), 1.005-5.066), p=0.049; HR 2.711 (95% CI, 1.319-5.573), p=0.007]. CONCLUSION: Our results suggest that the sub-classification of an NK could be applied in the prognostic assessments of BCR-ABL1+ ALL. In addition, allo-HSCT should be actively performed to improve prognosis in these patients.


Subject(s)
Humans , Adult , Hematopoietic Stem Cell Transplantation , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Prognosis , Retrospective Studies , Fusion Proteins, bcr-abl/genetics , Protein Kinase Inhibitors/therapeutic use , Karyotype
12.
Article in Chinese | WPRIM | ID: wpr-828935

ABSTRACT

OBJECTIVE@#To investigate the inhibitory effect of epidermal growth factor receptor tyrosine kinase inhibitor (EGFRTKI) HS-10296 on the proliferation of triple-negative breast cancer (TNBC) MDA-MB-231 cells and explore the possible molecular mechanism.@*METHODS@#MDA-MB-231 cells were treated with HS-10296 for 24, 48, or 72 h, and CCK-8 assay was used to assess the changes in the cell viability. The inhibitory effect of HS-10296 on cell proliferation was determined by clonogenic assay. JC-1 and flow cytometry were employed for analyzing the cell apoptosis, and the ultrastructure of the cells was observed under electron microscope. After pretreatment with autophagy inhibitor chloroquine (CQ), MDA-MB-231 cells were divided into control group, CQ treatment group, HS-10296 (4 and 6 μmol/L) treatment groups and combined treatment groups, and the sensitivity of the treated cells to HS-10296 was determined using CCK-8 assay. The effects of HS-10296 on EGFR pathway and apoptosis- and autophagy-related proteins in MDA-MB-231 cells were investigated using Western blotting.@*RESULTS@#HS-10296 significantly inhibited the proliferation of MDA-MB-231 cells with IC values at 24, 48 and 72 h of 8.393, 2.777 and 2.016 μmol/L, respectively. JC-1 and flow cytometry showed that HS-10296 induced obvious apoptosis of MDA-MB-231 cells, which showed an apoptosis rate of (21.63 ± 2.97)% following treatment with 8 μmol/L HS-10296. Autophagy vesicles were observed in the cells treated with HS-10296 under electron microscope. In MDA-MB-231 cells pretreated with CQ, inhibition of autophagy significantly enhanced HS-10296-induced cell death. Western blotting showed that the apoptosis-related protein caspase-3 was activated after HS-10296 treatment to cut its substrate PARP. The expression of autophagy-related protein light chain 3B (LC3B) was significantly enhanced after HS-10296 treatment ( < 0.01), which also resulted in inhibited phosphorylation of EGFR and AKT proteins in the cells.@*CONCLUSIONS@#HS-10296 can inhibit the proliferation and induce autophagy and apoptosis of MDA-MB-231 cells by inhibiting the EGFR/PI3K/AKT signaling pathway.


Subject(s)
Apoptosis , Autophagy , Breast Neoplasms , Cell Line, Tumor , Cell Proliferation , ErbB Receptors , Humans , Phosphatidylinositol 3-Kinases , Protein Kinase Inhibitors
13.
Article in Chinese | WPRIM | ID: wpr-828516

ABSTRACT

OBJECTIVE@#To investigate the inhibitory effect of epidermal growth factor receptor tyrosine kinase inhibitor (EGFRTKI) HS-10296 on the proliferation of triple-negative breast cancer (TNBC) MDA-MB-231 cells and explore the possible molecular mechanism.@*METHODS@#MDA-MB-231 cells were treated with HS-10296 for 24, 48, or 72 h, and CCK-8 assay was used to assess the changes in the cell viability. The inhibitory effect of HS-10296 on cell proliferation was determined by clonogenic assay. JC-1 and flow cytometry were employed for analyzing the cell apoptosis, and the ultrastructure of the cells was observed under electron microscope. After pretreatment with autophagy inhibitor chloroquine (CQ), MDA-MB-231 cells were divided into control group, CQ treatment group, HS-10296 (4 and 6 μmol/L) treatment groups and combined treatment groups, and the sensitivity of the treated cells to HS-10296 was determined using CCK-8 assay. The effects of HS-10296 on EGFR pathway and apoptosis- and autophagy-related proteins in MDA-MB-231 cells were investigated using Western blotting.@*RESULTS@#HS-10296 significantly inhibited the proliferation of MDA-MB-231 cells with IC values at 24, 48 and 72 h of 8.393, 2.777 and 2.016 μmol/L, respectively. JC-1 and flow cytometry showed that HS-10296 induced obvious apoptosis of MDA-MB-231 cells, which showed an apoptosis rate of (21.63 ± 2.97)% following treatment with 8 μmol/L HS-10296. Autophagy vesicles were observed in the cells treated with HS-10296 under electron microscope. In MDA-MB-231 cells pretreated with CQ, inhibition of autophagy significantly enhanced HS-10296-induced cell death. Western blotting showed that the apoptosis-related protein caspase-3 was activated after HS-10296 treatment to cut its substrate PARP. The expression of autophagy-related protein light chain 3B (LC3B) was significantly enhanced after HS-10296 treatment ( < 0.01), which also resulted in inhibited phosphorylation of EGFR and AKT proteins in the cells.@*CONCLUSIONS@#HS-10296 can inhibit the proliferation and induce autophagy and apoptosis of MDA-MB-231 cells by inhibiting the EGFR/PI3K/AKT signaling pathway.


Subject(s)
Antineoplastic Agents , Pharmacology , Apoptosis , Autophagy , Breast Neoplasms , Drug Therapy , Cell Line, Tumor , Cell Proliferation , ErbB Receptors , Metabolism , Humans , Protein Kinase Inhibitors , Pharmacology , Signal Transduction
14.
Article in Chinese | WPRIM | ID: wpr-828505

ABSTRACT

OBJECTIVE@#To investigate the effects of blocking the activation of ERK pathway on the expression of matrix metalloproteinase-9 (MMP-9) and the formation of cerebral edema in SD rats after brain injury.@*METHODS@#Ninety SD rats were randomly divided into 3 equal groups, including a sham-operated group, modified Feeney's traumatic brain injury model group, and ERK inhibition group where the ERK inhibitor SCH772984 (500 μg/kg) was injected via the femoral vein 15 min before brain trauma. At 2 h and 2 days after brain trauma, the permeability of blood-brain barrier was assessed by Evans blue method, the water content of the brain tissue was determined, and the phosphorylation level of ERK and the expression level of MMP-9 mRNA and protein were measured by RT-PCR and Western blotting.@*RESULTS@#Compared with the sham-operated group, the rats with brain trauma exhibited significantly increased level of ERK phosphorylation at 2 h and significantly increased expression of MMP-9 mRNA and protein 2 days after the injury ( < 0.01). Treatment with the ERK inhibitor significantly decreased the phosphorylation level of ERK after the injury ( < 0.01), suppressed over-expression of MMP-9 mRNA and protein 2 days after the injury ( < 0.01). The permeability of blood-brain barrier increased significantly 2 h after brain trauma ( < 0.05) and increased further at 2 days ( < 0.01); the water content of the brain did not change significantly at 2 h ( > 0.05) but increased significantly 2 d after the injury ( < 0.01). Treatment with the ERK inhibitor significantly lowered the permeability of blood-brain barrier and brain water content after brain trauma ( < 0.01).@*CONCLUSIONS@#Blocking the activation of ERK pathway significantly reduced the over-expression of MMP-9 and alleviates the damage of blood-brain barrier and traumatic brain edema, suggesting that ERK signaling pathway plays an important role in traumatic brain edema by regulating the expression of MMP-9.


Subject(s)
Animals , Brain Edema , Drug Therapy , Brain Injuries, Traumatic , Drug Therapy , Gene Expression Regulation, Enzymologic , Indazoles , Pharmacology , Therapeutic Uses , MAP Kinase Signaling System , Matrix Metalloproteinase 9 , Genetics , Piperazines , Pharmacology , Therapeutic Uses , Protein Kinase Inhibitors , Pharmacology , Therapeutic Uses , Random Allocation , Rats , Rats, Sprague-Dawley
15.
Article in English | WPRIM | ID: wpr-827399

ABSTRACT

Chronic myeloid leukemia (CML) is one of the most common hematological malignancies and characterized by the formation of Philadelphia (Ph) chromosome. Recently, tyrosine kinase inhibitors (TKI) treatment greatly improved the prognosis of CML. However, the options may be limited when a patient develops traditional TKI resistance or gene mutation. Herein, we reported a case. A 38-year-old male CML patient developed a BCR-ABL1 gene mutation of T315I after 2.5 years of TKI treatment, including imatinib and dasatinib. We adjusted the treatment with the combined application of dasatinib and axitinib. BCR-ABL1 gene copies dropped down and achieved an early molecular response at 2 months later. Subsequently, he received hematopoietic stem cell transplantation. Axitinib and dasatinib were applied for another half year after the allogeneic hematopoietic stem cell transplantation (allo-HSCT). Two years after the allo-HSCT, the BCR-ABL1 gene was still undetectable. It provided a successful example in treating CML patients carrying BCR-ABL1 T315I mutation via combination of axitinib with conditional TKI.


Subject(s)
Adult , Axitinib , Dasatinib , Therapeutic Uses , Drug Resistance, Neoplasm , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Drug Therapy , Genetics , Male , Mutation , Protein Kinase Inhibitors , Therapeutic Uses
16.
Chinese Journal of Biotechnology ; (12): 2298-2312, 2020.
Article in Chinese | WPRIM | ID: wpr-878487

ABSTRACT

Polo-like kinase 1 (Plk1) is widely regarded as one of the most promising targets for cancer therapy due to its essential role in cell division and tumor cell survival. At present, most Plk1 inhibitors have been developed based on kinase domain, some of which are in clinical trial. However, inhibitors targeting kinase domain face off-target effect and drug resistance owing to the conserved nature and the frequent mutations in the ATP-binding pocket. In addition to a highly conserved kinase domain, Plk1 also contains a unique Polo-Box domain (PBD), which is essential for Plk1's subcellular localization and mitotic functions. Inhibitors targeting Plk1 PBD show stronger selectivity and less drug resistance for cancer therapy. Therefore, Plk1 PBD is an attractive target for the development of anti-cancer agents. In this review, we will summarize the up-to date drug discovery for targeting Plk1 PBD, including the molecular structure and cellular functions of Plk1 PBD. Small-molecule inhibitors targeting Plk1 PBD not only provide an opportunity to specifically inhibit Plk1 activity for cancer treatment, but also unveil novel biological basis regarding the molecular recognition of Plk1 and its substrates.


Subject(s)
Cell Cycle Proteins/genetics , Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Protein-Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins/genetics
17.
Chinese Medical Journal ; (24): 2987-2997, 2020.
Article in English | WPRIM | ID: wpr-877884

ABSTRACT

Lung cancer is a malignant tumor characterized by a rapid proliferation rate, less survivability, high mortality, and metastatic potential. This review focuses on updated research about the clinical application of traditional Chinese medicine (TCM) as an adjuvant therapy to lung cancer treatment and the mechanisms of TCM effect on lung cancer in vitro and in vivo. We summarized the recent 5 years of different research progress on clinical applications and antitumor mechanisms of TCM in the treatment of lung cancer. As a potent adjuvant therapy, TCM could enhance conventional treatments (chemotherapy, radiation therapy, and epidermal growth factor receptors [EGFRs] tyrosine kinase inhibitors [TKIs]) effects as well as provide synergistic effects, enhance chemotherapy drugs chemosensitivity, reverse drug resistance, reduce adverse reactions and toxicity, relieve patients' pain and improve quality of life (QOL). After treating with TCM, lung cancer cells will induce apoptosis and/or autophagy, suppress metastasis, impact immune reaction, and therapeutic effect of EGFR-TKIs. Therefore, TCM is a promisingly potent adjuvant therapy in the treatment of lung cancer and its multiple mechanisms are worthy of an in-depth study.


Subject(s)
Combined Modality Therapy , Drugs, Chinese Herbal/therapeutic use , Humans , Lung Neoplasms/drug therapy , Medicine, Chinese Traditional , Protein Kinase Inhibitors , Quality of Life
18.
Chinese Journal of Oncology ; (12): 807-816, 2020.
Article in Chinese | WPRIM | ID: wpr-877492

ABSTRACT

Anlotinib hydrochloride is the only anti-angiogenic, multi-targeted tyrosine kinase inhibitor, which has been approved for non-small cell lung cancer and small cell lung cancer in China. In order to provide guidance for clinical practitioners to use anlotinib hydrochloride safely and efficiently, the Chinese Association for Clinical Oncologists, the Expert Committee of Vascular Targeted Therapy of Chinese Society of Clincal Oncology and the Cancer Targeted Therapy Professional Committee of China Anti-Cancer Association co-organized experts and integrated multiple evidences of Anlotinib Hydrochloride, from both clinical trial, post-marketed clinical data and the associated experiences of experts accumulated in clinical practice, etc. The present consensus covers the clinical data of anlotinib hydrochloride applied in advanced non-small cell lung cancer and small cell lung cancer, and the safety management recommendations.


Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , China , Consensus , Humans , Indoles/therapeutic use , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Quinolines/therapeutic use
19.
Säo Paulo med. j ; 137(6): 505-511, Nov.-Dec. 2019. tab, graf
Article in English | LILACS | ID: biblio-1094519

ABSTRACT

ABSTRACT BACKGROUND: Lung cancer is the fourth most common cancer in Brazil. In the 2000s, better understanding of molecular pathways led to development of epidermal growth factor receptor (EGFR)-targeted treatments that have improved outcomes. However, these treatments are unavailable in most Brazilian public healthcare services (Sistema Único de Saúde, SUS). OBJECTIVE: To assess the potential number of years of life not saved, the budget impact of the treatment and strategies to improve access. DESIGN AND SETTING: Pharmacoeconomic study assessing the potential societal and economic impact of adopting EGFR-targeted therapy within SUS. METHODS: We estimated the number of cases eligible for treatment, using epidemiological data from the National Cancer Institute. We used data from a single meta-analysis and from the Lung Cancer Mutation Consortium (LCMC) study as the basis for assessing differences in patients' survival between use of targeted therapy and use of chemotherapy. The costs of targeted treatment were based on the national reference and were compared with the amount reimbursed for chemotherapy through SUS. RESULTS: There was no life-year gain with EGFR-targeted therapy in the single meta-analysis (hazard ratio, HR, 1.01). The LCMC showed that 1,556 potential life-years were not saved annually. We estimated that the annual budget impact was 125 million Brazilian reais (BRL) with erlotinib, 48 million BRL with gefitinib and 52 million BRL with afatinib. Their incremental costs over chemotherapy per life-year saved were 80,329 BRL, 31,011 BRL and 33,225 BRL, respectively. A drug acquisition discount may decrease the budget impact by 30% (with a 20% discount). A fixed cost of 1,000 BRL may decrease the budget impact by 95%. CONCLUSION: Reducing drug acquisition costs may improve access to EGFR-targeted therapy for lung cancer.


Subject(s)
Humans , Health Care Costs , Quality-Adjusted Life Years , Protein Kinase Inhibitors/economics , ErbB Receptors/economics , Lung Neoplasms/economics , Quinazolines/economics , Quinazolines/therapeutic use , Brazil , Budgets , Survival Analysis , Cost-Benefit Analysis/economics , Risk Sharing, Financial/methods , Protein Kinase Inhibitors/therapeutic use , Molecular Targeted Therapy/economics , ErbB Receptors/therapeutic use , Health Services Accessibility/economics , Lung Neoplasms/mortality , Lung Neoplasms/drug therapy
20.
Article in Chinese | WPRIM | ID: wpr-772331

ABSTRACT

Tyrosine kinase inhibitor (TKI) have been proved to be effective in the treatment of advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) sensitive mutation, which is superior to chemotherapy. However, there are still some patients with sensitive mutations have primary drug resistance. It may be related to the coexistence of susceptible and resistant mutations of EGFR gene, downstream mutations of EGFR pathway, MET amplification and BIM deletion polymorphism. We present 2 cases of primary drug resistance and analyze the reasons.
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Subject(s)
Carcinoma, Non-Small-Cell Lung , Diagnostic Imaging , Drug Therapy , Genetics , Disease Progression , Drug Resistance, Neoplasm , Genetics , ErbB Receptors , Genetics , Fatal Outcome , Humans , Lung Neoplasms , Diagnostic Imaging , Drug Therapy , Genetics , Male , Middle Aged , Mutation , Protein Kinase Inhibitors , Therapeutic Uses , Treatment Outcome
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