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OBJECTIVE To eva luate the economy of loratinib versus crizo tinib in the first-line treatment of anaplastic lymphoma kinase （ALK）-positive advanced non-small cell lung cancer （NSCLC）from the perspective of China ’s health system ， and to provide reference for the product pricing and related medical decisions of the drug in other regions of China except for Hong Kong. METHODS Markov model and partition survival model both constructed based on the CROWN data （the simulation time limit was 10 years and the cycle period was 4 weeks）；the quality adjusted life year （QALY）was used as the outcome index to calculate the incremental cost-effectiveness ratio （ICER）. One-way sensitivity analysis ，probability sensitivity analysis and scenario analysis were used to verify the robustness of the results. RESULTS The basic analysis results based on Markov model showed that compared with crizotinib group ，the per capita cost of loratinib group increased by 17 867 588.63 yuan，the per capita utility increased by 1.76 QALYs，and the ICER was 10 152 038.99 yuan/QALY. The basic analysis results based on the partition survival model showed that compared with the crizotinib group ，the Δ 基金项目：江苏省博士后科研资助计划项目（No.2021K496C）； per capita cost of loratinib group increased by 18 009 592.54 2020年度高校哲学社会科学研究一般项目（No.2020SJA0070） yuan，the per capita utility increased by 1.74 QALYs，and the ＊硕士研究生 。研究方向 ：药物经济学 、卫生经济与政策 。 E-mail：sunlei_cpu@163.com ICER was 10 350 340.54 yuan/QALY. The results of one-way # 通信作者：教授，博士生导师。研究方向：药物经济学、卫生经 sensitivity analysis of the two models both showed that 济与政策。E-mail：ma86128@sina.com progression-free survival （PFS）state utility v alue，progression- ·1102· China Pharmacy 2022Vol. 33 No. 9 中国药房 2022年第33卷第9期 disease（PD）state utility value and loratinib cost had great influence on the results. The results of probability sensitivity analysis showed that when 1-3 times of China ’s per capita GDP in 2020 was taken as the willingness to pay threshold ，the probability of loratinib being economical was 0. The recommended unit price of loratinib per 100 mg was 657.10-815.60 yuan. CONCLUSIONS For patients with ALK-positive advanced NSCLC ，loratinib is more effective than crizotinib in the first-line treatment ，but it is not economical under the current price ；reasonably lowering the price of loratinib can increase the probability of its economy.
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OBJECTIVE To evaluate the econo mical efficiency of ensatinib i n the first-line treatment of anaplastic lymphoma kinase（ALK）positive-advanced non-small cell lung cancer （NSCLC），so as to provide reference for China ’s medical insurance decision-making and rational drug use in clinic. METHODS A three-state partitioned survival model was constructed from the perspective of China ’s health system ，based on the data of the international multi-center phase Ⅲ clinical trial （eXalt3 trail），with simulation time limit of 10 years，cycle period of 30 days. The economical efficiency of ensatinib was compared with that of crizotinib（standard treatment ）in the first-line treatment of ALK positive-advanced NSCLC. The incremental cost-effectiveness ratio （ICER） was calculated with quality-adjusted life years （QALYs） as utility index. The stability of basic analysis results was validated through uncertainty analysis. RESULTS The basic analysis results showed that compared with crizotinib group ， incremental cost per capita of ensatinib group was －343 370.36 yuan，incremental utility per capita was 0.76 QALYs，ICER was －454 292.25 yuan/QALY，which was far lower than the willingness-to-pay （WTP）threshold of 1 time of China ’s per capita gross domestic product （GDP，80 976 yuan）in 2021. The results of univariate sensitivity analysis showed that progression-free survival （PFS）status utility ，progression of disease （PD）status utility and subsequent treatment cost of crizotinib had a greater impact on ICER，but these parameters could not cause the reversal of basic analysis results. Probabilistic sensitivity analysis showed that with 1 time of China ’s per capita GDP in 2021 as the WTP threshold ，the probability of ensatinib group ’s treatment possessed economical efficiency was 100％. In the situational analysis ，ICER obtained by changing the ensatinib group ’s follow-up treatment regimen was －217 671.43 yuan/QALY，which was far below WTP threshold. CONCLUSIONS For Chinese patients with ALK positive-advanced NSCLC ，compared with commonly used the first-line treatment （crizotinib），ensartinib is economical and absolutely dominant.
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Objective:To investigate the efficacy and safety of targeted therapy with Crizotinib for children with ALK gene mutation positive inflammatory myofibroblastic tumor (IMT). Methods:A retrospective analysis was performed on 4 children with ALK gene mutation positive IMT admitted to Shanghai Children′s Hospital from January 2019 to June 2021.Among them, 3 cases were given the targeted drug Crizotinib[280 mg/(m 2· time), q12h] orally, and 1 case was observed after complete tumor resection to analyze the efficacy and adverse drug reactions. Results:All 4 cases were male, aged from 2 years and 3 months to 11 years and 3 months.The tumors originated from the abdominal cavity in 2 cases, the right orbit in 1 case, and the right lung in 1 case.Pathological immunohistochemistry and fluorescence in situ hybridization were both positive for ALK gene mutation, and complete remission was achieved after comprehensive treatment.Among them, 3 patients were treated with oral Crizotinib, and 2 patients were tried to stop taking the drug for 1 year, relapsed 1 month later, and still achieved complete remission after the second treatment.The 4 cases were followed up for 8-30 months, and all survived.All the cases showed no abnormalities in blood image, liver and kidney function, myocardial enzyme profile, cardiac function, hearing and vision, and 2 cases showed prolonged Q-T interval in the course of Crizotinib treatment, which could be recovered by temporary withdrawal of drug, and no abnormality in electrocardiogram was found in continued drug use. Conclusions:Crizotinib was used to treat ALK mutation positive IMT, shrink tumor and consolidate postoperative treatment, which is a good choice for IMT in children with difficult surgical resection and refractory recurrence.
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Objective:To study the effect of crizotinib on acute radiation-induced lung injury in mice and its possible mechanism.Methods:A total of 72 mice were randomly divided into 4 groups by the random number table method: healthy control group (NC group, n=12), crizotinib-only group (CRZ group, n=12), radiotherapy-only group (RT group, n=24), and radiotherapy pluscrizotinib group (RT+ CRZ group, n=24). The whole lungs were exposed to a single dose of 12 Gy X-rays. Lung tissue and bronchoalveolar lavage fluid (BALF) were obtained at 1, 2, 4, and 8 weeks after radiotherapy. The total number of nucleated cells was counted under a light microscope, and the total protein content of BALF was detected by bicinchoninic acid (BCA) protein assay. The pathological changes of lung tissue were observed by HE staining and MASSON staining. The expressions of TGF-β1 and ICAM-1 mRNA in lung tissue were detected by real-time quantitative polymerase chain reaction (qPCR), the locations and expressions of MPO and ICAM-1 proteins were observed by immunohistochemical staining, and the expressions of TGF-β1, Smad3, p-Smad3 and ICAM-1 proteins in lung tissue were detected by Western blot. Results:At different time points after irradiation, the pathological manifestations such as inflammation and exudation of lung tissue in the RT+ CRZ group were significantly increased, and the total number of cells and protein content in BALF was higher than that of the other three groups, compared with RT group, the difference was statistically significant at 4 week ( t=-5.031, -2.814, P<0.05). Compared with RT group, the expressions of ICAM-1 and TGF-β1 mRNA in lung tissue of the RT+ CRZ group were significantly increased, while the expression of TGF-β1 increased significantly at 1, 4 and 8 weeks after irradiation ( t=-2.687, -7.032, -5.221, P<0.05), and the expression of ICAM-1 increased significantly at 2 and 4 weeks after irradiation ( t=-4.819, -6.057, P<0.05). The expressions of these two gradually increased from 1 to 4 weeks and peaked in 4 weeks, then decreased at 8 weeks. At the same time, the trend of the expression of MPO mRNA was consistent with ICAM-1 and TGF-β1. At 4 week, there was no difference in the expression of Smad3 protein in these four groups ( P>0.05). The expressions of TGF-β1, p-Smad3, ICAM-1 and p-Smad3/Smad3 proteins of the RT+ CRZ group were all higher than those of the other three groups ( F=14.74, 10.03, 35.29, 22.94, P<0.05). Conclusions:Crizotinib combined with radiotherapy can aggravate acute radiation-induced lung injury, which may due to the increase of ICAM-1 expression by up-regulating the TGF-β1 signaling pathway.
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BACKGROUND@#Anaplastic lymphoma kinase (ALK) is an important therapeutic target for advanced non-small cell lung cancer (NSCLC). In recent years, with the emergence of several ALK tyrosine kinase inhibitors (TKI), the overall survival (OS) of ALK fusion positive patients is gradually extended. This paper reports the treatment of a late stage non-small cell lung cancer (NSCLC) patient with ALK fusion positive for more than 5 years, and analyzes the treatment process and effect evaluation, so as to provide experience for the follow-up treatment of patients.@*METHODS@#The diagnosis and treatment process of a patient with advanced ALK fusion mutation positive lung cancer admitted to the third ward of Department of oncology, Chifeng hospital, Inner Mongolia on July 3, 2015 was retrospectively analyzed.@*RESULTS@#A 42 years old male patient was admitted to our department on July 3, 2015 for "intermittent cough, chest tightness for 2 months, diagnosed with lung adenocarcinoma for 1 day". Imaging examination showed a space occupying lesion in the left lower lobe of the lung, accompanied by mediastinal lymphadenopathy and left encapsulated pleural effusion. Bronchoscopic pathology showed non-small cell carcinoma, and adenocarcinoma was tentatively suggested.@*DIAGNOSIS@#left lower lobe adenocarcinoma T1bN2M1a stage IV. Fluorescence in situ hybridization (FISH) indicated the translocation of ALK (2p23) chromosome. After 2 cycles of docetaxel+cisplatin (DP) regimens chemotherapy, disease progression occurred, so we used 6 cycles of pemetrexed+carboplatin to apply combination chemotherapy, 4 cycles of pemetrexed monotherapy were used after that. The efficacy evaluation: PR. On April 9, 2016, the patient was treated with crizotinib. In August 2019, multiple intracranial metastases were found and whole brain radiotherapy was given. Since September 4, 2019, oral administration of nsatinib has been carried out. As of March 1, 2021, the patients were followed up well.@*CONCLUSIONS@#The advanced ALK fusion positive lung adenocarcinoma patients, though the first-line and the second-line chemotherapy, and the follwing application of ALK-TKI treatment, has procured a total OS has reached 68 months, and the current follow-up is good.
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Objective:To investigate the efficacy of anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKI) in treatment of inflammatory myofibroblastic tumor (IMT).Methods:The clinicopathological data of one recurrent abdominal IMT patient in Renmin Hospital of Wuhan University in 2018 were retrospectively analyzed. The clinicopathological and molecular characteristics, ALK-TKI treatment efficacy and prognosis of 41 patients with IMT reported in the literature from January 2010 to August 2020 were systematically reviewed.Results:This patient with abdominal IMT in Renmin Hospital of Wuhan University was a 27-year-old female who relapsed 2 months after surgery. Chemotherapy combined with bevacizumab was ineffective. After oral administration of crizotinib, the condition resolved after 1 month, and complete remission (CR) was achieved after 29 months. The median age of onset of 41 IMT cases reported in the literature was 22 years old (0-61 years old), of which 32 cases (78.0%) had multiple organ involvement, all of which had recurrence or metastasis. There were 38 cases of ALK mutation and 3 cases of TFG-ROS1 fusion gene-positive. Thirty-four patients treated with crizotinib in the first-line treatment of ALK-TKI, and the median resistance time of crizotinib was 8 months (2-48 months). The total clinical benefit rate of ALK-TKI was 85.3% (29/34), and 20 patients achieved CR. The median time for the first CR was 11 months (4-36 months), and the median duration time of medication for CR patients was 19.5 months (2-60 months). The median progression-free survival (PFS) time of 24 patients who underwent surgery and/or chemotherapy and radiotherapy was 4 months (1-45 months); after progression, ALK-TKI treatment was performed, and the median PFS time was 14 months (3-62 months).Conclusions:IMT is a true neoplasm with characteristics of recurrence and metastasis. Reasonable combination of ALK-TKI with surgery, radiotherapy and chemotherapy can improve the prognosis of IMT patients.
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ABSTRACT The concomitant epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) translocations in lung adenocancers are very rare scenarios. Until now, 42 cases described in the literature have all been treated by different drugs. There is no overall consensus regarding the treatment for this adenocarcinoma subgroup. We report here a case of lung adenocarcinoma with concomitant EGFR mutation in exon 21 (L858R) and ALK rearrangement in primary tumour, EGFR mutation in exon 21 (L858R) and no ALK rearrangement in its synchronous metastasis. We treated this patient with crizotinib as the second-line therapy (after the first line docetaxel-cisplatin chemotherapy), but no response was obtained. The therapeutic choice for the lung adenocancer patients with concomitant EGFR mutation and ALK rearrangement is unclear. Examination of c-ros oncogene 1 mutation can be used as an indicator in the prediction of the crizotinib treatment success. The ALK mutation may not responsible for the resistance to EGFR-tyrosine kinase inhibitors (TKI), and EGFR-TKI can be initiated to EGFR and ALK dual mutant patients as the first treatment.
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Humans , Female , Middle Aged , Adenocarcinoma/genetics , Genes, erbB-1/genetics , Lung Neoplasms/genetics , Mutation/genetics , Adenocarcinoma/drug therapy , Exons/genetics , Cisplatin/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Docetaxel/therapeutic use , Crizotinib/therapeutic use , Lung Neoplasms/drug therapy , Antineoplastic Agents/therapeutic useABSTRACT
BACKGROUND@#Anaplastic lymphoma kinase (ALK) positive in non-small cell lung cancer (NSCLC) was about 5%-7% and ALK tyrosine kinase inhibitor (TKI) was the standard treatment in NSCLC. The aim of this study is to evaluate the efficacy and safety of crizotinib in patients with advanced ALK gene-positive or recurrent NSCLC.@*METHODS@#Three methods were used to screen patients with advanced or recurrent NSCLC harboring ALK gene fusion/translocation. The patients with ALK positive tested by flourescence in situ hybridization (FISH) was given orally crizotinib, 250 mg, bid. The objective response rate (ORR), progression-free survival (PFS) and safety were evaluated.@*RESULTS@#A total of 226 patients were screened, 39 of whom had ALK fusion or translocation, and 37 were enrolled in the study. 35 patients were evaluated for objective response, ORR was 70.3%, and disease control rate (DCR) was 94.6%, and median PFS was 11.8 mon. The main adverse reactions were elevated transaminase (Grade 1, 91.7%), elevated transaminases (Grade 2, 23.4%), nausea (Grade 1, 75.6%), anemia (Grade 1-2, 62.3%), visual impairment (Grade 1, 21.8%), weight loss (Grade 1, 31.4%), pneumonia (Grade 2, 3.5%).@*CONCLUSIONS@#Crizotinib can be used for the treatment of advanced NSCLC with ALK fusion/translocation. It is highly effective and well tolerated.
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OBJECTIVE： To observe the efficacy and safety of crizotinib in the treatment of anaplastic lymphoma kinase （ALK） positive advanced lung adenocarcinoma. METHODS： From Aug. 2015 to May 2017， 72 patients with ALK positive advanced lung adenocarcinoma were selected from our hospital. According to the simple random method， the patients were divided into control group and observation group， with 36 patients in each group. The control group was given Pemetrexed disodium for injection 500 mg/m2，d1， ivgtt+ Cisplatin for injection 75 mg/m2，d1-3，ivgtt； Dexamethasone acetate tablets 0.75 mg were given orally one day before administration， once in the morning and again in the evening； 7 days before administration， Folic acid tablets 0.4 mg were given orally till 21 days after the last administration of cisplatin； Vitamin B12 1 mg injection was injected intramuscularly every 3 weeks after intramuscular injection of cisplatin. Isotonic Glucose injection 100 g was intravenously dripped 1 day before medication； on the day of chemotherapy， isotonic Sodium chloride injection or Glucose injection was infused intravenously for 3 000-3 500 mL； at the same time， Potassium chloride injection 0.5 g， Mannitol injection 50 g， Furosemide injection 20 mg were given to ensure daily urine volume of 2 000-3 000 mL； a treatment course lasted for 21 d， and there were 2 courses in total. Observation group was additionally given Crizotinib capsules 250 mg orally， once at 7：00 in the morning and evening， swallowing whole capsule， not chewed or dissolved， for 42 days. The clinical efficacies， survival quality and the occurrence of toxic reaction were observed in 2 groups. RESULTS： Total response rate （61.11％） and stable rate of survival quality （83.33％） in observation group were significantly higher than those （27.78％， 44.44％） of control group （P＜0.05）； incidence of grade Ⅰ-Ⅳ myelosuppression， gastrointestinal reaction， abnormal liver function， peripheral neuritis and alopecia in observation group were significantly lower than those of control group； incidence of grade Ⅰ-Ⅳ visual effect in observation group was significantly higher than control group（P＜0.05）. There was no statistical significance in the incidence of edema between 2 groups（P＞0.05）. CONCLUSIONS： Based on routine chemotherapy， additional application of crizotinib can significantly improve therapeutic efficacy of patients with advanced ALK positive lung adenocarcinoma， and effectively improve survival quality of patients without increasing the occurrence of toxic reaction of other tissues or organs， but the incidence of toxic reaction is in high level relatively.
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Objective: To investigate the prognostic value of chest computed tomography (CT) characteristics in crizotinib-treated pa-tients with advanced non-small cell lung cancer (NSCLC). Methods: Forty-seven patients with advanced ALK-rearranged NSCLC who re-ceived crizotinib treatment from January 2014 to March 2017 were enrolled in this retrospective study. Pre-treatment CT characteris-tics were evaluated. Patients were followed up after crizotinib treatment, and the best overall response and progression-free survival (PFS) were assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Results: The median PFS of all patients was 10 months. There was no association between CT characteristics and response. In univariate analysis, large tumor size (P=0.009), central type (P=0.002), consolidation of surrounding lung tissue (P=0.002), pleural effusion (P=0.001), and lymphangitic carcino-matosis (P=0.019) suggested a poor prognosis. Multivariate Cox regression analysis showed that location (hazard ratio, 3.219; 95% con-fidence interval: 1.517-6.833; P=0.002) was an independent prognostic predictor. Conclusions: Pre-treatment CT characteristics are useful in predicting the PFS of crizotinib-treated patients with advanced NSCLC harboring ALK rearrangement.
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The incidence of ROS1 gene rearrangement/fusion in non-small cell lung cancer (NSCLC) is about 1%-2%. The advent of tar-geted drugs for ROS1 gene fusion has significantly improved the quality of life and total survival of NSCLC patients with ROS1 fusion;however, acquired drug resistance is still present in most patients after continuous treatment. This review has summarized the back-ground of the ROS1 fusion gene, detection method, clinical efficacy of ROS1-targeted therapy, and strategy and prospect of drug resis-tance.
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Recently, targeted therapy has achieved great success in the treatment of non-small cell lung cancer (NSCLC) patients. Mesenchymal to epithelial transition factor (MET) is considered to be another important molecular target for NSCLC since epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). Accumulating clinical trials and case reports have confirmed that MET inhibitors exhibited a potential prospect in treating patients with MET 14 exon skipping alterations, suggesting that MET 14 exon skipping mutation might be an effective biomarker for MET inhibitors, which remains to be confirmed by more clinical data. This review summarizes current research about the molecular mechanism, clinicopathological characterization, treatment strategies and drug resistance mechanisms of MET 14 exon skipping alterations in NSCLC. .
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Humans , Carcinoma, Non-Small-Cell Lung , Drug Therapy , Genetics , Exons , Genetics , Lung Neoplasms , Drug Therapy , Genetics , Molecular Targeted Therapy , Mutation , Proto-Oncogene Proteins c-met , GeneticsABSTRACT
PURPOSE: Crizotinib has demonstrated superior progression-free survival (PFS) and objective response rates (ORRs) versus chemotherapy in previously treated and untreated patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). We report the safety and efficacy of crizotinib in Asian subpopulations of two global phase III trials. MATERIALS AND METHODS: This analysis evaluated previously treated and untreated patients in two randomized, open-label phase III trials of crizotinib versus chemotherapy in ALK-positive advanced NSCLC in second-line (PROFILE 1007) and first-line settings (PROFILE 1014). Efficacy and safety were analyzed by race in the intention-to-treat and “as-treated” populations for efficacy and safety endpoints, respectively. RESULTS: In previously treated (n=157) and untreated (n=157) Asian patients, PFS was statistically significantly longer with crizotinib versus chemotherapy (hazard ratio for PFS, 0.526; 95% confidence interval, 0.363 to 0.762; p < 0.001 and hazard ratio, 0.442; 95% confidence interval, 0.302 to 0.648; p < 0.001, respectively). Similar antitumor activity was seen in the non-Asian and overall populations. ORRs were statistically significantly higher with crizotinib versus chemotherapy in both Asian and non-Asian previously treated and untreated patients (p < 0.05). The most common treatment-emergent adverse events (any grade)with crizotinib were vision disorder, diarrhea, and nausea, which were observed at a comparable incidence across Asian and non-Asian populations, irrespective of previous treatment status. Most adverse events were mild to moderate in severity. CONCLUSION: These data, currently the only analysis showing Asian and non-Asian populations in the same study, support the efficacy and safety of crizotinib in Asian patients with previously treated or untreated ALK-positive advanced NSCLC.
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Humans , Asia , Asian People , Carboplatin , Carcinoma, Non-Small-Cell Lung , Cisplatin , Racial Groups , Diarrhea , Disease-Free Survival , Drug Therapy , Incidence , Lymphoma , Nausea , Pemetrexed , Phosphotransferases , Vision DisordersABSTRACT
PURPOSE: Anaplastic large cell lymphoma (ALCL) is a rare aggresive non-Hodgkin lymphoma, of which over 50% of cases have an aberrant nucleophosmin (NPM)‒anaplastic lymphoma kinase (ALK) fusion protein. Both mechanistic target of rapamycin (mTOR) inhibitor everolimus and ALK inhibitor crizotinib have shown promising antitumor activity in ALK-positive cancer cell lines. However, their combined effect has not yet been investigated. MATERIALS AND METHODS: We evaluated the anti-proliferative effects of everolimus and/or crizotinib in ALK-positive ALCL cell lines, Karpas 299 and SU-DHL-1, and lung adenocarcinoma cell line, NCI-H2228. RESULTS: We found that individually, both everolimus and crizotinib potently inhibited cell growth in a dose-dependent manner in both Karpas 299 and SU-DHL-1 cells. A combination of these agents synergistically inhibited proliferation in the two cell lines. Crizotinib down-regulated aberrant AKT and ERK phosphorylation induced by everolimus. Combination treatment also significantly increased G0/G1 cell-cycle arrest, DNA damage, and apoptosis compared with everolimus or crizotinib alone in ALK-positive ALCL cells. In the Karpas 299 xenograft model, the combination treatment exerted a stronger antitumor effect than monotherapies, without significant change in body weight. The synergistic effect of everolimus and crizotinib was also reproduced in the ALK-positive lung adenocarcinoma cell line NCI-H2228. The combination treatment abrogated phosphoinositide 3-kinase/AKT and mTOR signaling pathways with little effect on the Ras/ERK pathway in NCI-H2228 cells. CONCLUSION: Crizotinib combinedwith everolimus synergistically inhibits proliferation of ALK-positive ALCL cells. Our results suggest that this novel combination is worthy of further clinical development in patients with ALK-positive ALCL.
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Humans , Adenocarcinoma , Apoptosis , Body Weight , Cell Line , DNA Damage , Everolimus , Heterografts , Lung , Lymphoma , Lymphoma, Large-Cell, Anaplastic , Lymphoma, Non-Hodgkin , Phosphorylation , Phosphotransferases , Sirolimus , TOR Serine-Threonine KinasesABSTRACT
The molecular target therapy of non-small cell lung cancer (NSCLC) has become a hot research direction in the field of medicine.Following the discovery of well-known tumor-driven genes such as epidermal growth factor receptor (EGFR),Kirsten rat sarcoma viral oncogene (KRAS) and anaplastic lymphoma kinase (ALK) genes,more and more scholars have shifted focus to ROS1 fusion gene.The protein encoded by ROS1 is a member of the receptor tyrosine kinase super family,and it plays an important role in cell growth and cell survival.ROS1 fusion gene plays a vital role in the occurrence,development and clinical treatment of NSCLC.
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Objective@#To explore the synergistic effect of silibinin combined with crizotinib on anaplastic lymphoma kinase positive (ALK+ ) non-small cell lung cancer (NSCLC) cells and its mechanism.@*Methods@#H2228 and H3122 cells were treated with silibinin, crizotinib alone or in combination. Cell proliferation was measured by 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and colony formation assay. Migration or invasion ability was tested by wound healing assay or transwell assay, respectively. Expressions of E-Cadherin and vimentin protein were examined by immunofluorescence staining. The protein expressions of ALK, p-ALK, E-Cadherin and Vimentin were detected by western blotting.The anti-cancer effect of silibinin combined with crizotinib in vivo was determined by subcutaneously injecting 2×106 H2228 cells into immunodeficient nude mice.@*Results@#The result of MTT assay showed that the cell viability of H2228 or H3122 treated with 100 μmol/L silibinin was (88.38±4.10)% or (72.27±3.62)%, respectively, marginally decreased compared with that of the control. The 50% inhibitory concentration (IC50) of H2228 cells treated with crizotinib alone or combined with 100 μmol/L silibinin was (917.10±7.75) nmol/L or (238.73±7.67) nmol/L, respectively. The IC50 of H3122 cells treated with crizotinib alone or combined with 100 μmol/L silibinin was (472.50±15.70) nmol/L or (206.10±12.01) nmol/L, respectively. The IC50s of H2228 and H3122 cells were significantly decreased by combined treatment of crizotinib and silibinin compared to crizotinib treatment alone (P<0.01). When compared with the control group, colony forming ratios of H2228 cells were (83.34±2.72)% in 100 μmol/L silibinin treatment group, (69.42±3.06)% in 400 nmol/L crizotinib treatment group and (27.32±1.42)% in combined treatment group. When compared with the control group, colony forming ratios of H3122 cells were (84.45±5.67)% in 100 μmol/L silibinin treatment group, (45.02±5.83)% in 400 nmol/L crizotinib treatment group and (17.43±3.83)% in combined treatment group. Silibinin combined with crizotinib treatment significantly inhibited the colony formation ability of H2228 and H3122 cells (P<0.01). Migration and invasion results showed that combined treatment of crizotinib and silibinin markedly inhibited the migration and invasion ability of H2228 cells (P<0.01). Western blot results indicated that treated with silibinin alone or in combination of crozitinib for 48 hours, the protein level of E-cadherin in H2228 cells was upregulated, while the expressions of p-ALK and vimentin were downregulated, without obvious alteration of ALK protein expression. In the xenograft model, the mean tumor weight was (9.40±2.58)g in crizotinib treatment group and (4.58±1.07)g in the combined treatment group. The inhibitory effect of tumor growth in vivo of combined treatment was significantly superior to that of crizotinib treatment alone (P<0.05).@*Conclusion@#Silibinin enhances the inhibitory effect of crizotinib on ALK positive NSCLC cells, which may be associated with suppression of ALK activity and mesenchymal-epithelial transition.
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Objective To investigate the efficacy and safety of crizotinib in patients with advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC),and focuse on analysis of its prognostic factors.Methods Fifty patients with advanced (stage m B-Ⅳ) ALK-positive NSCLC confirmed by cytology or histology in Peking Union Medical Collage Hospital from January 2013 to September 2016 were collected.The relevant clinical imformation and treatment protocols were recorded.The efficacy and safety of crizotinib were followed up,and its prognostic factors were analyzed.Results At the end of follow-up,the median progression free survival (PFS) of progressed patients (n =24) was 9.6 months (95％ CI:8.3-10.9 months),of which five patients died.The median follow-up time of non-progressed patients (n =26) was 10.7 months.The most common adverse event was abnormal liver function (48.0％,24/50).In the single factor analysis of Kaplan-Meier,younger or equal to 40 years old patients had a longer PFS (P =0.017),and the COX regression analysis (Enter method) also had statistical significance differences (HR =6.1,95％ CI:1.4-27.5,P =0.018).However,gender (HR =0.8,95％ CI:0.2-2.6,P =0.697),smoking history (HR =1.5,95％ CI:0.4-5.6,P =0.524),pathology (HR =1.1,95％ CI:0.3-4.2,P =0.922),tumor stage (HR =1.7,95％ CI:0.4-8.4,P =0.502),epidermal growth factor receptor (EGFR) mutant type (HR =0.4,95％ CI:0.4-4.3,P =0.461),EGFR unknown (HR =1.3,95％ CI:0.3-6.1,P =0.727),Eastern Cooperative Oncology Group Performance Status (ECOG) PS score (HR =2.0,95％ CI:0.6-6.8,P =0.290),the status of previous treatment (HR =0.6,95％ CI:0.2-1.8,P =0.385) and brain metastasis (HR=0.7,95％CI:0.1-3.2,P=0.628) were not associated with disease progression Conclusion Crizotinib has good efficacy and is safe and well-tolerated to advanced ALK-positive NSCLC patients,and age is the independent prognostic factor.
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Objective To explore the expression of anaplastic lymphoma kinase(ALK) in human ovarian serous adenocarcinoma cell line SKOV3 and to further investigate the effect of crizotinib on SKOV3 cells.Methods The expression of ALK in SKOV3 cells were examined by Western blotting and immunocytochemical methods,and the effect of ALK inhibitor crizotinib on proliferation of SKOV3 cells were evaluated by cell proliferation assay.Results Both Western blotting and immunocytochemical methods showed the expression of ALK in SKOV3 cells.The results of cell proliferation assay suggested that the cell viability of SKOV3 cells was close to 1 when the drug concentration was less than 106 nmol·L-1,and close to 64% when the drug concentration was up to 107nmol·L-1.Conclusion ALK is overexpressed in human ovarian serous adenocarcinoma cell line SKOV3,but SKOV3 cells were insensitive to the therapy of ALK inhibitor crizotinib.
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Anaplastic lymphoma kinase (ALK)-positive diffuse large B-cell lymphoma (DLBCL) is a rare and distinct variant of DLBCL. It is classified as a unique subtype of DLBCL in the 2008 WHO classification of lymphomas. No standard and effective therapeutic regi-men is available for ALK+DLBCL because it shows a more aggressive clinical course and frequent relapse. Therefore, a standardized and individualized treatment is needed to benefit more patients diagnosed with ALK+DLBCL through a multiple disciplinary team. This arti-cle presents a case of an ALK+DLBCL patient who relapsed after transplantation and was successfully treated with the ALK kinase inhibi-tor Crizotinib.
ABSTRACT
Objective To screen 8 series of LY compounds, c-Met tyrosine kinase inhibitors, and evaluate their anti-tumor effects in vitro and in vivo. Methods Preliminary screening was carried out by detecting the c-Met kinase phosphor?ylation inhibition activity of the compounds. CCK-8 assay was adopted for secondary anti-tumor screen of the selected com?pounds using MKN-45, U87MG, Caki-1 and PC-3 cell lines in vitro. The transplanted tumor model of U87MG cells in nude mice was established to evaluate the antitumor activity in vivo. Results Four compounds (LY22, LY25, LY28 and LY32) with better activities were selected by HTRF method, in which LY28 had better inhibitory effect on c-Met than that of Crizo?tinib. The above active compounds showed different degrees of inhibition on the four kinds of target cells (MKN-45, U87MG, Caki-1 and PC-3) detected by CCK-8 method, and the inhibitory effect of LY28 showed the most obvious. Antitumor activi?ty in vivo showed that LY28 can significantly inhibited tumor growth in a dose-dependent manner. The tumor inhibitory rate in high-dose of LY28 was 78.13%. Conclusion The compound LY28 has good antitumor activity in vitro and in vivo, which will be a new tyrosine kinase inhibitor.