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肺癌靶向药物

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ZD1839 易瑞沙(吉非替尼)的基础研究

  在很多人类肿瘤中都存在着表皮生长因子受体(EGFR)和c-erbB2的过表达,研究表明,它们与肿瘤的侵略行为和患者的不良预后有关。EGFR酪氨酸激酶家族起到把细胞外信号转导到细胞内的作用,增加了肿瘤细胞的增殖,阻止凋亡,增强了其活性、粘附性和侵袭性,其中最重要的是由原癌基因c-erbB-1/HER-1/EGFR和c-erbB-2/her2/neu编码的EGFR[1],针对EGFR和它的信号转导的靶向治疗能抑制肿瘤细胞的增殖、血管生成和DNA损伤修复。ZD 1839是一种高特异性的EGF受体酪氨酸激酶抑制剂,阻断信号转导的第一步,抑制了EGFR磷酸化作用,而有抑制肿瘤细胞增殖的作用[2],与放疗和化疗联合应用有协同作用。
    1 表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)的作用机理

    1.1 EGFR的结构与功能 EGFR是一个分子量为17kDa的跨膜糖蛋白,有配体依赖性的酪氨酸激酶活性,除造血干细胞外,存在于大多数细胞中,在多种肿瘤中都有过表达,如结直肠癌、乳腺癌、胰腺癌、前列腺癌和非小细胞肺癌等,其中NSCLC的鳞状细胞癌表达率最高为57%~92%[3]。EGFR由3个主要区域组成:一个N端细胞外区域,一个疏水的跨膜区和一个C端细胞内区域,细胞内包括酪氨酸区域。细胞外区域是多种多肽生长因子的配体结合点,其中最重要的是表皮生长因子(EGF)和转移生长因子α(TGFα)[4]。细胞外配体结合区与EGF和TGFα结合后,发生受体二聚合,导致细胞内酪氨酸激酶区域被激活,与一个ATP分子结合,受体自身磷酸化和其他受体单体的脱磷酸化。自体磷酸化把磷酸盐并入C-末端残基的酪氨酸中,使其成为一些包括信号传导体(如p85,Grb2/Sos,PLCγ1等)的Src同源体2(SH2),它的作用是把增殖和生存信号传导到受体的下游信号传导途径中[5]。在配体诱导的激活后,EGFR能连接很多参与信号转导瀑布反应的细胞内蛋白质,包括PLCγ、PI3K、小G蛋白、p21 Ras、GAP和Src家族激酶[6,7],通过不同的受体类型和磷酸化结合的位点,使不同的信号蛋白被激活。这个过程使不同的细胞外信号被传导到细胞核中。EGFR的酪氨酸激酶活性代表了它的有效结构,并且是信号传导的基础,细胞能通过生长因子自体分泌方式发生自身恶变,而为了获得恶性转变,需要活性配体的存在和EGFR的高水平表达[8]。除了促增殖外,活化的EGFR对肿瘤发展起重要作用的生物学反应还包括:对细胞运动性的影响、细胞粘附、浸润、细胞生存和血管生成[9]。

    1.2 抗肿瘤治疗的新靶向 由于EGFR酪氨酸激酶在肿瘤细胞中的生物学活性,因此它已经成为抗肿瘤治疗的新靶向。酪氨酸激酶磷酸化抑制剂作用在细胞内受体区域,通常被称为TKIs,大多数是完全占据ATP结合位点,因而对EGFR酪氨酸激酶有很好的选择性。4-苯胺奎哪唑啉是一种与ATP位点结合的有效和选择性的抑制剂。这类药物的结构—活性关系清楚定义了其结合方式,奎唑啉环与腺嘌呤结合,苯胺环与邻近的单一的亲脂区结合。一个单独的邻近奎唑啉结合位点的半胱氨酸(Cys-773)导致了不可逆的抑制作用[10]。其中的代表为口服药ZD1839(商品名为Iressa)。ZD1839是一种口服的有活性、选择性和可逆性的表皮生长因子受体(EGRF)酪氨酸激酶抑制剂,它阻断了在肿瘤细胞增殖和生存中包含的信号传导途径。

    1.3 ZD1839的药物代谢动力学 ZD1839是有效的EGFR-TKI(IC(50) = 0.033 micro M),口服给药,一天一次,对肿瘤生长的抑制呈剂量依赖形式,并且肿瘤异种移植物EGFR的表达水平并不影响对ZD1839的敏感性[11]。健康志愿者(28名)的药物代谢动力学的研究结果显示单一口服ZD1839后,血浆药物浓度峰值(Cmax)出现在3~7小时,Cmax随后成双向下降,半衰期介于27和41小时之间,剂量范围在10mg~100mg之间,Cmax及AUC24h(0到24小时曲线下面积)和剂量之间呈线性上升关系[12]。

    2 人类肿瘤细胞系和动物模型中的研究

    通过人类肿瘤细胞系和无胸腺裸鼠人类肿瘤异种移植物模型对ZD1839的研究可以证实其具有抗增殖、抗血管生成和增加凋亡的作用。Ciardiello等[13]评估了ZD1839在共同表达TGFα和EGFR的人类结肠(GEO,SW480和CaCo2)、乳腺(ZR-75-1,MCF-7 ADR)、卵巢(OVCAR-3)和胃(KATO III 和N87)的癌细胞系中的抗血管生成和抗肿瘤作用,GEO异种移植的免疫缺陷鼠,在ZD1839治疗后,用免疫组化分析GEO异种移植物显示了肿瘤细胞中TGFα、bFGF和VEGF的表达下降呈明显的剂量依赖性,由微血管计数测定的抗新血管生成作用亦有剂量依赖性。英国一个试验组[14]在对原位导管癌(Ductal carcinoma in situ,DCIS)的异种移植物模型的研究中发现,口服ZD1839(100~200 mg/kg,共14 天)使上皮细胞增殖降低了56%。Anderson NG等[15]观察到在体外,EGFR过表达的A431和MDA-MB-231乳腺癌细胞系的增殖在给予ZD1839最大有效剂量的一半时就有50%~70%被抑制,抑制了20%~80%EGFR(+)erbB2过表达的肿瘤细胞(SKBr3、SKOV3、BT474)的增殖, ZD1839抑制了无胸腺裸鼠异种移植MDA-MB-231和SKOV3肿瘤的生长,分别为71%和32%。

    2.1 ZD1839与细胞毒药物联合应用的研究 ZD1839与多种细胞毒药物化疗联合应用具有协同的抗肿瘤活性,这种抑制作用不仅见于进展期转移的肿瘤,还见于早期病灶,如人类乳腺导管原位癌。Magne等[16]在CA133细胞系(一种高表达EGFR的人类头颈部癌细胞系)中先加入ZD1839孵育48小时,再加入顺铂和5-Fu孵育48小时。结果发现ZD1839单药诱导细胞聚集于G0/G1期,在24小时p21、p27 和Bax表达增高,Bcl2表达和Akt磷酸化明显降低。48小时时DNA-PK降低。ZD1839单独应用对caspase-3活性没有影响,但是与顺铂/5-Fu联合应用时在96小时出现caspase-3的明显增高。

    实验证实在GEO异种移植物模型中,细胞毒药物PTX联合应用ZD1839抗癌活性增加[13]。观察到所有联合应用ZD1839和PTX治疗的小鼠肿瘤全部都有缩小,并且有对TGFα、VEGF和 bFGF 表达的抑制作用明显加强,很少伴有或不伴有微小血管形成。并且16只GEO异种移植鼠中有6只在联合应用ZD1839和PTX治疗后最终均未出现GEO肿瘤组织学证据。这些结果说明ZD1839的抗肿瘤效果伴随有对自分泌和旁分泌生长因子TGFα、VEGF和 bFGF的抑制,而这些生长因子维持促进了局部组织的生长和新血管的生成。意大利一个研究组[17]对表达EGFR的人类卵巢癌(OVCAR-3)、乳腺癌(ZR-75-1,MCF-10A ras)和结肠癌(GEO)细胞系给予ZD1839联合细胞毒药物(顺铂、卡铂、草酸铂、紫杉醇、多西紫杉醇、表阿霉素、依托泊甙、拓扑替康和raltitrexed)进行观察,发现ZD1839联合任一种化疗药均有协同抑制细胞生长的作用。同时对GEO异种移植的裸鼠,用2.5mgZD1839联合紫杉醇、拓扑替康和raltitrexed治疗,在治疗的第4周末,和未治疗或单药治疗组比较,对肿瘤的生长有明显的抑制作用(P=0.01)。美国的一个肿瘤中心[18]研究了对小细胞肺癌(LX-1)、非小细胞肺癌(A549,SK-LC-16)、前列腺癌(PC-3,TSU-PR1)的异种移植物联合应用ZD1839和铂类化疗药、紫杉醇、阿霉素和edatrexade治疗,证实ZD1839能提高这些细胞毒药物的抗肿瘤作用,并且ZD1839抗肿瘤活性的提高并不要求这些肿瘤EGFR水平的高表达,提示对没有EGFR高水平表达的肿瘤,应用ZD1839联合细胞毒药物有很大的临床潜力。

    2.2 ZD1839与放疗联合应用的研究 EGFR的表达与肿瘤的放疗抵抗相关。最近证实EGFR信号传导在体外能增加放疗后细胞的增殖[13],并有人认为肿瘤细胞放疗后的修复部分是由于放疗后EGFR信号激活所致[19]。应用ZD1839可以抑制放疗后肿瘤的生长,提高放疗敏感性,增加治疗反应。在人类头颈部鳞状细胞癌的体外和移植物模型中应用ZD1839与放疗联合治疗[20],证实ZD1839明显提高了放疗反应,肿瘤抑制作用增强并且延缓了肿瘤的再生长和复发。Wlilliams等[21]在体外将LoVo细胞系(人类结肠癌细胞系)与ZD1839(0.5 microM)孵育1~5天后,分割放疗(2 Gyday(-1), days1-3)的抗增殖效应明显提高 (P=0.002)。对裸鼠LoVo人类结肠癌异种移植物模型研究了单剂量放疗(5Gy)及分割放疗(2Gy×5次)联合应用ZD1839对肿瘤的疗效,结果发现不论是单剂量放疗还是分割放疗,联合ZD1839,对肿瘤的生长抑制作用均增强(P≤0.001),而以分割形式放疗ZD1839的放疗增敏作用更明显,可能是由于放疗分割间期中ZD1839对再增殖细胞的抗增殖效应。

    Shintani S等[22]对5个头颈部鳞状细胞癌(HNSCC)细胞系(HSC2, HSC3, HSC4, SCC25 and Ca9-22)测定了EGFR表达水平与放疗敏感性的关系,结果发现这些HNSCC细胞系的放疗敏感性差异很大,并且EGFR的表达也不同,EGFR 表达水平(EGFR numbers/cell)与肿瘤对放疗抵抗增加有关(f[x]= 4.54 X, R2 = 0.715;f[x]: EGFR numbers/cell, X: radiosensitivity; D10)。1.0 microM ZD1839 联合放疗(0~10 Gy)时,HNSCC细胞系的生长抑制作用增强,ZD1839可以改善肿瘤细胞对放疗的反应。Magne N 等[23]对6个头颈部细胞系研究了放疗联合ZD1839治疗的细胞毒效应,认为在放疗前给予ZD1839可以获得最好的效果(P=0.002)。

    Bianco 等[24]在ZD1839联合放疗在人类结肠癌(GEO)、卵巢癌(OVCAR-3)、非小细胞肺癌(A549和Calu-6)和乳腺癌(MCF-7 ADR)细胞系中都观察到了剂量依赖性生长抑制。电离辐射后给予ZD1839,观察到有抗增殖和促凋亡效应,并伴有抗凋亡蛋白bcl-xL和bcl-2表达和Akt蛋白的磷酸化形式的抑制。GEO异种移植物接受RT也为剂量依赖性生长抑制,这种抑制作用在治疗终止后可以逆转。RT联合ZD1839后有长期的GEO肿瘤生长抑制。联合治疗组小鼠的生存期同对照组相比(P < 0.001),同RT治疗组相比(P < 0.001), 或同ZD1839治疗组相比(P < 0.001)均明显延长。只有联合RT和ZD1839治疗组的小鼠生存达10周,并有10%的小鼠在26周后仍为无病生存。RT与ZD1839联合应用还伴随有TGFα、BEFG和bFGF在细胞表达的明显抑制,这导致GEO肿瘤中的抗血管生成作用。

    Solomon等[25]发现体外A431(过表达EGFR的人类阴道鳞状细胞系)放疗后应用ZD1839,细胞增殖减少,凋亡增加并且生存期缩短。A431异种移植物无胸腺裸鼠(100 mm3)接受10Gy单次分割或4天每天2.5 Gy分割放疗,联合或不联合ZD1839(75 mg/kg/d 腹腔给药10天)时对肿瘤生长的抑制效应。结果显示不论10Gy(提高比1.5)单次分割或是4天每天2.5 Gy分割放疗(提高比4)联合应用ZD1839后对肿瘤生长的延迟都有更强的效应。ZD1839 减少了肿瘤的血管分布,以及有EGF诱导的VEGF蛋白和mRNA的水平,提示有抑制血管生成的作用。用ZD1839抑制EGFR介导的信号传导途径可以加强单分割和多分割放疗效果的作用。

    She Y 等[26]也证实了ZD1839可以明显提高放疗的抗肿瘤活性。人类非小细胞肺癌(A549和SK-LC-16)和乳腺癌(MDA-MB468)和人类间皮瘤(JMN)模型中,当肿瘤达到0.4mm~0.6 mm后,开始予ZD1839的最大耐受剂量(MTD) (150 mg/kg ,每天1次×5天,连续2周),RT(总剂量40 Gy,分割放疗4 Gy/天×5 天,连续2周)及ZD1839与RT联合治疗。结果显示单独给予ZD1839一种肿瘤生长35%~40%,RT抑制18%~72%,联合治疗抑制50%~99%,并且联合应用并未增加毒性。

    3 总结与展望

    ZD1839是一种口服有活性和选择性的EGFR-TKI,阻断信号传导途径,抑制肿瘤细胞的增殖和血管生成,它的基础研究已经证实ZD1839对多种肿瘤有抗肿瘤活性,不论是间断给药还是持续给药,都具有很好的耐受性。在细胞系和异种移植物的研究中已经证实ZD1839同放疗或化疗联合应用具有附加的协同作用,可以提供抗肿瘤活性,为进一步联合治疗的临床试验提供了理论依据。

==== 汉译英 ====

In many human tumors in both the existence of epidermal growth factor receptor (EGFR) and c-erbB2 over-expression studies have shown that they are acts of aggression with the tumor and the patient's bad prognosis. EGFR tyrosine kinase family play the extracellular signal transduction role within the cell, an increase of tumor cell proliferation, preventing apoptosis, enhancing its activity, adhesion and invasion, the most important thing is the original oncogene c-erbB-1/HER-1/EGFR and c-erbB-2/her2/neu encoding EGFR [1], for the EGFR and its signal transduction of targeted therapy can inhibit tumor cell proliferation, vascular generation and DNA damage repair. ZD 1839 is a highly specific EGF receptor tyrosine kinase inhibitor, blocked the first step in signal transduction, inhibited EGFR phosphorylation, while inhibition of tumor cell proliferation [2], and radiation and synergistic effect of combination chemotherapy.
     An epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) Mechanism of

     1.1 EGFR structure and function of EGFR is a molecular weight of 17kDa transmembrane glycoprotein, there are ligand-dependent tyrosine kinase activity, in addition to hematopoietic stem cells, present in most cells, in a variety of tumors have been expression, such as colorectal, breast, pancreatic, prostate cancer and non-small cell lung cancer, including NSCLC, squamous cell carcinoma of the expression rate of up to 57% ~ 92% [3]. EGFR by the three main zones: an N terminal extracellular region, a hydrophobic transmembrane domain and a C-terminal cell within the region, cells, including tyrosine region. Extracellular region is a variety of polypeptide growth factor ligand-binding points, the most important of the epidermal growth factor (EGF) and transforming growth factor α (TGFα) [4]. Extracellular ligand-binding domain combined with EGF, TGFα occurs aggregation receptor 2, leading to intracellular tyrosine kinase region is activated, with an ATP molecule binding, receptor autophosphorylation, and other receptor monomer dephosphorization acidification. Since the body of the phosphates, phosphoric acid into the C-terminal tyrosine residues in, making a number of bodies, including signal transduction (such as p85, Grb2/Sos, PLCγ1, etc.) of the Src homologue 2 (SH2), which The role is to proliferation and survival signaling downstream of the receptor signal transduction pathways [5]. In the ligand-induced activation, EGFR can connect to many involved in signal transduction cascade of intracellular proteins, including PLCγ, PI3K, the small G protein, p21 Ras, GAP, and Src family kinases [6,7], through different subject Body type and combination of phosphorylation sites, so that the different signaling proteins are activated. This process is bringing people of different extracellular signals are transmitted to the nucleus. EGFR tyrosine kinase activity on behalf of its effective structure, and is the basis of signal transduction, cell growth factors from the body through the secretion of its own way in malignant and malignant transformation in order to obtain required the presence of active ligands and the high level of EGFR expression [8]. In addition to promoting proliferation, the activation of EGFR plays an important role in tumor development in the biological responses include: the effects on cell motility, cell adhesion, invasion, cell survival and angiogenesis [9].

     1.2 The new targeted anti-cancer therapy due to EGFR tyrosine kinase in tumor cells in the biological activity, it has become a new targeted anti-cancer therapy. The role of tyrosine kinase phosphorylation inhibitor receptors in the cell area, often referred to as TKIs, is completely occupied the majority of ATP-binding site, and thus EGFR tyrosine kinase have a good selectivity. 4 - Which oxazoline aniline-Kui is a site with the ATP binding and effective and selective inhibitors. Such drugs structure - activity relationship of a clear definition of its binding mode, Kui-oxazoline ring and adenine binding, aniline ring and the adjacent area with a single pro-fat. A single near-Kui oxazoline binding sites of the cysteine (Cys-773) led to irreversible inhibition [10]. In which representatives of oral ZD1839 (trade name Iressa). ZD1839 is an orally are activity, selectivity and reversibility of the epidermal growth factor receptor (EGRF) tyrosine kinase inhibitors, which block the proliferation and survival in tumor cells contained in the signal transduction pathway.

     1.3 ZD1839 pharmacokinetics ZD1839 is effective in EGFR-TKI (IC (50) = 0.033 micro M), oral administration, once a day for tumor growth inhibition was dose-dependent form, and EGFR in tumor xenografts ZD1839 did not affect the expression of the sensitivity of [11]. Healthy volunteers (28) and pharmacokinetic studies showed that a single oral administration of ZD1839, the peak plasma concentration (Cmax) appeared in 3 ~ 7 hours, Cmax decreased subsequently into a two-way, half-life ranged between 27 and 41 hours , 10mg ~ 100mg dose range in between, Cmax, and AUC24h (0 Dao 24 Xiao Shi area under the curve) and the dose relationship between the linear increase in [12].

     Two human tumor cell lines and animal models of

     By human tumor cell lines and non-thymus in nude mice model of human tumor xenograft studies of ZD1839 can confirm that its has anti-proliferative, anti-angiogenesis and increased apoptosis. Ciardiello et al [13] evaluated the ZD1839 in the TGFα and EGFR co-expression of human colon (GEO, SW480, and CaCo2), breast (ZR-75-1, MCF-7 ADR), ovarian (OVCAR-3) and gastric (KATO III and N87) of the cancer cell lines in the anti-angiogenesis and anti-tumor effect, GEO xenotransplantation of immunodeficient mice in the ZD1839 treatment, using immunohistochemical analysis of GEO xenografts showed tumor cells, TGFα, bFGF, and decreased the expression of VEGF were dose-dependent, measured by microvessel counts in the new anti-angiogenic effect is also dose-dependent manner. England a test group [14] In situ ductal carcinoma (Ductal carcinoma in situ, DCIS) of the xenograft model studies found that oral ZD1839 (100 ~ 200 mg / kg, a total of 14 days) to enable the proliferation of epithelial cells reduced 56%. Anderson NG, etc. [15] observed that in vitro, EGFR over-expression of A431 and MDA-MB-231 breast cancer cell line proliferation in the maximum effective dose of ZD1839 given half the time there is 50% ~ 70% were inhibited by 20 % ~ 80% EGFR (+) erbB2 over-expression of tumor cells (SKBr3, SKOV3, BT474) proliferation, ZD1839 inhibited the non-thymus in nude mice xenograft MDA-MB-231 and SKOV3 tumor growth, respectively, 71% and 32%.

     2.1 ZD1839 with cytotoxic drugs of ZD1839 in combination with a variety of cytotoxic chemotherapy in combination with a synergistic anti-tumor activity, this inhibitory effect is seen not only the transfer of advanced tumors, but also found in early lesions, such as human ductal in situ cancer. Magne et al [16] In the CA133 cell line (a high expression of EGFR in human head and neck cancer cell lines) to join the ZD1839 incubated for 48 hours, and then adding cisplatin and 5-Fu incubated for 48 hours. The results showed that ZD1839 monotherapy-induced cell aggregation in the G0/G1 phase, in 24 hours p21, p27, and Bax expression increased, Bcl2 expression and Akt phosphorylation significantly reduced. 48 hours, when DNA-PK reduced. ZD1839 alone on caspase-3 activity did not affect, but with the cisplatin / 5-Fu combination occurs at 96 hours was significantly higher in caspase-3.

     Experiments confirmed the GEO xenograft model, cytotoxic anti-cancer activity of ZD1839 in combination PTX increased [13]. Observed in all the joint application of ZD1839 and PTX treatment of mice with tumors all had narrowed, and there are pairs of TGFα, VEGF and bFGF significantly inhibited the expression of enhanced rarely associated with or without the formation of tiny blood vessels. And 16 GEO xenograft mice have 6 of the Joint Application of ZD1839 and PTX ultimately did not occur after treatment histological evidence of GEO. These results indicate that the anti-tumor effect of ZD1839 is accompanied by pairs of autocrine and paracrine growth factor TGFα, VEGF and bFGF inhibition, and these growth factors contributed to the maintenance of local tissue growth and formation of new blood vessels. Italy, a research group [17] The expression of EGFR in human ovarian cancer (OVCAR-3), breast (ZR-75-1, MCF-10A ras), and colon (GEO) cell lines for ZD1839 combined cytotoxic drugs (cis - platinum, carboplatin, oxaliplatin, paclitaxel, docetaxel, epirubicin, etoposide, topotecan, and raltitrexed) were observed and found that either of ZD1839 combined with chemotherapy drugs have a synergistic role in inhibiting cell growth. At the same time on the GEO xenografts in nude mice, using 2.5mgZD1839 paclitaxel, topotecan and raltitrexed treatment, the first 4 weeks of treatment, and no treatment or single-drug treatment group compared to the growth of tumors significantly inhibited ( P = 0.01). The United States, a Cancer Center [18] studied the small-cell lung cancer (LX-1), non-small cell lung cancer (A549, SK-LC-16), prostate cancer (PC-3, TSU-PR1) of the xenografts combination of ZD1839 and platinum chemotherapy drugs, paclitaxel, adriamycin, and edatrexade treatment, confirmed that ZD1839 can improve the cytotoxic anti-tumor effect and enhance the antitumor activity of ZD1839 does not require such a high level of tumor EGFR expression, suggesting that the absence of high levels of EGFR expression in tumors, the application ZD1839 combined cytotoxic drugs have great clinical potential.

     2.2 ZD1839 in combination with radiotherapy of EGFR expression and radiation resistance in tumors. Recently confirmed that EGFR signal transduction in vitro can increase cell proliferation after radiotherapy [13], and it was that the tumor cells repair after radiation therapy was partly due to EGFR signaling activation induced by radiotherapy [19]. Application of ZD1839 can inhibit tumor growth after radiotherapy to improve radiation sensitivity and increase response to treatment. In the human head and neck squamous cell carcinoma in vitro and models the application of ZD1839 graft combined treatment with radiotherapy [20], confirmed that ZD1839 markedly enhanced the radiation response, tumor inhibition to enhance and further delayed tumor growth and recurrence. Wlilliams et al [21] In the LoVo cell lines in vitro (human colon cancer cell lines) and ZD1839 (0.5 microM) incubated for 1 ~ 5 days after radiotherapy (2 Gyday (-1), days1-3) anti-proliferative effects are more obvious increased (P = 0.002). LoVo human colon cancer in nude mice xenograft model of a single dose of radiotherapy (5Gy) and fractionated radiotherapy (2Gy × 5 times) combined with the efficacy of ZD1839 on tumor and found that both a single dose of radiotherapy, or radiotherapy, the Joint ZD1839 of tumor growth inhibition are enhanced (P ≤ 0.001), and in order to split the form of radiation sensitizing effect of radiotherapy ZD1839 is more obvious, may be due to radiation and then split between the mid-term ZD1839 on cell proliferation in anti-proliferative effect.

     Shintani S et al [22] The five heads and neck squamous cell carcinoma (HNSCC) cell lines (HSC2, HSC3, HSC4, SCC25 and Ca9-22) expression level of EGFR was determined by the relationship between radiation sensitivity and found that these HNSCC cells Department of Radiation Sensitivity in very different, and the expression of EGFR are also different, EGFR expression (EGFR numbers / cell) and tumor resistance to radiotherapy increase in the (f [x] = 4.54 X, R2 = 0.715; f [x]: EGFR numbers / cell, X: radiosensitivity; D10). 1.0 microM ZD1839 combined with radiotherapy (0 ~ 10 Gy), when, HNSCC cell lines enhanced the growth inhibition, ZD1839 can improve the response of tumor cells to radiation. Magne N et al [23] The six heads and neck cell lines studied the treatment of radiotherapy combined cytotoxic effects of ZD1839 that ZD1839 given before radiotherapy can get the best results (P = 0.002).

     Bianco et al [24] In the ZD1839 combined with radiotherapy in human colon cancer (GEO), ovarian cancer (OVCAR-3), non-small cell lung cancer (A549 and Calu-6) and breast cancer (MCF-7 ADR) cell lines have been observed in to a dose-dependent growth inhibition. Ionizing radiation given ZD1839, observed that there are anti-proliferative and pro-apoptotic effects, and accompanied by anti-apoptotic protein bcl-xL and bcl-2 expression and Akt phosphorylation forms of suppression. GEO xenografts receiving RT also dose-dependent growth inhibition, this inhibition could be reversed after the termination of treatment. RT combined ZD1839 after a long-term GEO tumor growth inhibition. Combination therapy groups of mice survival as compared with the control group (P <0.001), compared with the RT treatment group (P <0.001), or with ZD1839 treatment group compared with (P <0.001) were significantly prolonged. Only combined RT and ZD1839 treated mice to survive up to 10 weeks, and 10% of the mice at 26 weeks remained disease-free survival. ZD1839 in combination with RT is also accompanied by TGFα, BEFG, and bFGF expression in the cells significantly inhibited, which leads to GEO tumor anti-angiogenesis effect.

     Solomon et al [25] found that in vitro A431 (over-expression of EGFR of human vaginal squamous cell line) after radiotherapy applications ZD1839, reduced cell proliferation, apoptosis increased and shortened survival. A431 xenografts in nude mice without thymus (100 mm3) received 10Gy single partition or 4 days per day 2.5 Gy fractionated radiotherapy, combined with or without ZD1839 (75 mg / kg / d intraperitoneally administered 10 days), the pairs of tumor growth The inhibitory effect. The results showed that regardless of 10Gy (raise more than 1.5) a single partition, or 4 days per day 2.5 Gy fractionated radiotherapy (better than 4) after the combined application of ZD1839 on tumor growth have a stronger effect of the delay. ZD1839 reduced the distribution of tumor blood vessels, as well as EGF-induced VEGF protein and mRNA levels, suggesting an inhibitory role in angiogenesis. With ZD1839 inhibited EGFR-mediated signal transduction pathway can enhance the single-split and multi-effect role of fractionated radiotherapy.

     She Y et al [26] also confirmed that ZD1839 can significantly enhance the anti-tumor activity of radiation therapy. Human non-small cell lung cancer (A549 and SK-LC-16) and breast cancer (MDA-MB468) and human mesothelioma (JMN) model, when the tumor reached 0.4mm ~ 0.6 mm, we began to be the maximum tolerated ZD1839 dose (MTD) (150 mg / kg, 1 time per day × 5 days, for 2 weeks), RT (total dose 40 Gy, fractionated radiotherapy 4 Gy / day × 5 days, for 2 weeks) and the combined treatment of ZD1839 with RT . The results showed a tumor growth ZD1839 given alone 35% ~ 40%, RT inhibited 18% ~ 72%, combination therapy inhibited 50% ~ 99%, and the combination did not increase toxicity.

     3 Summary and Outlook

     ZD1839 is an orally active and selective with EGFR-TKI, block the signal transduction pathway, inhibit tumor cell proliferation and angiogenesis, and its basic research on a variety of tumors have confirmed that ZD1839 has anti-tumor activity, whether it is intermittent to the the sustained delivery of drugs, or, have a good tolerance. In the cell lines and xenograft studies have confirmed that ZD1839 in combination with radiotherapy or chemotherapy with an additional synergies can provide anti-tumor activity, in order to further clinical trials of combination therapy provides a theoretical basis.

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更新日期: 2014-02-26 07:33
作者: : mcyclub
修订: 1.1

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