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Abstract: Platinum-based therapy is commonly used for the treatment of lung cancer and has been widely accepted by clinicians, but the chemotherapy responses differ greatly among individuals. TNFα/TNF-R1/R2 signal pathway can trigger the extrinsic pathway of apoptosis after DNA damage was caused by platinum-based treatment. The aim of this study was to investigate the association of TNFα -308 A/G, TNF-R1 -383A>C, -609T>G and TNF-R2 +676 T>G and the response of platinum-based chemotherapy in 313 Chinese advanced-stage non-small-cell lung cancer (NSCLC) patients. MassARRAY was used to detect these four SNPs in three apoptosis-related genes. TNFα -308 A/G was significantly correlated with better clinical benefit. Patients carrying A allele tended to have a favorable prognosis after treated with platinum-based chemotherapy (P=0.043, OR=0.488, 95%CI=0.244-0.979). The patients with CA genotype have significantly reduced risk of platinum resistance compared with wild-type homozygotes CC genotype (P=0.025, OR=0.447, 95% CI=0.220-0.906). No association was found in other polymorphisms. In conclusion, our data suggest that TNFα -308 A/G polymorphism may serve as the indicator of platinum-based chemotherapy response in NSCLC patients. Keywords: TNFα, TNF-R1, TNF-R2, chemotherapy response, genetic polymorphism, lung cancer.Download Full Article |
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Abstract: DNA double-strand breaks (DSBs) can lead to genomic instability and cancer susceptibility if unrepaired. EME1 is one of the key proteins that participate in the recognition and repair of DSBs in humans. We hypothesized that the exonic variants of EME1 are associated with lung cancer risk. In a two-stage case-control study of 1559 lung cancer patients and 1679 cancer-free controls, we genotyped two exonic variants of EME1(Glu69Asp: rs3760413T>G and Ile350Thr: rs12450550T>C) and analyzed their associations with risk of lung cancer. We found that the Asp variant genotypes conferred 1.35-folds risk of lung cancer compared to the Glu/Glu genotype (OR = 1.35, 95%CI = 1.18-1.56, P = 2.18 × 10-5) in both stages. However, the SNP Ile350Thr was not confirmed to be associated with cancer risk in both stages. Moreover, by querying the gene expression database, we further found that the 69Asp variant genotypes confer a significantly lower mRNA expression of EME1 than the Glu/Glu genotype in 260 cases of lymphoblastoid cells (P=0.013). Our findings suggested that the SNP Glu69Asp of EME1 is associated with an increased risk of lung cancer, and may be a functional biomarker to predict lung cancer risk in Chinese. Validations in other ethnics are warranted. Keywords: Lung cancer, EME1, exonic variant, functional biomarker.Download Full Article |
Editor’s Choice : An Audit to Evaluate the Clinical Safety and PSA Response of Firmagon® (Degarelix) in Patients with Advanced Metastatic Prostate Cancer
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Abstract: Objectives: To evaluate the clinical safety and PSA response in patients with metastatic prostate cancer being treated with Firmagon® (Degarelix) and to assess the drug's safety profile. Patients and Methods: This was an audit of 35 patients with PSA levels >50 and advanced metastatic prostate cancer at presentation who received Firmagon® (Degarelix) as per our North East & Cumbria Cancer Drug Approvals Group (NECDAG), UK guidelines. The audit was conducted using results from three hospitals in North East England with an aim to evaluate the safety profile, clinical and PSA response with this new drug. Baseline symptoms at diagnosis, presenting PSA and post treatment parameters on the commencement of with Firmagon® (Degarelix) were recorded. All patients in our cohort were homogenous having had not received any previous treatment including any form of LHRH analogue therapy. PSA levels were measured at 6 weekly intervals initially followed by 3 monthly intervals to evaluate initial and long term response to treatment withFirmagon® (Degarelix). Results: There was no incidence of anaphylaxis or injection site complications on immediate administration ofFirmagon® (Degarelix). No of our patients had renal or liver toxicity in our series. There was no incidence of tumour flare in any patient. A total of 23% of patients who presented primarily with severe bone pain described a complete resolution of Firmagon® (Degarelix) and required no adjuvant treatment such as bisphosphonates or palliative radiotherapy. A significant reduction in PSA levels were noted immediately at 6 weeks and 3 months following treatment with Firmagon® (Degarelix) (p=0.0038). Conclusions: Firmagon® (Degarelix) is a safe drug is well tolerated in patients with advanced metastatic prostate cancer. The reason of how bone pain completely resolves in some patients with extensive bone metastasis on the commencement of Firmagon® (Degarelix) needs to be evaluated. Keywords: Firmagon® (Degarelix), prostate cancer, PSA response, bone pain.Download Full Article |
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Abstract: Chemotherapy is one of the main therapies in cancer and plays an important role in controlling tumor progression, which can offer a longer overall survival (OS) for patients. But as the accumulation of drugs used in vivo, cancer cells develop drug resistance, even multi-drug resistance (MDR), that can cause failure of the whole therapy. The similar phenomenon can be observed in vitro. There are several mechanisms of drug resistance such as drug efflux, mediated by extracellular vesicles. Exosomes, a subset of extracellular vesicles (EVs), can be secreted by many types of cells and transfer proteins, lipids, and miRNA/mRNA/DNAs between cells in vitro and in vivo. Particularly cancer cells secrete more exosomes than healthy cells and resistance cells secrete more exosomes than sensitive cells. Exosomes have function of intercellular communication and molecular transfer, both associated with tumor growth, invasion, metastasis, angiogenesis, and drug resistance. In this paper, we will review the current knowledge regarding the emerging roles of exosomes and its cargo in drug resistance. Keywords: Exosomes, drug resistance, drug efflux, antibody, miRNAs, lncRNA, P-glycoprotein, EMT. Download Full Article |
Editor’s Choice : B5H7, a Morpholine Derivative of 23-Hydroxybetulinic Acid, Reverses Doxorubicin Resistance in HepG2/ADM
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Abstract: Multidrug resistance (MDR) is the major cause of the failure of cancer chemotherapy. Development of MDR reversers is an important strategy to improve the efficacy of cancer chemotherapy. Here, we have found a morpholine derivative of 23-hydroxybetulinic acid, B5H7, with a reversal effect on MDR cancer cells. Our studies showed that B5H7 enhanced cytotoxicity of doxorubicin, but no cisplatin in MDR cancer cells HepG2/ADM. And we found that B5H7 not only increased the intracellular accumulation of P-glycoprotein substrates doxorubicin and rhodamine123, but also reduced the efflux of rhodamine123 in HepG2/ADM cells. Further studies showed B5H7 did not alter the protein level of P-glycoprotein and it also had no effect on P-glycoprotein ATPase activity. Taken together, we have found that B5H7 could reverse doxorubicin resistance in HepG2/ADM cells by inhibiting the transport function of P-glycoprotein. These findings contribute to developing B5H7 as an adjuvant to anticancer chemotherapy with doxorubicin. Keywords: Doxorubicin resistance, ABC transporter, P-glycoprotein, 23-HBA derivative B5H7, HepG2/ADM.Download Full Article |