ABSTRACT
Alectinib, an inhibitor of anaplastic lymphoma kinase (ALK), was approved by the Food and Drug Administration (FDA) for the treatment of patients with ALK-positive non-small cell lung cancer (NSCLC). Here we investigated the reversal effect of alectinib on multidrug resistance (MDR) induced by ATP-binding cassette (ABC) transporters, which is the primary cause of chemotherapy failure. We provide the first evidence that alectinib increases the sensitivity of ABCB1- and ABCG2-overexpressing cells to chemotherapeutic agents in vitro and in vivo. Mechanistically, alectinib increased the intracellular accumulation of ABCB1/ABCG2 substrates such as doxorubicin (DOX) and Rhodamine 123 (Rho 123) by inhibiting the efflux function of the transporters in ABCB1- or ABCG2-overexpressing cells but not in their parental sensitive cells. Furthermore, alectinib stimulated ATPase activity and competed with substrates of ABCB1 or ABCG2 and competed with [125I] iodoarylazidoprazosin (IAAP) photolabeling bound to ABCB1 or ABCG2 but neither altered the expression and localization of ABCB1 or ABCG2 nor the phosphorylation levels of AKT and ERK. Alectinib also enhanced the cytotoxicity of DOX and the intracellular accumulation of Rho 123 in ABCB1-overexpressing primary leukemia cells. These findings suggest that alectinib combined with traditional chemotherapy may be beneficial to patients with ABCB1- or ABCG2-mediated MDR.
Subject(s)
Humans , Adenosine Triphosphatases , Carcinoma, Non-Small-Cell Lung , Doxorubicin , Drug Resistance, Multiple , Drug Therapy , In Vitro Techniques , Leukemia , Lymphoma , Parents , Phosphorylation , Phosphotransferases , Rhodamine 123 , United States Food and Drug AdministrationABSTRACT
BACKGROUND:Static cold storage is the main storage method of liver transplantation in the past 40 years. There are success cases in foreign countries about the use of mechanical reperfusion in liver transplantation, but there is no large-scale development in China. OBJECTIVE:To investigate and compare the inflammatory cytokines and apoptotic factors in isolated liver between static cold storage and hypothermic machine perfusion before and after liver transplantation. METHODS:There were donor group, static cold storage group and hypothermic machine perfusion group in the study, and 30 dogs were in each group. Liver specimens from donor dogs were subjected to static cold storage and then transplanted into dogs in the static cold storage group. Liver specimens from dogs in the static cold storage group were subjected to hypothermic machine perfusion and then transplanted into dogs in the hypothermic machine perfusion group. Liver specimens from dogs in the hypothermic machine perfusion were used in other experiments. Dogs in the donor group were euthanatized. After liver transplantation, 20 dogs from static cold storage group and hypothermic machine perfusion group were selected respectively for further study. RESULTS AND CONCLUSION: When the liver was separated from the dogs, inflammatory cytokines and apoptosis factors had no significant difference in the static cold storage group and hypothermic machine perfusion group (P > 0.05). P53 expression in these two groups had no significant difference before and after transplantation (P > 0.05). Interleukin-1βand interleukin-8 in these two groups had no significant difference before transplantation (P > 0.05). Compared with the static cold storage group, expressions of tumor necrosis factor-α, macrophage inflammatory protein-1α, macrophage inflammatory protein-1β, CC chemokine ligand 20 and FASR were significantly lower in the hypothermic machine perfusion group before transplantation (P< 0.01). Compared with the static cold storage, interleukin-1β, tumor necrosis factor-α, interleukin-8, macrophage inflammatory protein-1α, macrophage inflammatory protein-1β, CC chemokine ligand 20, FASR and nuclear factor-κB were reduced significantly in the hypothermic machine perfusion group at 60 minutes after transplantation (P < 0.01). Taken together, hypothermic machine perfusion can significantly reduce inflammatory cytokines and apoptosis factor, which is conducive for liver transplantation.
ABSTRACT
<p><b>OBJECTIVE</b>To apply low-dose multi spiral computed tomography (MSCT) chest scans in the early diagnosis and differential diagnosis of pneumoconiosis.</p><p><b>METHODS</b>One hundred and twenty dust-exposed volunteers were examined by MSCT chest scans at conventional dose and low dose, and the results of conventional-dose scans were set as the gold standard. Comparative analysis was performed on the major CT findings and quality of post-processing images, including 1.5 mm and 5.0∼10.0 mm thick high -resolution reconstructed images, multiplanar reformat images, and maximum intensity projection images.</p><p><b>RESULTS</b>One hundred and twenty cases of small circular shadows, 36 cases of ribbon shadows in pulmonary parenchyma, 1 case of honeycombing shadow, and 13 cases of big shadows were all showed on low -dose MSCT. But 94 (95.9%) of 98 cases of interlobular septal thickening shadows and 98 (93.3%) of 105 cases of short branched shadows were detected on low-dose MSCT. There were no significant differences in display of the mentioned large and small shadows between low-dose scans and conventional-dose scans (P > 0.05). Eighty-five cases of small airway disease, 8 cases of pulmonary inflammatory lesions, and 47 cases of hilar and mediastinal lymph node swelling were all detected by MSCT. As for the 46 cases of emphysema, 38 (82.6%) were shown. The low-dose MSCT images of 1.5 mm thickness had more artifacts than those of other thickness. The radiation dose of low-dose MSCT was about 1/3-1/5 of that in the conventional-dose MSCT.</p><p><b>CONCLUSION</b>There is no difference in display of pneumoconiosis between low-dose and conventional-dose MSCT chest scans. With lower radiation dose, low-dose MSCT can be applied in the diagnosis of pneumoconiosis.</p>
Subject(s)
Adult , Aged , Female , Humans , Male , Middle Aged , Dust , Lung , Diagnostic Imaging , Occupational Exposure , Pneumoconiosis , Diagnostic Imaging , Tomography, X-Ray Computed , MethodsABSTRACT
Background and purpose:Ever since the use of anthracycine and /or taxanes-based regimen for the adjuvant and/or neoadjuvnat chemotherapy of breast cancer,there have few sensitive agents for advanced breast cancer(ABC)when it occurs drug resistance to anthracycine and /or taxanes.The aim of this study is to evaluate the effect of gemcitabine plus cicplatin in advanced breast cancer after the failure of treatment with anthracycines and /or taxanes.Methods:From May,2005 to Jan 2007,34 ABC cases with anthracycine and/or taxanes resistance were treated with GEM(1000 mg/m2.day1,day8)and DDP(30 mg/m2,day 1 to day 3)every 3 weeks.A median of 5 cycles(2-6 cycles)of the treatment was delivered.All cases were followed up more than 6 months.Results:3 cases(8.8%)had complete response(CR),13 cases(38.2%)had partial response(PR),while 12 cases(35.3%)had stable disease(SD)and progressive disease(PD)was 6 cases(17.7%);the overall response rate was 47.0%.The median time to progression(TTP)was 6.5 months,grade 3/4 diarrhoea and thrombocytopenia were main side effects.Conclusions:GEM plus DDP are effective in the treatment of advanced breast cancer with anthracycine and/or taxanes resistance.
ABSTRACT
<p><b>BACKGROUND</b>To evaluate the efficacy and toxicity of concomitant chemoradiotherapy in patients with brain metastases from non-small cell lung cancer (NSCLC).</p><p><b>METHODS</b>Thirty patients suffering from NSCLC with brain metastasis were prospectively included in this study. Twenty-four patients had neurological symptoms and an ECOG performance index between 0 and 3. Treatment consisted of concomitant whole brain radiotherapy (WBRT) with a dose of 30 Gy in 15 fractions, followed by a local boosted dose of 20 Gy in 10 fractions for those that the number of the remained lesions were less than 3, or by WBRT with a total dose of 50 Gy for those that the number of the remained lesions were more than 3. Concomitant chemotherapy of FVP regimen with floxuridine 600 mg/(m²*d), teniposide 60 mg/(m²*d), cisplatin 20 mg/(m²*d) on d1 to d5,repeating every 3 or 4 weeks. The response was evaluated by brain CT or MRI after WBRT and 2 cycles of chemotherapy being completed.</p><p><b>RESULTS</b>All the patients completed WBRT and concomitant chemotherapy including 68 cycles (2 to 4 cycles for each patient). The follow-up rate was 93.3% with a median survival duration of 11.3 months. Total response rate was 46.7%, with CR for 2 and PR for 12. Specific evaluation of brain response demonstrated CR for 8 patients, and PR for 10 patients (the objective brain response rate, 60.0% ). The objective primary disease response rate was 18% for 22 cases of previously untreated primary NSCLC. Other specific evaluation of metastases included 1 PR patient in 6 patients with lung metastases, 3 CR patients and 4 PR patients in 17 patients with lymph node metastases, 1 PR patient with liver metastases, and 1 PR patient with eye metastasis. Twenty four patients with neurological symptoms benefited improvements to different extent. The main adverse effects were myelotoxicity, nausea/vomiting, constipation and alopecia. Grade III and IV toxicities were observed as following: leucopenia (19.1%), anemia (10.3%), thrombocytopenia (7.4%), nausea/vomiting (4.4%), diarrhea (2.9%), alopecia (5.9%), glutamio oxaloacetic transaminase (GOT) and glutamio pyruvic transaminase (GPT) elevation (1.5%). Dehydration therapy was needed at 2 weeks after WBRT in all patients.</p><p><b>CONCLUSIONS</b>Concomitant WBRT plus FUDR+VM-26+DDP chemotherapy is tolerable in NSCLC patients with brain metastases and the short term response is comparable to the results of others.</p>