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    • br Non small cell lung cancer

    2018-10-25


    Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers. NSCLC is frequently diagnosed at a late stage and has a high mortality rate. Genetic mutations in DNA found in the serum of patients with NSCLC were first observed in 1998. The ErbB family of tyrosine kinases includes epidermal growth factor receptor (EGFR), HER2, ErbB3 and ErbB4. Dysregulation of these tyrosine kinases and their downstream PI3K/AKT pathway is implicated in cancer cell metastasis, proliferation and angiogenesis. EGFR signaling is triggered by the binding of growth factors, such as epidermal growth factor (EGF), resulting in the dimerization of EGFR molecules or heterodimerization with other closely receptors (e.g. HER2/neu). Autophosphorylation and transphosphorylation of the receptors through their tyrosine kinase domains cause the recruitment of downstream effectors and the activation of proliferative and cell-survival signals. Exon 19 Apicidin manufacturer (Del19) and exon 21 Leu858Arg substitution (L858R) account for 90% of EGFR mutations as common mutations. Although activating EGFR mutations occur in only 1–3% of patients with NSCLC, the ErbB family still represents a rational therapeutic target. EGFR-TKIs are used for the first-line treatment of advanced NSCLC and activating EGFR mutations. Patients with EGFRm+ could achieve good responses to the treatment with the first-generation EGFR-TKIs, such as erlotinib and gefitinib. The use of EGFR-TKIs was associated with dramatic, durable, and tolerable responses and side effect profiles when applied to the palliation of advanced EGFRm+ NSCLC. However, despite initial benefit, the majority of patients treated with anEGFR-TKI developed resistance to therapy within about 12 months, approximately 50% of patients due to a second-site mutation, the T790M mutation occurring within exon 20. Clinical trials have shown that EGFR-TKIs did not improve the survival of patients with EGFRm+ NSCLC because of the high crossover of treatments. Zhao et al. putforward that EGFR-TKI therapy was an independently prognostic factor for NSCLC with mutated EGFR. A more effective therapy was needed for patients with wild-type EGFR. Gefitinib targeted the ATP cleft within the tyrosine kinase, which was overexpressed in 40 to 80 percent of NSCLC and many other epithelial cancers .
    Molecular targeted therapy for FLT3-ITD mutation in acute myeloid leukemia Acute myeloid leukemia (AML) has achieved a high prevalence of complete remission (CR) with the gold standard for induction chemotherapy using daunorubicin and cytarabine. However, 20–30% AML patients harbor an internal tandem duplication mutation of the FMS-like tyrosine kinase receptor (FLT3-ITD mutation). FLT3 is a proto-oncogene involved in crucial steps of haematopoiesis such as proliferation, differentiation and survival. FLT3 mutations have been associated with the clinical prognosis, treatment and survival of patients. The most common form of FLT3 mutation is internal tandem duplication (ITD) that promotes ligand-independent auto-phosphorylation and constitutive activation of the receptor. The CR rate was lower and the overall and disease-free survival was shorter than those of non-FLT3-ITD AML patients. Homoharringtonine (HHT) was a natural alkaloid and used in China for the treatment of hematological diseases for the past 30years. It may work in the way of inhibiting protein synthesis by preventing the initial elongation step of protein synthesis via an interaction with the ribosomal A-site and by reducing p-eIF4E levels. This leaded to a rapid loss of proteins with short half-lives such as c-Myc, Mcl-1 and CyclinD1. HHT has been reported to act against AML, MDS and CML cells. In an open-label, randomized, controlled phase III study performed by Xia Li’s group, with the homoharringtonine-based induction regimen HAA (homoharringtonine, cytarabine and aclarubicin), it showed 73% of patients (150/206) with AML (non-acute promyelocytic leukemia (APL)) achieved CR, which was significantly higher than that in the DA (daunorubicin and cytarabine) group (61%, 125/205). Also, 40 FLT3-ITD mutant patients were included and the HAA regimen showed good curative effect of treatment.