01);FCM显示联合组凋亡率增高,阻滞于G1期的细胞增多,S期明显减少(P0.05);LY294002组p-AKT水平降低,p-ERK水平增高;AZD6244组p-ERK水平降低,p-AKT水平增高;联合组p-AKT、p-ERK水平均降低,cyclin D1表达较其余各组低,激活型caspase-3较其余各组高。结论

PI3K抑制剂LY294002联合MEK抑制剂AZD6244通过促进细胞凋亡及阻滞细胞周期进展协同抑制SKOV3/DDP细胞生长。
PI3K/AKT/mTOR通路的异常活化在结直肠癌的发生发展中起到重要作用,以此通路为靶点的药物已成为结直肠癌治疗的研究热点,临床前和临床试验研究证明,针对PI3K/AKT/mTOR通路的多种抑制剂具有抗肿瘤活性。越来越多的临床数据显示,PTEN缺乏或PIK3CA基因突变对PI3K/AKT/mTOR通路抑制剂敏感,KRAS突变则预示着耐药;寻找针对这一通路抑制剂敏感的优势人群也成为结直肠癌的研究热点;此外,PI3K/AKT/mTOR通路也会影响常规治疗的疗效,因此PI3K/AKT/mTOR通路抑制剂联合细胞毒治疗方案在结直肠癌中可能起到协同作用。
Administration 因为 of monoclonal antibodies(mAbs)against epidermal growth factor receptor(EGFR)such as cetuximab and panitumumab in combination with conventional chemotherapy

substantially prolongs survival of patients with metastatic colorectal cancer(mCRC).However,the efficacy of these mAbs is limited due to genetic KU63794 variation among patients,in particular K-ras mutations.The discovery of K-ras mutation as a predictor of non-responsiveness to EGFR mAb therapy has caused a major change in the treatment of mCRC.Drugs that inhibit transformation caused by oncogenic alterations of Ras and its downstream components such as BRAF,MEK and AKT seem to be promising cancer therapeutics as single agents or when given with EGFR inhibitors.Although multiple therapeutic strategies to overcome EGFR mAb-resistance are under investigation,our understanding of their mode of action is limited.Rational drug development

based on stringent preclinical data,biomarker validation,and proper selection of patients is of paramount importance in the treatment of mCRC.In this review,we will 此网站 discuss diverse approaches to overcome the problem of resistance to existing anti-EGFR therapies and potential future directions for cancer therapies related to the mutational status of genes associated with EGFRRas-ERK and PI3K signalings.
为筛选到活性更好的抗肿瘤PI3K抑制剂,以2,4-二羟基吡啶为原料,经氯化后和吗啡啉反应、碘代、Sonogashira偶联、脱保护基与叠氮化反应得到三氮唑中间体8~13,最后经Suzuki反应,偶联上芳基得到2-芳基-4-吗啉-6-三氮唑基嘧啶14~27,其结构均经1HNMR和LC-MS确证。用MTT法评价了化合物14~27对PI3K高表达的人卵巢细胞A2780增殖的抑制活性,其中,在化合物测试浓度为10μmol/L时,14和25的抑制活性均高于正在临床实验的阳性对照药物GDC-0941和BEZ-235,抑制率分别达到76.7%与77.2%。这两个化合物在小鼠体内代谢良好,其中化合物25更为优异t1/2为3.