Design, synthesis, and cytotoxicity evaluation of new 2,4-disubstituted quinazolines as potential anticancer agents

A series of new 2, 4-disubstituted quinazolines were synthesized by an analog design approach. The synthesis oftitle compounds (3a–f, 4a–c, 5a–c, and 6a–c) was achieved from the corresponding key intermediates 2-(pyridin3-yl) quinazolin-4(3H)-one(2a), 2-(pyridin-3-yl) quinazolin-4(3H)-one (2b) and 2-(pyrazin-2-yl)quinazolin-4(3H)-one (2c) with appropriate amines. The synthesized compounds were characterized by the spectral studies. All thesynthesized compounds were evaluated for in vitro anticancer activity employing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay against human adenocarcinoma (HT-29), breast cancer (MDA-231), and Ehrlichascites carcinoma cell lines. Among the tested compounds, 5a has a significant anticancer activity (5.33 µM/ml)against the human adenocarcinoma cell line. Other compounds have shown a moderate anticancer activity against thetested cell lines.

Changes and clinical significance of serum tumor markers in patients with non-small cell lung cancer before and after gefitinib targeted therapy / 中国医师杂志

Objective To investigate the changes and clinical significance of serum tumor markers in patients with non-small cell lung cancer before and after gefitinib targeted therapy.Methods 80 cases of non-small cell lung cancer patients in our hospital from June 2015 to May 2017 were divided into control group and observation group randomly,40 cases in each group.The control group were treated with docetaxel conventional chemotherapy,and the observation group were treated with gefitinib targeted therapy.The clinical treatment effect,changes of serum tumor markers cancer antigen125 (CA125),carcinoembryonic antigen (CEA),neuron specific enolase (NSE) and adverse reactions were observed and compared between the two groups before and after treatment.Results The effective rate and disease control rate of the observation group were higher than that in the control group,with statistically significant difference (P ＜ 0.05).The levels of serum tumor markers CA125,CEA and NSE in the control group and the observation group before treatment were not significantly different (P ＞ 0.05).After 1 months of treatment,the levels of serum tumor markers CA125,CEA and NSE in the two groups were all decreased,and the level of serum tumor markers,CA125,CEA and NSE in the observation group were lower than those in the control group,with statistically significant difference.The incidence of adverse reactions in the observation group was lower than that in the control group (P ＜ 0.05),with statistically significant difference.Conclusions Gefitinib is effective in the treatment of non-small cell lung cancer.It reduces the level of serum tumor markers CA125,CEA,NSE,and reduces postoperative adverse reactions.It is worthy of clinical application.

Effects of gefitinib on cancer cell apoptosis and survival time of patients with advanced NSCLC / 中国医师杂志

Objective To study the effect of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) gefitinib on cancer cell apoptosisand survival time of patients with advanced non-small cell lung cancer (NSCLC).Methods A total of 126 cases of patients diagnosised as NSCLC stage Ⅲ B-ⅣV in our hospital during June 2013-October 2015 were randomly divided into group A received AC chemotherapy,group B received gefitinib,and group C received AC chemotherapy combined with gefitinib therapy.The progression free survival (PFS) rate and objective response rate (ORR) were measured during 12 months follow-up,tumor markers contents in serum and the mRNA expression of apoptosis molecules in tumor lesions were measured.Results The 12-month ORR and PFS of group C were significantly higher than those in groups A and B.The 12-month ORR and PFS of group B were significantly higher than those in group A.For 1 cycle after treatment,serum carcinoembryonic antigen (CEA),cytokeratin 19 (CY-FRA21-1),and thymidine kinase-1 (TK-1) contents among three groups were significantly lower than those before treatment.Caspase-3,Caspase-8,and Caspase-9 mRNA expressions in tumor were significantly higher than those before treatment.For 1 cycle after treatment,serum CEA,CYFRA21-1,and TK-1 contents of group C were significantly lower than groups A and B.Caspase-3,Caspase-8,and Caspase-9 mRNA expressions in tumor were significantly higher than those groups A and B,and serum CEA,CYFRA211,and TK-1 contents of group B were significantly lower than group A.Caspase-3,Caspase-8,and Caspase-9 mRNA expressions in tumor were significantly higher than thsoe of group A.Conclusions Gefitinib combined with intravenous chemotherapy can prolong the survival time of patients with advanced NSCLC and kill tumor cells,induce apoptosis.

Effects of gefitinib combined with DC-CIK on advanced lung adenocarcinoma / 中国医师杂志

Objective To investigate the short-term efficacy and safety of gefitinib combined with dendritic cells-cytokine induced killer (DC-CIK) cells in the treatment of advanced lung adenocarcinoma.Methods Fifty patients with lung adenocarcinoma who in previous had underwent radiotherapy and first-line chemotherapy failure received DC-CIK in combination with gefitinib treatment,blood count changes,imaging data,carcinoembryonic antigen and changes in the quality of life before and after treatment were compared and evaluated.Results DC-CIK could improve effectively and relieve bone marrow suppression response after chemotherapy and significantly increase the WBC content of blood (P ＜ 0.01).After treatment,the tumor carcinoembryonic antigen (CEA) was significantly lower in patients (P ＜ 0.01).Fifty cases of patients in complete remission (CR) were 0 cases,partial remission (PR) were 24 cases,stable disease (SD) were 17 cases and progression (PD) were 9 cases,and the response rates (RR) were 48％;The quality of life of patients was significantly improved (P ＜ 0.05).Common adverse reactions were rash,diarrhea,chill and fever,but mild symptoms could be relieved after symptomatic treatment.Conclusions Gefitinib with autologous DC-CIK cell infusion second-line treatment of advanced lung cancer have a certain short-term efficacy,without significant adverse reactions.Gefitinib with autologous DC-CIK cell therapy can mitigate the response of bone marrow suppression in patients with advanced lung cancer and improve the quality of life of patients.Long-term effect remains to be investigated.

Research of the influence and mechanism about metformin on the proliferation of differentiated endometrial carcinoma cells / 中华妇产科杂志

Objective To investigate the effects of metformin on cell proliferation in differentiation degree of endometrial carcinoma cells and related mechanisms. Methods The endometrial cancer cell lines Ishikawa and AN3CA were used. Cell proliferation was assessed after exposure to metformin with or without epithelial growth factor receptor (EGFR) inhibitor AG1478 by cell counting kit-8 (CCK-8) method. EGFR mRNA was determined by reverse transcription (RT)-PCR. The expression of phosphorylation EGFR (p-EGFR) and total EGFR (t-EGFR) and phosphorylation extracellular signal-regulated kinase 1/2 (p-ERK1/2) and total ERK1/2 (t-ERK1/2) were examined by western blot. Results (1)CCK-8 experiment showed that metformin could inhibit the proliferation of endometrial cancer cells in a time-dependent manner and a dose-dependent manner (P0.05). But the expression levels of p-EGFR and p-ERK1/2 protein were significantly lower between two groups (P<0.01), which showed a time-dependent manner(P<0.01). Conclusion Metformin could inhibit the proliferation of endometrial cancer cells, the inhibition is associated with the differentiation degree of cancer cells. Metformin could enhance the EGFR signaling pathway inhibitor AG1478 inhibition of endometrial cancer cells, which may inhibit EGFR expression of phosphorylated proteins to inhibit the phosphorylation of ERK1/2 proteins and then inhibit proliferation of endometrial cancer cells.

The Continuation of Erlotinib Treatment in Non-Small Cell Lung Cancer Patients Whose Brain Lesion Is the Only Site of Progression: Prospective Pilot Study / 한양의대학술지

There have been conflicting reports on the continuation of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in patients with newly developed or progressive brain metastasis of non-small cell lung cancer (NSCLC). Patients with newly developed or progressive intracranial lesions, but who maintained well-controlled extracranial disease during erlotinib treatment, were enrolled in this study. The proposed therapy included stereotactic radiosurgery (SRS), whole brain radiotherapy (WBRT), and/or surgical resection for intracranial lesions. Erlotinib treatment was continued simultaneously unless extracranial disease progressed. The evaluation of both extra- and intra-cranial lesions was performed every 3 months. From October 2009 to June 2012, 14 patients were enrolled in this pilot study. For intracranial disease, 4 patients received SRS alone, 7 patients received both SRS and WBRT, 2 patients received SRS, WBRT and surgical resection, and 1 patient received no local therapy due to the presence of asymptomatic lesions. Of the patients with extracranial disease who were placed on continued erlotinib therapy, 6 patients (42.9%) showed partial response (PR), while 7 patients (50.0%) remained in stable disease (SD). The progression-free survival (PFS) of extracranial and intracranial disease was 11.1 (range 1.6-34.6) and 10.2 (range 1.5-34.6) months, respectively. In 5 cases, brain lesions relapsed before the progression of extracranial disease. Overall survival (OS) was 22.6 (range 2.1-50.4) months. For NSCLC patients with progression of only intracranial disease during erlotinib treatment, the continuation of erlotinib in combination with local therapy to brain metastases can be an effective treatment option.

Relationship between microRNA-200c expression, epithelial-mesenchymal transition and the sensitivity to gefitinib in colon cancer cells / 中华消化杂志

Objective To explore the relationship between microRNA (miRNA)-200c expression,epithelial-mesenchymal transition (EMT) and the sensitivity to gefitinib in colon cancer cells.Methods The inhibitory effects of gefitinib on four types of colon cancer cell lines (HT29,SW620,HCT1116,SW480) were examined by cell counting kit-8 (CCK-8) assay.The expressions of miRNA-200c,epithelial marker (E-cadherin) and mesenchymal markers (vimentin and zinc finger Ebox binding homeobox 1 ZEB 1) at mRNA level in four types of colon cancer cell lines were detected by fluorescence quantitative polymerase chain reaction.The expressions of E-cadherin,vimentin and ZEB 1 at protein level were determined by Western blot.After up-or down-regulated the expression of miRNA-200c,the changes of the expression of EMT related genes and the sensitivity to gefitinib were observed.Results HT29 cells were most sensitive to gefitinib (IC50 =(7.70 ± 0.31) μmol/L),in which the expressions of both miRNA-200c and E-cadherin were the highest,and the expressions of vimentin and ZEB1 were extremely low.HCT116 and SW480 were moderately sensitive to gefitinib (IC50=(11.88±0.97) and (16.63±0.45) μmol/L),and the expressions of miRNA-200c and Ecadherin were moderate.SW620 cell line was most insensitive to gefitinib (IC50 =(26.43 ± 3.68)μmol/L),the expressions of miRNA-200c and E-cadherin were the lowest.The expressions of vimentin and ZEB 1 in SW620 were higher than that of the other three types of cell lines.After upregulated the expression of miRNA 200c,the expression of E-cadherin in SW620 cells increased,the expression of ZEB 1 and vimentin decreased,and the sensitivity to gefitinib increased.After downregulated the expression of miRNA-200c,the expression of E-cadherin in HT29 cells decreased,the expression of ZEB 1 and vimentin increased,and the sensitivity to gefitinib decreased.Conclusion miRNA-200c may up-regulate the expression of E-cadherin through EMT regulation,and then influence the sensitivity to gefitinib in colon cancer cells.

Effect of aurora kinase B inhibitor AZD1152 in the treatment of cisplatin-resistant ovarian carcinoma / 中华妇产科杂志

Objective To investigate whether AZD1152 (AZD),the selective inhibitor of aurora kinase B,may play a role in the treatment of cisplatin-resistant ovarian carcinoma when administrated alone or in combination with cisplatin.Methods Hey (cisplatin-resistant ovarian cancer cell line) cells were analyzed.According to the treatment plan,Hey cells were divided into four groups (AZD group,cisplatin group,AZD + cisplatin group and control group).Methyl thiazolyl tetrazolium (MTT) assay was used to test the cells proliferation,caspase-3/7 activity analysis was used to analyze cells apoptosis,and fluorescence insitu hybridization (FISH) assay was used to determine the copy the number of chromosome 7 and checked the copy numbers of hTERC gene and C-myc gene.Results MTT test showed that proliferation of AZD group was lower than that in control group(P ＜ 0.01).The cells proliferation with the treatment with 10 and 20 nmol/L AZD for 24 hours was (81.4 ± 3.6)％ and (81.4 ± 3.6)％ respectively,and the cells proliferation for 48 hours was (43.1 ± 2.0) ％ and (38.5 ± 1.6) ％ respectively,which was significantly lower than control group (100％,P ＜ 0.01) ; Treated with the same concentration of AZD,inhibition of proliferation was significantly enhanced as the time extended (P ＜ 0.01).Proliferation in group AZD+cisplatin was lower than that in cisplatin group (P ＜ 0.01) which suggest that there were additive effects after combined AZD with cisplatin.Compared with control group,caspase-3/7 activity in AZD group increased significantly (P =0.000),and the same results was seen between AZD ± cisplatin group and cisplatin group or AZD group (all P ＜ 0.01).Compared with cisplatin group or control group,the copy numbers of hTERC,C-myc and the number of chromosome were significantly increased in AZD group and AZD + cisplat group (all P ＜ 0.05).Conclusions AZD could inhibite ovarian cancer cells proliferation and induce cells apoptosis significantly.AZD alone or in combination with cisplatin may result in the increased cells polyploidy.

A Case of Fatal Fenazaquin Intoxication Showing Severe Lactic Acidosis

Fenazaquin (4-[[4 (1,1-dimethylethyl) pheynyl]ethoxy]quinazoline) is an insecticide that inhibits NADH ubiquinone oxidoreductase of the mitochondria, which is also known as complex I. An 83 year old female was brought to our emergency department (ED) having been found collapsed and unconscious at home by her family. She had ingested up to 100 ml from a bottle of 20% fenazaquin solution. In the ED, she showed severe persistent lactic acidosis despite a seemingly stable hemodynamic condition. Despite intensive supportive management, including positive pressure ventilation, packed red cell transfusion, hemodialysis, and intravenous N-acetylcysteine administration, the lactic acidosis did not respond. To our knowledge, this is the first report of fenazaquin poisoning in humans. No antidote for fenazaquin is known. In this case report, we discuss clinical characteristics and possible pathophysiologic mechanism of fenazaquin poisoning with a literature review.

Secondary resistance of gefitinib in non-small-cell lung cancer treatment / 国际肿瘤学杂志

Gefitinib (iressa),an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor,has antitumor activity in non-small-cell lung cancer (NSCLC).Despite the dramatic response to this inhibitor,most patients nevertheless ultimately have relapses because of the secondary resistance.In human lung adenocar-cinomas with EGFR mutation,a second-site point mutation that substitutes methionine for threonine at position 790(T790M) is associated with approximately half of cases of secondary resistance to gefitinib.Other mecha-nisras that contribute to gefitinib resistance include EGFR receptor internalization and MET gene amplification.