CN101432012B - 用于难治性肿瘤的治疗和/或难治性肿瘤对于抗癌药物的化学敏化的药物组合 - Google Patents

用于难治性肿瘤的治疗和/或难治性肿瘤对于抗癌药物的化学敏化的药物组合 Download PDF

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CN101432012B
CN101432012B CN2007800152341A CN200780015234A CN101432012B CN 101432012 B CN101432012 B CN 101432012B CN 2007800152341 A CN2007800152341 A CN 2007800152341A CN 200780015234 A CN200780015234 A CN 200780015234A CN 101432012 B CN101432012 B CN 101432012B
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cytostatic agent
medicine
tumor
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cell
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CN101432012A (zh
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S·E·佩里亚罗德里格斯
Y·佩雷拉尼格林
A·罗德里格斯乌略亚
J·希尔巴尔德斯
Y·拉莫斯戈麦斯
L·R·卡斯特拉诺斯萨拉
L·H·贝坦科特纽涅兹
A·桑切斯普恩特
J·费尔南德斯德科西奥多尔塔杜克
B·E·阿塞韦多卡斯特罗
L·J·冈萨雷斯洛佩斯
V·贝萨达佩雷斯
D·F·阿隆索
D·E·戈麦斯
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Abstract

本发明涉及这样的药物组合，其包含酪蛋白激酶2(CK2)磷酸化抑制剂(称为P15)和用于癌症化学疗法的细胞生长抑制剂，它们同时、分开或顺次施用。优选的细胞生长抑制剂为铂类、紫杉烷类、长春花生物碱、5-氟尿嘧啶、多柔比星、环磷酰胺、依托泊苷、丝裂霉素C、伊马替尼、易瑞沙和万珂(硼替佐米)。肽P15和抗癌化合物之间的协同作用意味着，所述组合中的每种细胞生长抑制剂的有效浓度比相应于单独的细胞生长抑制剂的有效浓度低10-100倍。因此，本发明中描述的组合具有比对于抗癌细胞生长抑制剂所报道的毒性低得多的毒性，这代表了其用于癌症治疗中的关键优点。此外，顺次施用的所述组合通过用肽P15进行预处理而导致难治性肿瘤对于所提及的细胞生长抑制剂的化学敏化。

Description

用于难治性肿瘤的治疗和/或难治性肿瘤对于抗癌药物的化学敏化的药物组合
技术领域
本发明涉及分子和实验肿瘤学领域，特别涉及描述旨在难治性肿瘤的治疗和/或难治性肿瘤对于常规细胞生长抑制剂的化学敏化的药物组合。 
现有技术
在过去30年中，使用化学药物作为用于癌症治疗的细胞生长抑制剂构成了作为用于某些实体和造血系统肿瘤的第一线治疗的选择之一。用于癌症治疗的最常用的化学药物尤其是：铂类、紫杉烷类长春花生物碱、多柔比星、5-氟尿嘧啶和环磷酰胺(Jackman A.L.，KayeS.，Workman P.(2004)The combination of cytotoxic andmolecularly targeted therapies-can it be done？Drug DiscoveryToday 1：445-454)。然而，来自临床试验的结果显示出这类药物在癌症治疗中的低的治疗指数(如由边际治疗益处(marginaltherapeutic benefit)所证实的)，以及在患者中所观察到的高毒性特性谱(Schrader C.等人M.(2005)Symptoms and signs ofan acutemyocardial ischemia caused by chemotherapy with paclitaxel(taxol)in a patient with metastatic ovarian carcinoma.EurJ Med Res 10：498-501)。例如，许多作者同意，顺铂构成了用于肺癌的第一线治疗，然而，通常观察到适度功效，并且临床症状和6周存活增加具有很少的改善(Grillo R.，Oxman A.，Julian J.(1993) Chemotherapy for advanced non-small cell lung cancer.J ClinOncol11：1866-1871；Bouquet P.J.，Chauvin F.等人(1993)Polychemotherapy in advanced non-small cell lung cancer：ameta-analysis.Lancet 342：19-21)。因此，目前用于达到最佳治疗益处的策略集中于基于常规细胞生长抑制剂以及分子靶向疗法的药物组合。目前的抗癌药物中的一些被分类为癌症靶向疗法，例如，尤其是靶向在慢性髓性白血病的发展中起重要作用的Ab1激酶的格列卫(伊马替尼)(Giles J.F.，Cortes J.E.，Kantarjian H.M.(2005)Targeting the Kinase Activity of the BCR-ABL Fusion Protein inPatients with Chronic Myeloid Leukemia.Current Mol Med 5：615-623)，以及靶向与表皮生长因子(EGF)受体相关的酪氨酸激酶的易瑞沙(Onn A.，Herbst R.S.(2005)Molecular targeted therapyfor lung cancer.Lancet 366：1507-1508)，和通过靶向蛋白酶体机制来阻断蛋白质降解的万珂(硼替佐米)(SpanoJ.P.等人(2005)Proteasome inhibition：a new approach for the treatment ofmalignancies.Bull Cancer 92：E61-66)。考虑到常规化学治疗剂的非特异性机制集中于细胞有丝分裂的废除，新型癌症靶向治疗剂的使用提供了实现产生抗肿瘤效应的协同作用的药物组合的极大前景。 
另一方面，抗药性现象被认为是当使用化学治疗剂时，癌症疗法失败的主要原因。尽管在肿瘤位置处的亚最佳药物浓度可以影响抗药性，但其他因素如细胞起源也在许多肿瘤的化学抗性中起重要作用。抗药性是依赖于多个独立机制的多因素现象，所述独立机制包括细胞内解毒、细胞应答的变化、对应激的耐受性和凋亡信号传导途径中的缺陷(Luqmani A.(2005)Mechanisms of drug resistance in cancerchemotherapy.Med Princ.Pract 14：35-48)。糖蛋白-P和谷胱甘肽S-转移酶是介导与癌症中的抗药性现象相关的细胞内解毒过程的主要蛋白质(Saeki T.，Tsuruo T.，Sato W.，Nishikawsa K.(2005)Drug resistance in chemotherapy for breast cancer.CancerChemo ther Pharmacol 56：84-89)(Hara T.等人(2004)Gluthathione S-transferase P1 has protective effects on cell viabilityagainst camptothecin.Cancer Letters 203：199-207)。已报道其他蛋白质如β-微管蛋白参与抗药性现象，并且其水平与对紫杉醇的肿瘤抗性直接相关(OrrG.A.等人(2003)Mechanisms of Taxolresistance related to microtubules.Oncogene 22：7280-7295)。此外，已报道顺铂抗性受不同蛋白质的过表达的影响，所述蛋白质如T-丝束蛋白(Hisano T.等人(1996)Increased expression ofT-plastin gene in cisplatin-resistant human cancer cells：identification by mRNA differential display.FEBS Letters 397：101-107)、热休克蛋白(HSP70)和(HSP90)(Jaattela M.(1999)Escaping cell death：survival proteins in cancer.Exp Cell Res248：30-43)和转录因子YB1(Fujita T.等人(2005)Increasednuclear localization of transcription factor Y-box bindingprotein accompanied by up-regulation of P-glycoprotein inbreast cancer pretreated with paclitaxel.Clin Cancer Res 11：8837-8844)。此外，已报道糖酵解和丙酮酸合成途径的加剧对于在肿瘤细胞中观察到的化学抗性现象起重要作用(Boros L.G.等人(2004)Use of metabolic pathway flux information in targeted cancerdrug design.Drug Disc.Today 1：435-443)。 
来自不同团体的报道已表明，存在这样的一系列蛋白质，其抑制凋亡和增加肿瘤细胞的存活，从而促成肿瘤的化学抗性现象。实例之一是核磷蛋白，其在促进细胞周期、抑制凋亡中起关键作用，并且已被视为癌症中的不良预后标记(Ye K.(2005)Nucleophosmin/B23，a multifunctional protein that can regulate apoptosis.CancerBiol Ther 4：918-923)。此外，CK2酶在细胞存活和肿瘤细胞针对凋亡的抗性中起重要作用(Tawfic S.，Yu S.，Wang H.，Faust R.，Davis A.，Ahmed K.(2001)Proteinkinase CK2signal in neoplasia.Histol.Histopathol.16：573-582)。先前的发现已揭示，CK2活性在上皮实体瘤中相对于正常组织升高3-7倍(Tawfic S.，Yu S. 等人(2001)Protein kinase CK2 signal in neoplasia.HistolHistopatol.16：573-582；Faust R.A.，Gapany M.等人(1996)Elevated protein kinase CK2 activity in chromatin of head andneck tumors：association with malignant transformation.CancerLetters 101：31-35)。此外，CK2活性是恶性转化的重要细胞事件，并且它为一种肿瘤进展标记(Seldin D.C.，Leder P.(1995)CaseinKinase IIα transgene-induced murine lymphoma：relation totheileroiosis in cattle.Science 267：894-897)。CK2磷酸化代表了保护肿瘤细胞免于凋亡的强信号这一事实导致这种酶被视为细胞生理学中的抗凋亡介体(Ahmed K.，Gerber D.A.，Cochet C.(2002)Joining the cell survival squad：an emerging role for proteinkinase CK2.Trends Cell Biol，12：226-229；Torres J.，Rodríguez J.等人(2003)Phosphorylation-regulated cleavage ofthe tumor suppressor PTEN by caspase-3：implications for thecontrol of protein stability and PTEN-protein interactions.JBiol Chem，278：30652-60)。 
总之，CK2磷酸化是代表了用于癌症治疗的潜在靶标的生物化学事件，并且这个事件的特异性抑制剂可以产生对于癌症治疗而言具有前景的药物候选物。 
不同研究组已使用2种独立的方法开发出了抑制CK2磷酸化的不同策略：a)对CK2α催化亚基的直接抑制，b)对CK2底物上的酸性结构域的直接靶向(专利WO03/054002和Perea S.E.等人(2004)Antitumor effect of a novel proapoptotic peptide impairing thephosphorylation by the protein kinase CK2.Cancer Res.64：7127-7129)。通过使用这2种方法，作者已证实CK2抑制导致肿瘤细胞的凋亡这一构思。这些发现加强了CK2作为合适靶以开发抗癌药物的实验确认。 
比较蛋白质组学研究以及分子生物学的发展已部分地使得能够了解参与细胞恶性转化和肿瘤化学抗性的分子机制。因此，癌症治疗方 案应将其注意力集中于产生有效的药物组合，其极大地减少毒性并且还降低化学抗性出现的可能性。 
因此，当前癌症治疗的主要目标之一是通过减少由这类药物的有效剂量和固有毒性来增加目前的细胞生长抑制剂的治疗指数。其他的目前策略是克服针对常规细胞生长抑制剂的肿瘤化学抗性。 
发明详述 
本发明解决了上文提及的问题，因为它提供了包含下述2种成分的药物组合：CK2磷酸化抑制剂(肽P15)和药学上可接受的细胞生长抑制剂。 
在本发明中，“药学上可接受的细胞生长抑制剂”指用于实体瘤和造血系统起源的肿瘤的癌症化学疗法的所有细胞生长抑制性化学化合物。优选的细胞生长抑制剂是与合适的载体相混合的铂类(例如，卡铂和顺铂)、紫杉烷类(例如，紫杉醇和多西他赛)、长春花生物碱(例如，长春新碱和长春碱)、5-氟尿嘧啶、多柔比星、环磷酰胺、依托泊苷、丝裂霉素C、伊马替尼、易瑞沙和万珂(硼替佐米) 
在本发明中，“CK2磷酸化的抑制剂”这一术语还包括阻断底物或酶本身的任何化学或肽性化合物。根据情况，这种药物组合的活性成分可以同时、分开或顺次施用。这种药物组合的施用可以通过全身、局部或口服途径来进行。 
本发明还涉及在哺乳动物尤其是人中难治性肿瘤的治疗和/或化学敏化，包括施用上文提及的药物组合。此外，本发明还涉及这种药物组合的成分在制备药物中的用途，所述药物用于治疗化学难治性肿瘤并增强本发明中提及的细胞生长抑制剂的抗肿瘤效应。 
实施例1(表1)显示了，本发明中描述的药物组合在体外产生协同的抗肿瘤效应。因此，亚最佳剂量的肽P15以及顺铂、紫杉醇、多柔比星、长春新碱、依托泊苷、丝裂霉素C、5-氟尿嘧啶、伊马替尼或易瑞沙的同时组合实现了本发明中提及的每种细胞生长抑制剂的有 效剂量10或100倍减少。有效剂量是达到50％抗肿瘤效应的剂量，这在体外增殖测定法中也称为50％抑制浓度(IC50)。在本发明中，“亚最佳剂量”指低于IC50的那些剂量。 
实施例2举例说明了通过使用这种药物组合增强了体内抗肿瘤效应，所述药物组合包含肽P15以及顺铂(图1A)、环磷酰胺(图1B)和丝裂霉素C(图1C)。该药物组合在相关动物模型(如在裸鼠中异种移植的人肿瘤的动物模型)中导致完全的肿瘤消退。然而，与在安慰剂组中观察到的效应相比较，作为单一疗法来使用这种药物组合的成分仅产生在肿瘤生长方面的少量延迟。 
这种药物组合的成分的顺次施用证实，P15处理在体外和体内克服了肿瘤化学抗性。在本发明中，应当理解“克服肿瘤化学抗性或化学敏化”指在用肽P15预处理后降低了对于产生50％抗肿瘤效应而言所需的药物剂量的事件。实施例3(表2)举例说明了肽P15预处理在肿瘤细胞的化学敏化中的效应，并且它导致有效药物剂量10-100倍减少。类似地，表3中显示的数据表示，所述药物组合的顺次施用在体外克服了肿瘤细胞的固有化学抗性。在本发明中，当IC50值达到高于1000μM的浓度时，被视为具有体外化学抗性。 
类似于体外结果，在体内用肽P15预处理克服了肿瘤的固有化学抗性(实施例4)(图2A、2B、2C)。 
肽P15成分(氨基酸序列：CWMSPRHLGTC)先前已被报道为CK2抑制剂(Perea S.E.等人(2004)Antitumor effect of a novelproapoptotic peptide impairing the phosphorylation by theprotein kinase CK2.Cancer Res.64：7127-7129)。然而，这种肽出乎意料地在肿瘤细胞中调节一组蛋白质(表4)，所述蛋白质加强并阐明所述药物组合中的成分的协同抗肿瘤效应以及通过用肽P15预处理而产生的化学敏化。例如，由P15调节的蛋白质在肿瘤细胞增殖的控制和凋亡中起重要作用，并且这些机制独立于由这种药物组合的其余组分例如在本发明中优选的细胞生长抑制剂所采用的机制。 
同样地，由成分P15调节的其他蛋白质是这样的蛋白质，其参与 对于本发明中优选的细胞生长抑制剂的肿瘤化学抗性的分子机制。这些出乎意料的结果构成了当成分顺次施用时，由这种药物组合产生的肿瘤化学敏化的分子基础。 
本发明的特点是下述事实：与细胞生长抑制剂单独使用时的有效剂量相比较，所述药物组合中的细胞生长抑制剂的有效浓度减少10-100倍。这表示，在CK2抑制剂和本发明中优选的细胞生长抑制剂之间发生协同相互作用。从实际观点来看，这种协同相互作用意味着，基于这种药物组合的药物的毒性比仅基于细胞生长抑制剂的药物的毒性低得多。 
类似地，在顺次施用这种药物组合的成分后所引发的肿瘤的化学敏化表现出巨大优点，因为它允许治疗在实体瘤和造血系统起源的肿瘤中经常观察到的化学抗性。 
附图简述 
图1：在癌症动物模型中由所述药物组合增强了抗肿瘤效应：(A)显示了顺铂+P15的协同作用的结果，(B)显示了环磷酰胺+P15的协同作用的结果，(C)显示了丝裂霉素C+P15在体内的协同作用的结果。 
图2：在体内肽P15的化学敏化效应：(A)显示了对于顺铂的化学敏化，(B)显示了对于紫杉醇的化学敏化，和(C)显示了对于多柔比星的化学敏化。 
实施例的详细说明 
一般操作程序： 
细胞培养：H-125细胞系来源于人非小细胞肺癌(NSCLC)，而SW948细胞系来源于人结肠癌。将这2种细胞系维持在补充有10％胎牛血清 和庆大霉素(50μg/ml)的RPMI1640培养基(Gibco)中。细胞培养物的温育于37℃在5％CO2中进行。 
细胞生存力测定法：为了这个目的，将20μl四唑鎓(MTS)(Promega)加入至每个包含所播种的细胞的96孔平板中。于37℃放置2小时后，读取在492nm处的吸光度。最后，使用“CurveExpert”软件由各自的剂量-反应曲线估计IC50值。 
癌症动物模型：本发明中使用的动物模型基于在裸鼠(Nu/Nu，BaiBC)中植入人肿瘤。简而言之，将5×106个H-125细胞悬浮于磷酸盐缓冲溶液(PBS)中并进行皮下接种。在肿瘤出现(大约30mm3)后，使用本发明中描述的药物组合开始处理。为了评估所述药物组合的抗肿瘤效应，测量肿瘤体积，其通过使用下式来进行计算：V＝宽度2×长度/2。 
细胞提取物中蛋白质谱的分析：H-125细胞用本发明中描述的药物组合的肽P15成分处理40分钟或不进行此处理。随后，用PBS洗涤细胞单层并从表面上刮下细胞。在用冷PBS再洗涤2次后，将细胞粒状沉淀重悬浮于10mMtris-HCl pH7.5，0.25M蔗糖，1mM EGTA+蛋白酶抑制剂混合物中，并且如先前所述获得核内蛋白级分(GonzálezL.J.等人(2003)Identification of nuclear proteins of small celllung cancer cell line H82：An improved protocol for the analysisof silver stained proteins.Electrophoresis 24：237-252)。为了分析由P15调节的蛋白质，各核内蛋白提取物备选地在二维凝胶(pH4-7)中和/或通过与质谱法偶联的液相色谱(纳米HPLC)来进行解析。 
本发明通过下述实施例来进行说明： 
实施例1：肽P15+常规细胞生长抑制剂的组合的协同效应。 
在下述实验条件下评估了与不同细胞生长抑制剂相组合的肽P15成分的抗肿瘤协同效应：将H-125细胞种植在96孔平板中，并将肽 P15以10和50μM的浓度加入至每个平板中。同时，在本发明中优选的细胞生长抑制剂各自以1-2000nM的剂量加入，并且在相同条件下继续温育72小时。最后，如本发明中上文所述，测定细胞生存力和IC50值。表1中所示的结果证实，当同时与10或50μM的成分P15相组合时，每种细胞生长抑制剂的IC50值减少10-100倍。这些结果明确地证实，包含肽P15和在本发明中优选的细胞生长抑制剂作为成分的药物组合加强了抗肿瘤效应。 
表1.通过同时施用这种药物组合中的成分而获得的抗肿瘤协同相互作用 
  
变量 单独的细胞生长抑制剂 细胞生长抑制剂+P15(10μM) 细胞生长抑制剂+P15(50μM)
顺铂 720nM 530nM 40nM
紫杉醇 17nM 8nM 3nM
5-氟尿嘧啶 1200nM 420nM 60nM
长春新碱 856nM 100nM 8nM
多柔比星 423nM 200nM 76nM
环磷酰胺 2400nM 1004nM 85nM
丝裂霉素C 994nM 93nM 9nM
伊马替尼 600nM 200nM 58nM
万珂 2000nM 1200nM 700nM
易瑞沙 689nM 174nM 47nM
实施例2：在癌症动物模型中所述药物组合的抗肿瘤效应的加强。 
为此，如本发明中上文所述，将5×106个H-125肿瘤细胞植入6-8周大的BalBc裸鼠中。肿瘤出现后，如下施用所述药物组合的成分：在5天期间以0.5mg/kg/天经腹膜内施用在盐水溶液中的肽P15。与此同时，以相同的频率以1mg/kg/天来腹膜内注射顺铂(图1A)、环磷酰胺(图1B)或丝裂霉素C(图1C)。也将细胞生长抑制剂溶解 于盐水溶液中。如本发明中上文所述，记录肿瘤体积。图1A、1B和1C中所示的结果表明，当同时施用所述成分时，所述药物组合加强抗肿瘤效应，这表现为观察到完全的肿瘤消退。相反地，当作为单一疗法施用所述成分时，相对于安慰剂组仅观察到不大的抗肿瘤效应。因此，我们在相关的且预测性的临床前肿瘤模型中进一步证实了这种药物组合中的成分之间的协同相互作用。 
实施例3：在体外肽P15的化学敏化效应。 
在这个测定法中，我们评估了当成分顺次施用时所述药物组合的化学敏化作用。为此，将H-125细胞以2000个细胞/孔种植在96孔平板中，并且在24小时后加入20μM的肽P15。在与肽P15成分温育16小时后，将细胞单层用盐水溶液洗涤2次。最后，以1-2000nM的浓度添加在本发明中优选的细胞生长抑制剂，并将温育继续72小时。最后，如本发明中先前所述，测定每种细胞生长抑制剂的细胞生存力和IC50值。表2中所示的结果证实，用肽P15成分对肿瘤细胞进行预处理增加了这些细胞对本发明中优选的每种细胞生长抑制剂的敏感性。此外，我们评估了P15预处理对于SW948细胞的影响，所述SW948细胞固有地对于细胞生长抑制剂的效应具有抗性。结果证实，肽P15成分还将固有药物难治性肿瘤细胞转变成对于本发明中优选的细胞生长抑制剂敏感的细胞。(表3)。 
我们的数据证实，顺次施用肽P15成分和本发明中优选的细胞生长抑制剂导致肿瘤细胞对于此类药物的抗肿瘤效应的敏化。 
表2.顺次施用的药物组合的体外化学敏化效应 
  
变量 单独的细胞生长抑制剂 细胞生长抑制剂+P15预处理
顺铂 720nM 20nM
紫杉醇 17nM 0.9nM
5-氟尿嘧啶 1200nM 105nM
[0043] 
  长春新碱   856nM   83nM
  多柔比星   423nM   72nM
  环磷酰胺   2400nM   100nM
  丝裂霉素C   994nM   20nM
  伊马替尼   600nM   10nM
  万珂   2000nM   370nM
  易瑞沙   689nM   63nM
表3.顺次施用的药物组合对于固有药物难治性肿瘤细胞的体外化学敏化效应 
Figure DEST_PATH_GSB00000903038300011
通过在本发明中使用的肿瘤细胞之中观察到的由药物调节的蛋白质谱进一步验证了肽P15成分对于化学敏化的影响。为此，如本发明中先前所述，分析来自用肽P15成分处理或未处理的H-125细胞的核内蛋白提取物。表4显示了一组蛋白质，其由肽P15成分调节，并且通过其功能性质，其在分子水平上支持和证明了在本发明的药物组合中这种肽的化学敏化作用。 
表4.由P15调节的蛋白质谱 
Figure DEST_PATH_GSB00000903038300012
  
Y-boxl转录因子 3.33
促红细胞生成素前体 120
S-谷胱甘肽转移酶 4.87
蛋白酶体激活复合物 3.35
由泛素激活的E1酶 2.49
葡萄糖-6-磷酸异构酶 8.53
甘油醛-6-磷酸脱氢酶 6.62
丙酮酸激酶 8.34
在翻译方面受控制的肿瘤蛋白质 4.32
通过用肽P15成分进行处理而被激活的蛋白质 激活系数
抗增殖蛋白 2.28
微管蛋白α-1 3.23
微管蛋白β-2 2.56
微管蛋白β-3 3.15
实施例4：在体内肽P15成分的化学敏化效应。 
为此，如本发明中先前所述，将5×106个SW948细胞植入
Figure G2007800152341D0012185814QIETU
在肿瘤出现后，如下顺次施用所述药物组合：首先，在5天期间以0.5mg/kg/天经腹膜内施用肽P15成分。随后，在另外5天期间以5mg/kg/天施用顺铂(图2A)、紫杉醇(图2B)和多柔比星(图2C)。本文的结果证实，在体内用P15预处理化学难治性肿瘤能够恢复抗性表型，从而使得所述肿瘤变得能够对本发明中优选的细胞生长抑制剂作出应答。这些发现还提供了证据来证明，当顺次施用所述成分时，本发明的药物组合能够克服常常观察到的固有肿瘤抗性。

Claims (16)

1.药物，其包含用于同时或顺次施用的氨基酸序列为CWMSPRHLGTC的肽和药学上可接受的细胞生长抑制剂，与合适的载体相混合。
2.根据权利要求1的药物，其中所述细胞生长抑制剂是选自铂类、紫杉烷类和长春花生物碱的化合物。
3.根据权利要求2的药物，其中所述铂是卡铂或顺铂。
4.根据权利要求2的药物，其中所述紫杉烷是紫杉醇或多西他赛。
5.根据权利要求2的药物，其中所述长春花生物碱是长春新碱或长春碱。
6.根据权利要求1的药物，其中所述细胞生长抑制剂是5-氟尿嘧啶。
7.根据权利要求1的药物，其中所述细胞生长抑制剂是多柔比星。
8.根据权利要求1的药物，其中所述细胞生长抑制剂是环磷酰胺。
9.根据权利要求1的药物，其中所述细胞生长抑制剂是丝裂霉素C。
10.根据权利要求1的药物，其中所述细胞生长抑制剂是万珂，即硼替佐米。
11.根据权利要求1的药物，其中所述细胞生长抑制剂是易瑞沙。
12.根据权利要求1的药物，其中所述细胞生长抑制剂是伊马替尼。
13.氨基酸序列为CWMSPRHLGTC的肽和药学上可接受的细胞生长抑制剂在制备用于克服实体肿瘤或造血系统肿瘤对于药学上可接受的细胞生长抑制剂的抗性的药物中的用途。
14.根据权利要求13的用途，其中所述肽在DNA载体中表达。
15.氨基酸序列为CWMSPRHLGTC的肽以及药学上可接受的细胞生长抑制剂在制备用于癌症治疗的药物中的用途。
16.氨基酸序列为CWMSPRHLGTC的肽以及药学上可接受的细胞生长抑制剂在制备用于治疗对于细胞生长抑制剂具有抗性的肿瘤的药物中的用途。
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