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中国医学科学院肿瘤医院每天都要接待成百上千名来自全国各地的患者。
来源:央视财经《经济半小时》
【癌症患者的福音!中国原创抗癌药打破国外垄断!治疗费用每月便宜20万】我国癌症发病率接近世界水平,但死亡率高于世界水平。2012年中国癌症发病人数为306.5万,约占全球发病的五分之一;癌症死亡人数为220.5万,约占全球癌症死亡人数的四分之一。采访时央视财经《经济半小时》记者了解到,包括微芯公司在内,全球仅3家企业在生产同类药物,其中两家在美国,每月治疗费用分别为28万元人民币和14万元人民币。而相比之下,西达本胺每月费用为2万多元人民币。面对癌症,我们该如何应对呢?是什么样的技术让早癌治疗不需开刀,微创手术五天可出院?两周可工作?中国原创抗癌药打破国外垄断!治疗费用每月便宜20万?
海归研发中国原创抗癌新药
今年1月,深圳微芯生物科技有限责任公司研发的抗癌新药西达本胺获准全球上市,这意味着中国有了自己原创的抗癌新药。该公司总裁鲁先平为此花费了14年的心血。
鲁先平是中国协和医科大学分子生物学与肿瘤生物学博士,美国加州大学药理系博士后。2001年,他和另外5位海归创立了微芯生物,从事原创新药的研发。经过14年的努力,他和他的团队成功研发出西达本胺。
西达本胺(Chidamide,商品名爱谱沙/epidaza)属于全新作用机制的综合靶向抗肿瘤靶向药物,其首个适应症为复发及难治性外周T细胞淋巴瘤,前期临床结果显示,患者临床获益率近50%,生存期明显延长。
西达本胺是中国原创新药,是全球第一个亚型选择性的组蛋白去乙酰化酶抑制剂,也是中国首个授权美国等发达国家专利使用的原创新药,首个适应症为复发及难治性外周T细胞淋巴瘤。正是因为亚型选择性,西达本胺具有非常独特的抗肿瘤机制,比如激活患者抗肿瘤细胞免疫功能。
意味着中国有了自己原创的抗癌新药,中国药物研发已从仿制、高仿,逐步走入与发达国家同水平甚至超前的独立创新阶段。此举将填补我国T细胞淋巴瘤治疗药物的空白,也标志着我国基于结构的分子设计、靶点研究、安全评价、临床开发到实现产业化全过程的整合核心技术与能力得以显着提升,是我国医药行业的历史性突破。
西达本胺由鲁先平花费了14年和他的团队共同研发。
鲁先平,中国协和医科大学分子生物学与肿瘤生物学博士,美国加州大学药理系博士后。2001年,他和另外5位海归创立了微芯生物,从事原创新药的研发。
检索到研究论文14篇分布如下:
1.
Xu L. Tang HL. Gong X. Xin XL. Dong Y. Gao GX. Shu MM. Chen XQ.
Department of Hematology, Xijing Hospital, Fourth Military Medical University; Hematologic Disease Center of Chinese People's Liberation Army, Xi'an 710032, Shaanxi Province, China.
来源:Zhongguo Shi Yan Xue Ye Xue Za Zhi ( P 1009-2137 E ) H指数:7年: 2015 卷: 23 期: 2 页: 450-4
PMID: 25948203 [Pubmed]
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This study was aimed to explore the effect of a novel histone deacetylase inhibitor Chidamide on apoptosis of human multiple myeloma(MM) cells and its relevance to DNA damage response(DDR).
Zhao B. He T.
Department of General Surgery, Shanghai Seventh People's Hospital, Shanghai 200137, P.R. China.
来源:Oncol Rep ( P 1021-335X E 1791-2431 ) IF:2.191H指数:50年: 2015 卷: 33 期: 1 页: 304-10
PMID: 25384499 [Pubmed]
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Chidamide is a newly designed histone deacetylase (HDAC) inhibitor that has been applied in clinical trials. This study aimed to test the effect of Chidamide on proliferation and apoptosis in pancreatic cancer cell lines and in?vivo tumors, as well as to determine the underlying mechanism. The PaTu8988 pancreatic tumor cell line either in culture or inoculated in nude mice were used to evaluate the antitumor characteristics of Chidamide. Proliferation and apoptosis of cultured PaTu8988 cells were examined by CCK-8 assay and Annexin?V-FITC/PI double staining assay, respectively. Alterations in protein expression, including Caspase-3, Bcl-2?like protein 4 (Bax), B-cell lymphoma 2 (Bcl-2) and p21, were tested by western blot analysis. The mRNA of different HDACs was examined by quantitative polymerase chain reaction (qPCR) experiments. Chidamide suppressed cell proliferation and induced early apoptosis of pancreatic tumor cells in a dose?dependent manner after 48?h of treatment. Similarly, the in?vivo study using pancreatic tumor murine model showed that Chidamide administration significantly inhibited the growth of pancreatic tumor and induced tumor cell apoptosis. The in?vitro and in?vivo studies found that Chidamide treatment significantly decreased the expression of type I HDACs, uncleaved Caspase-3 and p21 and increased the ratio of Bax/Bcl-2 expression. The results from the in?vitro and in?vivo studies suggested Chidamide might suppress the proliferation of pancreatic tumor cells by downregulating the expression of type I HDACs and p21, and promoting mitochondrial apoptosis pathway-dependent cell apoptosis in a dose-dependent manner. The study provided more evidence for clinical administration of Chidamide that targets pancreatic tumor cells and identified potential molecular targets for the development of potent anticancer drugs.
Zhou Y. Pan DS. Shan S. Zhu JZ. Zhang K. Yue XP. Nie LP. Wan J. Lu XP. Zhang W. Ning ZQ.
Biomedical Research Institute, Shenzhen-PKU-HKUST Medical Center, Shenzhen, 518036 Guangdong, China; Chipscreen Biosciences Ltd., Bio-Incubator 2-601, 1st Ave. of Gaoxin Road, Hi-Tech Industrial Park, Shenzhen, 518057 Guangdong, China.
来源:Biomed Pharmacother ( P 0753-3322 E 1950-6007 ) IF:2.108H指数:53年: 2014 卷: 68 期: 4 页: 483-91
PMID: 24721323 [Pubmed]
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Combination of low doses of histone deacetylases inhibitors and chemotherapy drugs is considered as one of the most promising strategies to increase the anticancer efficacy. Chidamide is a novel benzamide chemical class of HDAC inhibitor that selectively inhibited HDAC1, 2, 3 and 10. We sought to determine whether chidamide may enhance platinum-induced cytotoxicity in NSCLC cells. In this study, the combination of chidamide with carboplatin showed a good synergism on growth inhibition with the mean combination index value as 0.712 and 0.639 in A549 and NCI-H157 cells, respectively. The used concentration of chidamide was non-toxic on cells by itself as low as 0.3μM. All of our experiments were comparisons between combination regimen and single carboplatin regimen in A549 and NCI-H157 cell lines. Phosphorylated histone H2A.X (γH2A.X), a hall marker of DNA damage response, was dramatically increased by the combination treatment. Cell cycle analysis by flow cytometry and phosphorylation level analysis of histone H3 (Ser10) by western blotting showed that combination treatment significantly increased the percentage of G2/M phase of cells. Mitochondrial membrane potential and cleaved-PARP1 level analysis indicate that chidamide synergistically enhances carboplatin-induced apoptosis. Additionally, synergistic effects of chidamide were found when it was combined with two other platinum drugs (cisplatin and oxaliplatin). The results suggest that Chidamide in combination with platinum drugs may be a novel therapeutic option for NSCLC.
Dong M. Hu XS. Chen SS. Xing PY. Feng FY. Shi YK.
Email: syuankaipumc@126.com.
来源:Zhonghua Zhong Liu Za Zhi ( P 0253-3766 E ) H指数:15年: 2013 卷: 35 期: 7 页: 481-485
PMID: 24257296 [Pubmed]
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暂无摘要
Yao Y. Zhou J. Wang L. Gao X. Ning Q. Jiang M. Wang J. Wang L. Yu L.
Department of Hematology and BMT Center, Chinese PLA General Hospital, Beijing, China.
来源:PLoS One ( P E 1932-6203 ) IF:3.534H指数:85年: 2013 卷: 8 期: 8 页: e70522
PMID: 23940586 [Pubmed]
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As one of the best known cancer testis antigens, PRAME is overexpressed exclusively in germ line tissues such as the testis as well as in a variety of solid and hematological malignant cells including acute myeloid leukemia. Therefore, PRAME has been recognized as a promising target for both active and adoptive anti-leukemia immunotherapy. However, in most patients with PRAME-expressing acute myeloid leukemia, PRAME antigen-specific CD8(+) CTL response are either undetectable or too weak to exert immune surveillance presumably due to the inadequate PRAME antigen expression and PRAME-specific antigen presentation by leukemia cells. In this study, we observed remarkably increased PRAME mRNA expression in human acute myeloid leukemia cell lines and primary acute myeloid leukemia cells after treatment with a novel subtype-selective histone deacetylase inhibitor chidamide in vitro. PRAME expression was further enhanced in acute myeloid leukemia cell lines after combined treatment with chidamide and DNA demethylating agent decitabine. Pre-treatment of an HLA-A0201(+) acute myeloid leukemia cell line THP-1 with chidamide and/or decitabine increased sensitivity to purified CTLs that recognize PRAME(100-108) or PRAME(300-309) peptide presented by HLA-A0201. Chidamide-induced epigenetic upregulation of CD86 also contributed to increased cytotoxicity of PRAME antigen-specific CTLs. Our data thus provide a new line of evidence that epigenetic upregulation of cancer testis antigens by a subtype-selective HDAC inhibitor or in combination with hypomethylating agent increases CTL cytotoxicity and may represent a new opportunity in future design of treatment strategy targeting specifically PRAME-expressing acute myeloid leukemia.
Wang X. Chen M. Wen C. Zhang Q. Ma J.
Analytical and Testing Center of Wenzhou Medical University, Wenzhou, 325035, China.
来源:Biomed Chromatogr ( P 0269-3879 E 1099-0801 ) IF:1.662H指数:37年: 2013 卷: 27 期: 12 页: 1801-6
PMID: 23857175 [Pubmed]
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A sensitive and selective liquid chromatography mass spectrometry method for determination of chidamide in rat plasma was developed. After addition of linezolid as internal standard, protein precipitation by acetonitrile-methanol (9:1, v/v) was used as sample preparation. Chromatographic separation was achieved on a Zorbax SB-C18 (2.1 × 150 mm, 5 μm) column with acetonitrile-0.1% formic acid as mobile phase with gradient elution. An electrospray ionization source was applied and operated in positive ion mode; selective ion monitoring mode was used for quantification using target fragment ions m/z 391.5 for chidamide and m/z 338.5 for the IS. Calibration plots were linear over the range of 10-2000 ng/mL for chidamide in rat plasma. The lower limit of quantification for chidamide was 10 ng/mL. The mean recovery of chidamide in plasma was in the range of 86.6-92.1%. The coefficients of variation of intra-day and inter-day precision were both <12%. This method is simple and sensitive and was applied successfully in a pharmacokinetic study of chidamide to rats.
Qiao Z. Ren S. Li W. Wang X. He M. Guo Y. Sun L. He Y. Ge Y. Yu Q.
Beijing Institute of Transfusion Medicine, Beijing, PR China.
来源:Biochem Biophys Res Commun ( P 0006-291X E 1090-2104 ) IF:2.281H指数:174年: 2013 卷: 434 期: 1 页: 95-101
PMID: 23541946 [Pubmed]
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Pancreatic cancer is a lethal human malignancy with an extremely poor prognosis and urgently requires new therapies. Histone deacetylase inhibitors (HDACIs) represent a new class of anticancer agents and have shown promising antitumor activities in preclinical models of pancreatic cancer. In this study, we sought to determine the antitumor effects of a novel HDACI, chidamide (CS055), in pancreatic cancer cells alone or in combination with gemcitabine. Treatments of BxPC-3 or PANC-1 pancreatic cancer cell lines with chidamide resulted in dose- and time-dependent growth arrest, accompanied by induction of p21 expression. When combined in a sequential schedule, chidamide synergistically enhanced gemcitabine-induced cell growth arrest and apoptosis, accompanied by cooperative downregulation of Mcl-1 and loss of mitochondrial membrane potential (ΔΨm). Chidamide enhanced gemcitabine-induced DNA double-strand breaks and S phase arrest, and abrogated the G2/M cell cycle checkpoint, potentially through suppression of CHK1 expression. Our results suggest that chidamide has a therapeutic potential for treating pancreatic cancer, especially in combination with gemcitabine.
Li YY. Wang YF. Wang J. Ke XY.
Department of Hematology, Peking University Third Hospital, Beijing, China.
来源:Zhongguo Shi Yan Xue Ye Xue Za Zhi ( P 1009-2137 E ) H指数:7年: 2012 卷: 20 期: 4 页: 893-9
PMID: 22931650 [Pubmed]
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This study was aimed to explore the effects of histone deacetylase inhibitor chidamide on the proliferation, apoptosis of B lymphoma cell lines Raji (Burkitt lymphoma), Maver and Z-138 (mantle cell lymphoma) and its mechanisms. Three B lymphoma cell lines were cultured in vitro with different concentrations of chidamide for different time. The cell proliferation was determined by CCK-8 method; the cell apoptosis and mitochondrial membrane potential were analyzed by flow cytometry; the protein levels of histone H3/H4 acetylation in cells and the activity of caspase-3 were detected by Western blot. The results showed that chidamide inhibited the proliferation of 3 B lymphoma cell lines in time- and concentration-dependent manners, especially in Z-138 cell line earlier and faster; chidamide could induce cell apoptosis and decline of mitochondrial membrane potential, which was more sensitive in Maver and Z-138 cells than that in Raji cells. Chidamide could elevate the histone H3/H4 acetylation level in 3 B lymphoma cell lines and the activity of caspase-3 in Maver and Z-138 cells. It is concluded that chidamide can inhibit proliferation of B lymphoma cell lines and promote cell apoptosis, the increase of histone H3/H4 acetylation induced by chidamide, triggering of mitochondrial pathway and activation of caspase-3 may be considered as possible mechanisms.
Wang H. Guo Y. Fu M. Liang X. Zhang X. Wang R. Lin C. Qian H.
State Key Laboratory of Molecular Oncology, Cancer Institute/Hospital, CAMS and PUMC, Beijing, People's Republic of China.
来源:Mol Med Rep ( P 1791-2997 E 1791-3004 ) IF:1.484H指数:7年: 2012 卷: 5 期: 6 页: 1503-8
PMID: 22484326 [Pubmed]
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Chidamide, the structural analog of MS-275, is a novel and promising histone deacetylase (HDAC) inhibitor for use in cancer therapy. To investigate its effects on cancer cell growth, MTT assay was performed in 10 human cancer cell lines. The data showed that the IC50 of Chidamide ranged from 1 to 13 μM, which was comparable to that of MS-275 in half of the tested cell lines. Furthermore, the growth curve indicated that cell growth was gradually inhibited with an increase in Chidamide dosage, and the inhibition was reversed after drug removal in two hepatocelluclar carcinoma cell lines, BEL-7402 and HCC-9204. To determine cell cycle and apoptosis, FACS was carried out in the BEL-7402 and HCC-9204 cells treated with Chidamide. A decrease in the cell population at S phase and an increase in the cell population at G1 phase occurred in a dose-dependent manner. In addition, Chidamide induced apoptosis and up-regulated p21 mRNA expression. These results suggest that Chidamide may arrest the cell cycle and inhibit the growth of hepatocellular carcinoma cells through up-regulation of p21. Further studies are required to clarify the antitumor activity of Chidamide in vivo and its mechanism in anticancer therapy.
Dong M. Ning ZQ. Xing PY. Xu JL. Cao HX. Dou GF. Meng ZY. Shi YK. Lu XP. Feng FY.
Department of Medical Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, No. 17 Panjiayuan, Chaoyang District, Beijing, 100021, China.
来源:Cancer Chemother Pharmacol ( P 0344-5704 E 1432-0843 ) IF:2.571H指数:66年: 2012 卷: 69 期: 6 页: 1413-22
PMID: 22362161 [Pubmed]
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Chidamide (CS055/HBI-8000) is a new benzamide class of histone deacetylase inhibitor with marked anti-tumor activity. This study reports the phase I results.
Gong K. Xie J. Yi H. Li W.
College of Life Sciences, Wuhan University, Wuhan 430072, PR China.
来源:Biochem J ( P 0264-6021 E 1470-8728 ) IF:4.779H指数:181年: 2012 卷: 443 期: 3 页: 735-46
PMID: 22339555 [Pubmed]
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CS055 (Chidamide/HBI-8000) is a novel benzamide-type HDACi (histone deacetylase inhibitor), which has entered Phase I clinical trials in the U.S. and Phase II/III in China. In the present study, we investigated the effects of CS055 on proliferation, differentiation and apoptosis in human leukaemia cell lines and primary myeloid leukaemia cells. The results showed that at low concentrations (<1?μM), CS055 induced G1 arrest. At moderate concentrations (0.5?μM-2?μM), CS055 induced differentiation, as determined by the increased expression of the myeloid differentiation marker CD11b. At relatively high concentrations (2?μM-4?μM), CS055 potently induced caspase-dependent apoptosis. Co-treatment with the ROS (reactive oxygen species) scavengers N-acetyl-L-cysteine or Tiron blocked CS055-induced cell differentiation and apoptosis, suggesting an essential role for ROS in these effects. Cytochrome c release and ROS-mediated mitochondrial dysfunction are involved in CS055-induced apoptosis of leukaemia. In addition to cell lines, CS055 also exhibits therapeutic effects in human primary leukaemia cells. Moreover, daily oral CS055 treatment of nude mice bearing HL60 cell xenografts suppressed tumour growth, induced tumour cell apoptosis and prolonged the survival of tumour-bearing mice. In conclusion, our findings demonstrate that CS055 is a novel HDACi with potential chemotherapeutic value in several haematological malignancies, especially leukaemia.
Ning ZQ. Li ZB. Newman MJ. Shan S. Wang XH. Pan DS. Zhang J. Dong M. Du X. Lu XP.
Chipscreen Biosciences Ltd, Bio-Incubator 2-601, 1st Ave of Gaoxin Road, Hi-Tech Industrial Park, Shenzhen 518057, Guangdong, China.
来源:Cancer Chemother Pharmacol ( P 0344-5704 E 1432-0843 ) IF:2.571H指数:66年: 2012 卷: 69 期: 4 页: 901-9
PMID: 22080169 [Pubmed]
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Chidamide (CS055/HBI-8000) is a new histone deacetylase (HDAC) inhibitor of the benzamide class currently under clinical development in cancer indications. This study reports the in vitro and in vivo antitumor characteristics of the compound.
Wong JC. Guo L. Peng Z. Zhang W. Zhang N. Lai W. Zhang Z. Zhang C. Zhang X. Song S. Pan D. Xie C. Li J. Ning Z. Lu X. He Y. Chen L.
Roche R&D Center China Ltd, 720 Cai Lun Road, Building 5, Pudong, Shanghai 201203, PR China. jason.wong@roche.com
来源:Bioorg Med Chem Lett ( P 0960-894X E 1464-3405 ) IF:2.331H指数:84年: 2011 卷: 21 期: 1 页: 110-6
PMID: 21145737 [Pubmed]
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Novel 2-aminoanilide histone deacetylase (HDAC) inhibitors were designed to increase their contact with surface residues surrounding the HDAC active site compared to the contacts made by existing clinical 2-aminoanilides such as SNDX-275, MGCD0103, and Chidamide. Their HDAC selectivity was assessed using p21 and klf2 reporter gene assays in HeLa and A204 cells, respectively, which provide a cell-based readout for the inhibition of HDACs associated either with the p21 or klf2 promoter. A subset of the designed compounds selectively induced p21 over klf2 relative to the clinical reference compound SNDX-275. A representative lead compound from this subset had antiproliferative effects in cancer cells associated with induction of acetylated histone H4, endogenous p21, cell cycle arrest, and apoptosis. The p21- versus klf2-selective compounds described herein may provide a chemical starting point for developing clinically-differentiated HDAC inhibitors for cancer therapy.
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