徐瑞华
长期从事肿瘤内科的临床工作及抗癌药物(化疗药物及分子靶向治疗药物)研究。在消化道肿瘤(肠癌、胃癌、食道癌、胰腺癌、肝癌)的综合治疗及研究有较深的造诣。
个性化签名
- 姓名:徐瑞华
- 目前身份:
- 担任导师情况:
- 学位:
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学术头衔:
博士生导师, 教育部“新世纪优秀人才支持计划”入选者
- 职称:-
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学科领域:
肿瘤学
- 研究兴趣:长期从事肿瘤内科的临床工作及抗癌药物(化疗药物及分子靶向治疗药物)研究。在消化道肿瘤(肠癌、胃癌、食道癌、胰腺癌、肝癌)的综合治疗及研究有较深的造诣。
徐瑞华,医学博士(M.D., Ph.D.),教授、主任医师、博士生导师,中心副主任、副院长,2007年教育部新世纪优秀人才。
个人简介:
长期从事肿瘤内科的临床工作及抗癌药物(化疗药物及分子靶向治疗药物)研究。在消化道肿瘤(肠癌、胃癌、食道癌、胰腺癌、肝癌)的综合治疗及研究有较深的造诣。2002年前往美国德州安德森(M.D. Anderson)癌症中心工作,被聘为客座副教授,2005年回国。负责执笔撰写中国版《NCCN结肠癌临床指导原则》和《NCCN直肠癌临床指导原则》临床共识,参与撰写中国版《NCCN胃癌临床指导原则》及《NCCN胰腺癌临床指导原则》临床共识,负责、参与了多项国际及国内抗肿瘤新药的临床试验。
在国内外重要期刊共发表文章70余篇,其中第一作者(或通讯作者)30余篇,近年来有多篇文章发表在国际上重要的学术期刊上,如《Journal of National Cancer Institute》,《Journal of Cell Biology》,《Cancer Research》, 《Oncogene》,《Leukemia》, 《Cancer》等负责及参与了近20余项国家、部省级的科研课题,并参加了一项美国国立卫生院的重大研究。
学术兼职:
广东省抗癌协会副理事长兼秘书长,中国抗癌协会临床肿瘤学协作中心委员会(CSCO)常务委员,中国抗癌协会大肠癌专业委员会常务委员,广东省抗癌协会胃癌专业委员会副主任委员,广东省抗癌协会大肠癌专业委员会常务委员,国家食品药品监督管理局(SFDA)药物审评咨询专家,广东省干部保健学术委员会委员及保健专家,美国临床肿瘤学会(ASCO)会员、美国癌症研究协会(AACR)会员。《癌症》、《临床肿瘤学杂志》、《肿瘤研究与临床》编委,《Cancer》、《Chemotherapy》、《BMC Cancer》等杂志审稿专家。
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9
徐瑞华
Cancer Res 2005; 65: (2). January 15, 2005,-0001,():
-1年11月30日
Cancer cells generally exhibit increased glycolysis for ATP generation (the Warburg effect) due in part to mitochondrial respiration injury and hypoxia, which are frequently associated with resistance to therapeutic agents. Here, we report that inhibition of glycolysis severely depletes ATP in cancer cells, especially in clones of cancer cells with mitochondrial respiration defects, and leads to rapid dephosphorylation of the glycolysis-apoptosis integrating molecule BAD at Ser112, relocalization of BAX to mitochondria, and massive cell death. Importantly, inhibition of glycolysis effectively kills colon cancer cells and lymphoma cells in a hypoxic environment in which the cancer cells exhibit high glycolytic activity and decreased sensitivity to common anticancer agents. Depletion of ATP by glycolytic inhibition also potently induced apoptosis in multidrug-resistant cells, suggesting that deprivation of cellular energy supply may be an effective way to overcome multidrug resistance. Our study shows a promising therapeutic strategy to effectively kill cancer cells and overcome drug resistance. Because the Warburg effect and hypoxia are frequently seen in human cancers, these findings may have broad clinical implications. (Cancer Res 2005; 65(2): 613-21)
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【期刊论文】Glycolysis inhibition for anticancer treatment
徐瑞华
Oncogene (2006) 25, 4633-4646,-0001,():
-1年11月30日
Most cancer cells exhibit increased glycolysis and use this metabolic pathway for generation of ATP as a main source of their energy supply.This phenomenon is known as the Warburg effect and is considered as one of the most fundamental metabolic alterations during malignant transformation.In recent years, there are significant progresses in our understanding of the underlying mechanisms and the potential therapeutic implications. Biochemical and molecular studies suggest several possible mechanisms by which this metabolic alteration may evolve during cancer development.These mechanisms include mitochondrial defects and malfunction, adaptation to hypoxic tumor microenvironment, oncogenic signaling, and abnormal expression of metabolic enzymes.Importantly, the increased dependence of cancer cells on glycolytic pathway for ATP generation provides a biochemical basis for the design of therapeutic strategies to preferentially kill cancer cells by pharmacological inhibition of glycolysis.Sev eral small molecules have emerged that exhibit promising anticancer activity in vitro and in vivo, as single agent or in combination with other therapeutic modalities.The glycolytic inhibitors are particularly effective against cancer cells with mitochondrial defects or under hypoxic conditions, which are frequently associated with cellular resistance to conventional anticancer drugs and radiation therapy.Because increased aerobic glycolysis is commonly seen in a wide spectrum of human cancers and hypoxia is present in most tumor microenvironment, development of novel glycolytic inhibitors as a new class of anticancer agents is likely to have broad therapeutic applications.
glycolysis, Warburg effect, glycolytic inhibitor, ATP, mitochondria
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徐瑞华
Leukemia (2004) 18, 1934-1940,-0001,():
-1年11月30日
B cell chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in the Western hemisphere, yet many biological and molecular features of the disease remain undefined. CLL cells generate increased levels of radical species such as superoxide and nitric oxide (NO), which is associated with mitochondrial DNA mutations. Considering that NO levels can affect mitochondrial biogenesis, we hypothesized that the inherent nitrosative stress in CLL cells may lead to hyperactive mitochondrial biogenesis. Here we report that primary CLL cells contained significantly more mitochondria than normal lymphocytes and that their mitochondrial mass was significantly related to endogenous NO levels. Expression of the mitochondrial biogenesis factors nuclear respiratory factor-1 and mitochondrial transcription factor A was elevated in most CLL specimens examined and appeared to be related to cellular NO levels. Treatment of B cells with exogenous NO caused a substantial increase in mitochondrial mass. In vitro sensitivity of CLL cells to fludarabine was highly related to mitochondrial mass in that cells with greater mitochondrial mass were less sensitive to the drug. Taken together, our results suggest that NO is a key mediator of mitochondrial biogenesis in CLL and that modulation of mitochondrial biogenesis by NO may alter cellular sensitivity to fludarabine.
chronic lymphocytic leukemia, mitochondria, nitric oxide, fludarabine
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【期刊论文】OSW-1: a Natural Compound With Potent Anticancer Activity and a Novel Mechanism of Action
徐瑞华
Journal of the National Cancer Institute, Vol. 97, No. 23, December 7, 2005,-0001,():
-1年11月30日
The naturally occurring compound 3 β, 16 β, 17 α -trihydroxycholest-5-en-22-one 16- O-(2-O-4-methoxybenzoyl-β-D-xylopyranosyl)-(1→3)-(2-O-acetyl-α--L -arabinopyranoside) (OSW-1) is found in the bulbs of Ornithogalum saudersiae and is highly cytotoxic against tumor cell lines. Using various human cancer and nonmalignant cell lines, we investigated the anticancer activity and selectivity of OSW-1 and its underlying mechanisms of action. OSW-1 exhibited extremely potent cytotoxic activity against cancer cells in vitro. Nonmalignant cells were statistically signifi cantly less sensitive to OSW-1 than cancer cells, with concentrations that cause a 50% loss of cell viability 40 – 150-fold greater than those observed in malignant cells. Electron microscopy and biochemical analyses revealed that OSW-1 damaged the mitochondrial membrane and cristae in both human leukemia and pancreatic cancer cells, leading to the loss of transmembrane potential, increase of cytosolic calcium, and activation of calcium-dependent apoptosis. Clones of leukemia cells with mitochondrial DNA defects and respiration defi ciency that had adapted the ability to survive in culture without mitochondrial respiration also were resistant to OSW-1. In vitro analysis revealed that OSW-1 effectively killed primary leukemia cells from chronic lymphocytic leukemia patients with disease refractory to fl udarabine. The promising anticancer activity of OSW-1 and its unique mechanism of action make this compound worthy of further investigation for its potential to overcome drug resistance. [J Natl Cancer Inst 2005; 97: 1781-5]
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徐瑞华, 邱妙珍, , 徐菲, 王树森, 骆卉, 王峰, 李方华, 孙晓菲, 徐光川, 林桐榆, 黄慧强, 姜文奇, 管忠震
《癌症》Chinese Journal of Cancer, 2007, 26(12): 1344-1349,-0001,():
-1年11月30日
成人软组织肉瘤(softtissuesarcoma,STS)发病率低,化疗效果不肯定。本研究通过分析成人软组织肉瘤病例的临床特征,探讨化疗在成人软组织肉瘤综合治疗中的意义。方法:回顾性分析2000年1月至2005年12月在中山大学肿瘤防治中心诊断为软组织肉瘤,并接受化疗的109例患者的临床资料和化疗情况,统计各一线化疗方案的有效率及患者的生存资料。结果:109例患者中有66例行姑息化疗,40例行辅助化疗,3例行新辅助化疗。姑息化疗患者一线化疗方案的总有效率为22.7%,中位生存期16.9个月,1年和2年生存率分别为63.6%和33I3%,中位无进展生存期为3,4个月。仅发生肺转移的患者中位生存期为25.1个月,仅发生肝转移的患者中位生存期为11.8个月,两者比较差异有统计学意义(P<0.05)。MAID方案是最常用的一线化疗方案,其次是CYVADIC方案,有效率(完全缓解+部分缓解)分别为28.0%和22.2%。确诊后半年内发生转移的患者比半年后转移的患者中位生存期短(11.8个月vs.42.9个月),两者之间差异有统计学意义(P=0.04)。结论:MAID和CYVADIC均为有效的化疗方案,既往使用过常规剂量的阿霉素±异环磷酰胺后进展的患者仍可能从大剂量异环磷酰胺化疗中获益。肝转移患者比肺转移患者对化疗更不敏感.确诊后半年内出现转移的患者预后较确诊半年后转移者差。
软组织肉瘤/, 药物疗法, 一线化疗, MAID方案, CYVADIC方案, 疗效, 中位生存期
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【期刊论文】CPT-11联合5-FO/CF(FOLFIR1)化疗方案治疗晚期结直肠癌
徐瑞华, 骆卉妍, , 李宇红, 张力, 姜文奇, 史艳侠, 王峰, 何友兼
《癌症》Chinese Journal of Cancer, 2007, 26(12): 1344-1349,-0001,():
-1年11月30日
CPT-ll联合5-FU/CF(FoLFIR[)化疗方案是治疗晚期结直肠癌的有效方案。但是,该方案作为一线方案治疗中国晚期结直肠癌患者的资料缺乏,其疗效和安全性仍需进一步确定。本文旨在探讨FOLFIR[方案作为一线治疗方案对中国晚期结直肠癌患者的疗效和安全性。方法:自2002年1月至2005年9月期间,共54例晚期结直肠癌患者采用FOLFIR[方案作为一线方案进行治疗.回顾性分析其治疗有效率(responserate,RR)、疾病进展时间(timet0progression。‘TIP)、总生存时间(overallsurvival,0S)和不良反应。结果:54例患者中52例可评价疗效。其中RR为42.6%,TIP为6个月,OS为15.2个月。最常见的不良反应为中性粒细胞减少(38.9%)、腹泻(37.1%)和恶心呕吐(50.0%),皿/Ⅳ级的发生率分别为5.6%、9.3%和9.3%,总体耐受性好。结论:FOLFIRI方案治疗中国晚期结直肠癌患者疗效肯定,作为一线化疗方案有较高的有效性,不良反应可以耐受。
结直肠癌/, 化学疗法, 依立替康, 氟尿嘧啶, 醛氢叶酸, 化疗., 联合
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徐瑞华, 史艳侠, , 姜文奇, 张力, 林桐榆, 李宇红, 夏忠军, 骆卉研, 韩冰, 王峰, 何友兼, 管忠震
《癌症》Chinese Journal of Cancer, 2007, 26(12): 1381-1384,-0001,():
-1年11月30日
吉西他滨是目前治疗晚期胰腺癌的最有效的药物之一,初步的研究显示,与奥沙利铂联合(GEMOX)的疗效优于吉西他滨单药,但国内使用GEMOX方案治疗胰腺癌的研究报道并不多。本研究目的是观察GEMOX方案治疗晚期胰腺癌患者的有效率、生存期和毒副反应,为临床治疗提供指导。方法:本研究为单中心、回顾性临床分析。选择32例未接受过化疗的初治Ⅲ-Ⅳ期胰腺癌患者。所有患者均至少接受2个周期的GEMOX方案(吉西他滨1000ms/m,静脉滴人,d。、d;奥沙利铂85-130ms/m,静脉滴人,d;每21d重复)化疗。结果:28例患者可评价疗效,8例部分缓解(partialremission,PR),8例病情稳定(stabledisease,SD),12例病情进展(progressivedisease,PD),4例不能评估(notassessable,NA),总有效率为25.0%,临床获益率46.9%(15例),中位无进展生存期(progression-freesurvival,PFS)为4.7个月,中位生存期8.6个月,1年生存率为32.6%。骨髓抑制的总发生率为70.9%,其中Ⅲ、Ⅳ度的发生率为32.3%(白细胞下降的发生率为19.4%,血红蛋白下降的发生率为12.9%,血小板下降的发生率为22.6%)。恶心、呕吐和腹泻的发生率为56.2%,其中Ⅲ度呕吐2例。肝功能异常的总发生率为25.0%,全部为I、Ⅱ度。外周神经毒性发生率为43.8%.全部为I度。无化疗相关的死亡。结论:GEMOX方案是治疗晚期胰腺癌的有效方案,总体临床耐受性良好,其主要的不良反应为骨髓抑制。
胰腺肿瘤/, 化学疗法, 吉西他滨/, 治疗应用, 奥沙利铂/, 治疗应用, 疗效
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徐瑞华, 韩冰, , 史艳侠, 李宇红, 骆卉妍, 王峰, 侯景辉, 蔡木炎, 姜文奇
《癌症》Chinese Journal of Cancer, 2006, 25(11): 1439-1442,-0001,():
-1年11月30日
近年来发现缺氧诱导因子ld(hypoxl-nduclblefactorld,HIF-ld)与多种恶性肿瘤的发生、发展、转移及预后等多种生物学行为相关。本研究通过免疫组织化学方法检测HIF-ld的表达、探讨HIF-ld在胃癌组织中的表达及其临床意义。方法:对96例患者的胃癌组织学蜡块.应用免疫组织化学sP法检测HIF-ld的表达\并分析HIF-ld的表达与患者临床病理特征及预后的关系。结果:96例患者中。802%(77/96)的患者HIF-ld呈阳性表达。其中(+)7例。(++)29例.(+++)27例。(++++)14例;I、Ⅱ期与Ⅲ、Ⅳ期患者的HIF-ld表达率分别为66.7%、87.3%(P=0.06)。Tl、T2浸润深度与T3、T4浸润深度的患者HIFld表达率分别为579%、88.0%(P=0.007)。无远处转移与有远处转移患者的HIFld表达率分别为75.9%、100.0%(P=0.055)。HIF-ld阳性表达患者的生存率低于阴性表达者:阳性表达与阴性表达的患者5年生存率分别为3l.2%及57.9%(P=0027)。经C0x多因素回归分析.HIF-ld尚不能做为胃癌的独立预后因素(P=0.158)。结论:HIF-ld的阳性表达与胃癌患者的总生存率、肿瘤分期、浸润深度及远处转移关系密切;提示HIF-1a可作为评估胃癌发展;转移及预后的参考指标之一。
冒肿瘤, HIF-1a, 预后, 多日素分析
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徐瑞华, , 史艳侠, 管忠震, 姜文奇, 黄河, 马智勇, 王建华, 胡晓桦, 谢伟敏, 李星庚, 刘亚利, 潘良熹, 戴爱娣, 庄武, 张春
《癌症》Chinese Journal of Cancer, 2006, 25(12): 1565-1568,-0001,():
-1年11月30日
奈达铂是第二代有机铂类抗癌药,国外的临床研究显示该药是一个广谱、高效的抗癌药物,治疗食管癌有效率较高,但是国产奈达铂的临床疗效及其不良反应尚不清楚。本研究目的是观察Ⅱ类新药国产奈达铂对晚期食管癌的疗效及其不良反应。方法:本研究为多中心、前瞻性、随机对照Ⅱ期临床研究。对52例未接受过化疗的初治食管癌患者进行随机分组,试验组30例,接受奈达铂联合5-Fu治疗。对照组22例,接受DDP联合5.Fu治疗。结果:3O例试验组患者中,27例可评价疗效,30例可评价不良反应。22例对照组患者均可评价疗效和不良反应。在疗效方面,试验组的总有效率高于对照组,分别为29.63%与22.73%(P<0.05)。其中试验组的CR率为18.51%,而对照组为4.55%。在骨髓抑制方面,Hh下降的发生率两组基本一致:试验组WBC下降和血小板抑制的发生率明显高于对照组.特别是Ⅲ、Ⅳ度血小板下降(20.68%VS.0%,P<O.01)。试验组消化道反应的总发生率低于对照组,其中呕吐的发生率和严重程度两组之间存在显著性差异(P<0.05)。两组其他不良反应发生率相比无显著性差异。结论:奈达铂对晚期食管癌有一定的疗效,与5-FU联合的有效率较DDP+5-FU联合方案有一定优势,临床耐受性较好,主要不良反应为骨髓抑制。特别是严重的血小板下降
食管肿瘤, 化学疗法, 奈达铂, 临床试验
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