CN104523664B - 姜黄素类抗肿瘤药物及其应用 - Google Patents
姜黄素类抗肿瘤药物及其应用 Download PDFInfo
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- CN104523664B CN104523664B CN201510026974.1A CN201510026974A CN104523664B CN 104523664 B CN104523664 B CN 104523664B CN 201510026974 A CN201510026974 A CN 201510026974A CN 104523664 B CN104523664 B CN 104523664B
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了姜黄素类抗肿瘤药物,包含1‑(2‑溴‑4‑羟基苯基)‑5‑(4‑羟基‑3‑甲氧基苯基)‑1,4‑戊二烯‑3‑酮(记为WZ26)、1‑(4‑羟基‑3‑甲氧基苯基)‑5‑(2‑硝基苯基)‑1,4‑戊二烯‑3‑酮(记为WZ35)和1‑(4‑羟基‑3‑甲氧基苯基)‑5‑(2,4,5‑三甲基苯基)‑1,4‑戊二烯‑3‑酮(记为WZ37)中的一种或几种。其分子结构如下所示:。
Description
技术领域
本发明属药物化学领域,具体涉及姜黄素类抗肿瘤药物及其在制备抗肿瘤药物及与肿瘤相关疾病的治疗药物中的应用。
背景技术
癌症是严重威胁人类生命和健康的重大疾病。2013年,据报道全球约有790万人死于癌症,其中肺癌死亡约130万,胃癌死亡约80.3万,结直肠癌死亡约63.9万,肝癌死亡约61万,乳腺癌死亡约51.9万。因此,寻找新的抗肿瘤药物一直是科学工作者关注的问题。
姜黄素是中药姜黄发挥药理作用的主要活性成分,在印度、巴西、菲律宾、日本、韩国等地都有上千年的食用和药用记载。近年来,药物化学和药理学研究发现姜黄素具有抗肿瘤、抗肿瘤、抗血管生成、抗突变、抗菌、抗病毒、抗氧化和神经保护等多种药理作用,其在抗肿瘤方面具有:抗肿瘤谱广、多靶点、逆转肿瘤多药耐药等优点引起了人们的广泛关注。姜黄素在美国已经进入I期临床实验阶段。正是因为多生物活性,以及低分子量、无毒等特点,姜黄素曾被认为是理想的化学治疗药物之一。然而,进一步的研究发现姜黄素在体内的活性偏低、体内吸收少、代谢过快和生物利用度低,极大地限制了它的应用。但是,考虑到它确切的生物活性、相对简单的分子结构,姜黄素仍不失为一种优秀的结构修饰和抗肿瘤药物筛选的先导化合物,目前,以保留其药物安全性、增加抗肿瘤活性和水溶性为目的的姜黄素类似物设计、合成、评估和筛选研究吸引了很多药物研发机构和药物公司。通过大量的文献和专利查阅,我们发现,虽然目前普遍认为姜黄素结构中的活性基团是其酚羟基和β-二酮基团,但在不含有这两个活性基团的姜黄素类似物研究方面,也发现不含有β-二酮的单羰基姜黄素类似物有时候也表现出更强的活性,这对于β-二酮基团是姜黄素的活性必需基团提出了质疑。而且,由于β-二酮结构的存在,姜黄素的稳定性较弱,只有在pH<6.5时才具有较好的稳定性。据此,去掉β-二酮基团我们前期设计了以丙酮、环己酮和环戊酮为中间碳链的稳定的姜黄素单羰基类似物并表征了其活性。
发明内容
本发明的目的之一在于提供一种姜黄素类抗肿瘤药物,所述姜黄素类抗肿瘤药物包含1-(2-溴-4-羟基苯基)-5-(4-羟基-3-甲氧基苯基)-1,4-戊二烯-3-酮、1-(4-羟基-3-甲氧基苯基)-5-(2-硝基苯基)-1,4-戊二烯-3-酮和1-(4-羟基-3-甲氧基苯基)-5-(2,4,5-三甲基苯基)-1,4-戊二烯-3-酮中的一种或几种,同时也可以是包含有1-(2-溴-4-羟基苯基)-5-(4-羟基-3-甲氧基苯基)-1,4-戊二烯-3-酮、1-(4-羟基-3-甲氧基苯基)-5-(2-硝基苯基)-1,4-戊二烯-3-酮和1-(4-羟基-3-甲氧基苯基)-5-(2,4,5-三甲基苯基)-1,4-戊二烯-3-酮的可药用盐中的一种或几种。本发明的另一目的在于提供该姜黄素类抗肿瘤药物的应用。
本发明提供的姜黄素类抗肿瘤药物,其中,1-(2-溴-4-羟基苯基)-5-(4-羟基-3-甲氧基苯基)-1,4-戊二烯-3-酮((1E,4E)-1-(2-bromo-4-hydroxyphenyl)-5-(4-hydroxy-3-methoxyphenyl)penta-1,4-dien-3-one)的结构式如下所示,记为WZ26:
其中,1-(4-羟基-3-甲氧基苯基)-5-(2-硝基苯基)-1,4-戊二烯-3-酮((1E,4E)-1-(4-hydroxy-3-methoxyphenyl)-5-(2-nitrophenyl)penta-1,4-dien-3-one)的结构式如下所示,记为WZ35:
其中,1-(4-羟基-3-甲氧基苯基)-5-(2,4,5-三甲基苯基)-1,4-戊二烯-3-酮((1E,4E)-1-(4-hydroxy-3-methoxyphenyl)-5-mesitylpenta-1,4-dien-3-one)的结构式如下所示,记为WZ37:
本发明所述姜黄素类抗肿瘤药物包含的化合物WZ26、WZ37、WZ37可以应用于制备抗肿瘤药物和与肿瘤相关疾病的治疗药物中,这3种化合物抗肿瘤谱较广,可以治疗的癌症的例子包括,但是不局限于,皮肤癌、肺癌、睾丸癌、淋巴癌、白血病、食道癌、胃癌、结肠癌、乳腺癌、子宫内膜癌、卵巢癌、中枢神经系统癌、肝癌和前列腺癌。
一种姜黄素类抗肿瘤药物,其含有治疗有效量的作为活性成分的以上所述姜黄素类化合物(WZ26、WZ35、WZ37)中的任何一种或几种或其可药用盐及其药用辅料。姜黄素类抗肿瘤药物指本发明所述3个姜黄素类化合物中的任何一种或多种或其可药用盐与现已上市的抗肿瘤药物联合使用,制备得到的抗肿瘤性疾病类药物,已上市的抗肿瘤药物包括各种生物烷化剂、抗代谢药物、抗肿瘤抗生素及分子靶向药物等。
本文中所用“药用辅料”指药学领域常规的药物载体,例如:稀释剂、赋形剂如水等,填充剂如淀粉、蔗糖等;粘合剂如纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮;湿润剂如甘油;崩解剂如琼脂、碳酸钙和碳酸氢钠;吸收促进剂如季铵化合物;表面活性剂如十六烷醇;吸附载体如高岭土和皂粘土;润滑剂如滑石粉、硬脂酸钙/镁、聚乙二醇等。另外还可以在组合物中加入其它辅剂如香味剂、甜味剂等。
本发明药物组合物的各种剂型可以按照药学领域的常规生产方法制备。例如使活性成分与一种或多种载体混合,然后将其制成所需的剂型。所述药物的制剂形式包括注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、软膏剂、控释或缓释剂或纳米制剂。本发明可以组合物的形式通过口服,鼻吸入、直肠或者肠胃外给药的方式施用于需要这种治疗的患者。用于口服时,可将其制成常规的固体制剂如片剂、粉剂、粒剂、胶囊等,制成液体制剂如水或油悬浮剂或其它液体制剂如糖浆、酏剂等;用于肠胃外给药时,可将其制成注射用的溶液、水或油性悬浮剂等。
本发明的有益效果在于:提供了三个稳定性和药代性抗肿瘤性能得到改善的姜黄素类抗肿瘤药物,并且提供了其在制备治疗肿瘤和与肿瘤相关疾病的药物中的应用。
附图说明
图1所示为本发明WZ26、WZ35和WZ37的分子结构图。
图2所示为本发明WZ26、WZ35和WZ37对人胃癌SGC-7901细胞和结肠癌HCT116细胞的存活率曲线图。
图3所示为本发明WZ26、WZ35和WZ37诱导人胃癌SGC-7901细胞凋亡的流式检测图。
图4所示为本发明WZ26、WZ35和WZ37诱导人结肠癌HCT116细胞凋亡的流式检测图。
图5所示为本发明WZ26、WZ35和WZ37对内质网应激途径中CHOP蛋白的影响。
图6所示为本发明WZ26、WZ35和WZ37对ROS的激活曲线图。
图7所示为本发明WZ26、WZ35和WZ37的体内抗肿瘤活性图。
具体实施方式
下文将结合具体实施例详细描述本发明的内容。应当注意的是,下述实施例中描述的技术特征或者技术特征的组合不应当被认为是孤立的,它们可以被相互组合从而达到更好的技术效果。
图1所示为本发明WZ26、WZ35和WZ37的分子结构图。
图2所示为本发明WZ26、WZ35和WZ37对人胃癌SGC-7901细胞和结肠癌HCT116细胞的存活率曲线图。
图3所示为本发明WZ26、WZ35和WZ37诱导人胃癌SGC-7901细胞凋亡的流式检测图。
图4所示为本发明WZ26、WZ35和WZ37诱导人结肠癌HCT116细胞凋亡的流式检测图。
图5所示为本发明WZ26、WZ35和WZ37对内质网应激途径中CHOP蛋白的影响。
图6所示为本发明WZ26、WZ35和WZ37对ROS的激活曲线图。
图7所示为本发明WZ26、WZ35和WZ37的体内抗肿瘤活性图。
实施例1
化合物WZ26、WZ35和WZ37的合成,其结构式如图1所示
步骤1、中间体:3-甲氧基-4-[(四氢-2H-吡喃-2-基)氧基]苯甲醛(1)的制备
量取二氢吡喃5.0ml(4.63g,55.3mol)溶于30ml二氯甲烷中,在搅拌下加入7.48g(46.2mmol)的香草醛和50mg(0.198mmol)对甲苯磺酸。在室温下搅拌5小时,反应完毕后加入50ml水,用二氯甲烷(100ml)萃取。合并有机层并用饱和食盐水洗涤,无水MgSO 4干燥,过滤,并真空浓缩。硅胶柱层析纯化得到无色油状物3-甲氧基-4-[(四氢-2H-吡喃-2-基)氧基]苯甲醛(1),产率90%。
步骤2、中间体:α,β-不饱和酮(2)的制备
称取2g(11.3mnol)上述无色油状物3-甲氧基-4-[(四氢-2H-吡喃-2-基)氧基]苯甲醛(1)溶解于20mL丙酮中,再滴加4mL NaOH(w%为20%),室温下搅拌,TLC监测反应过程,约5h后反应结束。先真空泵旋干丙酮,再加入50mL EtOAc萃取,再用H2O(50mL)和饱和NaCl(50ml)洗涤,并用无水MgSO4干燥,抽滤,真空泵旋干浓缩,硅胶柱层析(6∶1石油醚/EtOAC)得到淡黄色油状液体α,β-不饱和酮(2)。
步骤3、中间体:羟基保护的不对称单羰基姜黄素类似物(3)的制备
在室温下向含中间体α,β-不饱和酮(2)(0.28mmol)和含不同取代基的苯甲醛(0.3mmol)的二氧六环溶液(5ml)中,再向其中加入适量NaOH固体。将反应混合物在室温下搅拌过夜,然后用水(15mL)稀释混合物,并用EtOAc萃取。有机层用饱和NaCl(50ml)洗涤,并用无水MgSO4干燥,抽滤,真空泵旋干浓缩,硅胶柱层析得到深黄色油状物即羟基保护的不对称单羰基姜黄素类似物(3)。
步骤4、化合物WZ26、WZ35和WZ37的制备
将上述中间体羟基保护的不对称单羰基姜黄素类似物(3)置于含5ml无水乙醇的锥形瓶中,再向其中加入5%HCl水溶液,室温搅拌1h,析出沉淀,抽滤,并用乙醇与水的混合物溶液洗涤沉淀,得到纯的目标产物。以下为制得化合物WZ26、WZ35和WZ37的核磁共振谱图数据:
化合物(WZ26):1-(2-溴-4-羟基苯基)-5-(4-羟基-3-甲氧基苯基)-1,4-戊二烯-3-酮:
Yellow powder,61%yield,mp 99.0-111.4℃.1H NMR(600MHz,CDCl3):δ=8.10(d,J=16.2Hz,1H,Ar2-CH=C),8.00(d,J=9.6Hz,1H,Ar2-H3),7.72(d,J=15.6Hz,1H,Ar1-CH=C),7.71-7.67(m,3H,Ar2-H4,5,6),7.56(d,J=15.6Hz,1H,Ar1-C=CH),7.20(d,J=8.4Hz,1H,Ar1-H5),7.12(s,1H,Ar1-H1),6.96(d,J=8.4Hz,1H,Ar1-H6),6.91(d,J=16.2Hz,1H,Ar2-C=CH),5.93(s,1H,Ar1-OH),3.96(s,3H,Ar1-OCH3).ESI-MS m/z:326.7(M+1)+,calcd for C18H15NO5:325.32。
化合物(WZ35):1-(4-羟基-3-甲氧基苯基)-5-(2-硝基苯基)-1,4-戊二烯-3-酮:
Yellow powder,61%yield,mp 99.0-111.4℃.1H NMR(600MHz,CDCl3):δ=8.10(d,J=16.2Hz,1H,Ar2-CH=C),8.00(d,J=9.6Hz,1H,Ar2-H3),7.72(d,J=15.6Hz,1H,Ar1-CH=C),7.71-7.67(m,3H,Ar2-H4,5,6),7.56(d,J=15.6Hz,1H,Ar1-C=CH),7.20(d,J=8.4Hz,1H,Ar1-H5),7.12(s,1H,Ar1-H1),6.96(d,J=8.4Hz,1H,Ar1-H6),6.91(d,J=16.2Hz,1H,Ar2-C=CH),5.93(s,1H,Ar1-OH),3.96(s,3H,Ar1-OCH3).ESI-MS m/z:326.7(M+1)+,calcd for C18H15NO5:325.32。
化合物(WZ37):1-(4-羟基-3-甲氧基苯基)-5-(2,4,5-三甲基苯基)-1,4-戊二烯-3-酮:
Yellow powder,78%yield,mp 123.2-125.5℃.1H NMR(600MHz,CDCl3):δ=8.00(d,J=16.2Hz,1H,Ar2-CH=C),7.65(d,J=15.6Hz,1H,Ar1-CH=C),7.44(d,J=15.6Hz,1H,Ar1-C=CH),7.17(d,J=8.4Hz,1H,Ar1-H5),7.10(s,1H,Ar1-H1),6.92(s,2H,Ar2-H2,5),6.88(d,J=8.4Hz,1H,Ar1-H6),6.71(d,J=16.2Hz,1H,Ar2-C=CH),5.892(s,1H,Ar1-OH),3.96(s,3H,Ar1-OCH3),2.29(s,6H,Ar2-CH32,6),2.21(s,3H,Ar2-CH34).ESI-MS m/z:323.6(M+1)+,calcd for C21H22O3:32240。
实施例2
WZ26、WZ35和WZ37的体外抗肿瘤活性检测
使用的细胞株有:人胃癌细胞株SGC-7901和人结肠癌细胞株HCT116。以上细胞均购自中国科学院上海生命科学研究院细胞中心。
细胞分别接种于96孔培养板中,调整细胞悬液为含5%热灭活新生牛血清,青霉素100U/mL,链霉素100μg/mL的1640培养基,每孔加入100μL,使细胞密度为5000个/孔。于37℃含5%CO2饱和湿度的培养箱中培养。24h后把溶于DMSO的各种化合物加入培养板中并使最终浓度为20,10,5,2.5和1.25μmol/L,孵育72h后终止培养前3h每孔加入5mg/ml MTT 20μL。孵育完毕小心吸除孔内液体,每孔加100μL DMSO,置摇床上低速振荡10min,使结晶物充分溶解,在酶联免疫检测仪490nm波长下测定各孔光吸收值(A)。阳性对照物为姜黄素。根据吸光度计算细胞生长抑制率。细胞生长抑制率=[OD对照-OD实验]/[OD对照-OD空白]×100%。以同一药物的不同浓度对肿瘤细胞生长抑制率作图,可得到剂量反应曲线,根据线性回归方程求出该药物对细胞生长抑制率为50%的浓度即为半数抑制浓度IC50。结果见图2,由图2可知:WZ26、WZ35和WZ37能够对人胃癌SGC-7901细胞和结肠癌HCT116细胞增殖有很强的抑制能力。
实施例3
WZ26、WZ35和WZ37诱导人胃癌细胞SGC-7901和人结肠癌HCT116细胞凋亡的流式检测
使用的细胞株有:人胃癌细胞株SGC-7901人结肠癌细胞HCT116。以上细胞均购自中国科学院上海生命科学研究院细胞中心。SGC-7901和HCT116分别接种于6mm孔培养板中,24h后把溶于DMSO的WZ26、WZ35和WZ37加入培养板中并使最终浓度为5和10μM,孵育24h。然后用PBS缓冲液冲洗三次,加入0.25%tryptan-EDTA。离心,再使细胞悬浮于0.5ml PBS。然后在37℃,100mg/mL RNAse和0.1%Triton X-100情况下用Annexin V and propidiumiodide(PI)染色30min后进行流式细胞仪(FC500,Beckman,USA)分析。结果见表1,作图得图3和图4,从图3和图4可以看出,24h后WZ26、WZ35和WZ37呈现剂量依赖诱导细胞凋亡。图3为WZ26、WZ35和WZ37诱导人胃癌SGC-7901细胞凋亡的流式检测图,图4为WZ26、WZ35和WZ37诱导人结肠癌HCT116细胞凋亡的流式检测图。
表1WZ26、WZ35和WZ37诱导人胃癌细胞SGC-7901和人结肠癌HCT116细胞凋亡的流式检测表
DMSO | WZ26 | WZ35 | WZ37 | Cur(20μm) | |
SGC-7901 | 2.8% | 33.4% | 47.7% | 29.7% | 6.8% |
HCT116 | 0.79% | 21.5% | 60.4% | 30.7% | 2.7% |
实施例4
WZ26、WZ35和WZ37对内质网应激途径中CHOP蛋白的影响检测
内质网应激(ER stress)涉及和介导多种药物刺激的细胞凋亡。根据Haidara K等(Haidara K,et al.Toxicol Appl Pharmacol,2008,doi:10.1016/j.taap.2008.01.010)所述的试验方法,即将1.2×106个细胞用培养液培养于37℃,24小时后更新培养液并加入不同浓度的化合物(对照组加入3uL DMSO),继续处理相应的时间段后,收集细胞提取总蛋白,用Western Blot检测CHOP含量,GAPDH作为校准蛋白。采用WZ26、WZ35和WZ37对SGC-7901细胞进行ER stress往凋亡方向发展的试验。我们的研究发现,ER stress的3个信号通路在WZ26、WZ35和WZ37作用早期均被诱导激活,WZ26、WZ35和WZ37的刺激使得SGC-7901细胞ERstress往凋亡方向发展,因此CHOP(C/EBP-homologous protein)的激活是其不可逾越的一环。附图5的数据很好地显示了WZ26、WZ35和WZ37激活CHOP。CHOP是一个由抗凋亡向促凋亡转换的重要的信号分子,可见,WZ26、WZ35和WZ37通ER stress激活凋亡信号分子CHOP,发挥其抗癌作用。
实施例5
WZ26、WZ35和WZ37通过激活ROS诱导癌细胞凋亡检测
使用的细胞株有:人胃癌细胞株SGC-7901人结肠癌细胞HCT116。以上细胞均购自中国科学院上海生命科学研究院细胞中心。SGC-7901和HCT116分别接种于6mm孔培养板中,24h后把溶于DMSO的WZ26、WZ35和WZ37加入培养板中并使最终浓度为5和10μM,孵育0.5h。然后用PBS缓冲液冲洗三次,加入无EDTA的胰酶消化。离心,再使细胞悬浮于0.5ml PBS。然后在37℃,用DCFH-DA染色30min后进行流式细胞仪(FC500,Beckman,USA)分析。结果见图6,实验时,取1.2×106个细胞用1640培养液培养于37℃,24小时后更新培养液。加入不同浓度的WZ26、WZ35和WZ37和姜黄素处理细胞0.5小时后收集细胞,用流式细胞仪检测ROS的含量。如图6所示,24h后WZ26、WZ35和WZ37呈现剂量依赖诱导细胞凋亡。
实施例6
活性化合物WZ26、WZ35和WZ37对裸鼠皮下移植瘤抑制率实验
雌性BALB/cA nu/nu裸鼠从Vital River Laboratories购买。裸鼠用标准啮齿类动物食物和水饲养在恒温昼夜12-12h节律的动物房内。动物在实验开始前至少花一周时间进行环境适应性生长。涉及到动物使用的协议都获得温州医科大学动物政策与福利委员会的批准(批准文件:2012/APWC/0216)。以PBS收集SGC-7901细胞浓度至1×107细胞/100μL,取体重18-22克雌性裸鼠,每鼠右侧腹部皮下接种0.1毫升细胞悬液。次日随机分组,将WZ26,WZ35和WZ37配成悬液,灌胃给药(50毫克/千克);阴性对照组每鼠灌胃等量的生理盐水,连续给药7天;阳性对照药用姜黄素,分组时给药一次,灌胃0.2毫升相当于50毫克/千克。最后一次给药24h时后,颈推脱臼处死小鼠,称体重,剥取瘤块,称瘤重。实验结果如图7所示,其中左图为裸鼠皮下移植瘤中三个化合物对胃癌SGC-7901的肿瘤抑制活性图;右图为裸鼠皮下移植瘤中三个化合物对结肠癌HCT116的肿瘤抑制活性,下图为肿瘤重量与三个化合物服用量间的关系图。
本文虽然已经给出了本发明的一些实施例,但是本领域的技术人员应当理解,在不脱离本发明精神的情况下,可以对本文的实施例进行改变。上述实施例只是示例性的,不应以本文的实施例作为本发明权利范围的限定。
Claims (4)
1.姜黄素类抗肿瘤药物,其特征在于,包含:1-(2-溴-4-羟基苯基)-5-(4-羟基-3-甲氧基苯基)-1,4-戊二烯-3-酮、1-(4-羟基-3-甲氧基苯基)-5-(2-硝基苯基)-1,4-戊二烯-3-酮和1-(4-羟基-3-甲氧基苯基)-5-(2,4,5-三甲基苯基)-1,4-戊二烯-3-酮中的一种或几种,其分子结构如下所示:
2.如权利要求1所述的姜黄素类抗肿瘤药物,其特征在于,所述姜黄素类抗肿瘤药物包含1-(2-溴-4-羟基苯基)-5-(4-羟基-3-甲氧基苯基)-1,4-戊二烯-3-酮、1-(4-羟基-3-甲氧基苯基)-5-(2-硝基苯基)-1,4-戊二烯-3-酮和1-(4-羟基-3-甲氧基苯基)-5-(2,4,5-三甲基苯基)-1,4-戊二烯-3-酮的可药用盐中的一种或几种。
3.一种如权利要求1或2所述姜黄素类抗肿瘤药物的应用,其特征在于,可应用于制备抗肿瘤和与肿瘤相关疾病的治疗药物中。
4.一种如权利要求3所述姜黄素类抗肿瘤药物的应用,其特征在于,可应用于制备抗肿瘤和与肿瘤相关疾病的治疗药物中,所述与肿瘤相关疾病包括但不局限于:皮肤癌、肺癌、睾丸癌、淋巴癌、白血病、食道癌、胃癌、结肠癌、乳腺癌、子宫内膜癌、卵巢癌、中枢神经系统癌、肝癌和前列腺癌。
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