药物蛋白核苷酸多态性对靶向药物伊马替尼敏感性的影响

作为第一代酪氨酸激酶抑制剂（tyrosine kinase inhibitors,TKIs）,伊马替尼是临床上用于治疗慢性粒细胞白血病（chronicmyelogenous leukemia,CML）的一线药物。然而在临床治疗中,部分患者口服伊马替尼后疗效并不理想,出现伊马替尼耐药的情况。伊马替尼耐药机制比较复杂,除了TKIs的突变,国内外研究还发现ABC家族转运蛋白（ATP-binding cassette transporters,ABC）,有机阴离子转运体及有机阳离子转运体对伊马替尼药代动力学与药效学具有影响。本文主要从影响伊马替尼疗效的药物转运体基因多态性对伊马替尼治疗CML患者个体疗效差异予以综述,为进一步的临床研究提供参考依据。      

食物对口服靶向抗肿瘤药物代谢影响的研究进展

部分食物对口服靶向抗肿瘤药物的代谢具有临床意义的影响,包括：西柚可影响尼罗替尼、舒尼替尼、伊马替尼、克唑替尼、达沙替尼、厄洛替尼、拉帕替尼、帕唑帕尼、依维莫司、奥拉帕利、塞瑞替尼、凡德他尼、阿昔替尼的代谢;酸橙可影响奥拉帕利的代谢;蔓越莓对伊马替尼、生姜对克唑替尼、苹果对厄洛替尼、人参对伊马替尼及达沙替尼、芹菜对达沙替尼、烟草对厄洛替尼的代谢存在影响;合并使用质子泵抑制剂时,可乐可影响厄洛替尼的代谢。临床用药需要重视食物对口服靶向抗肿瘤药物代谢的影响,注意合理搭配药物与食物,保障药物的有效性和安全性。     

晚期非小细胞肺癌3种EGFR-TKI 治疗的临床疗效及药物经济学分析

目的：从药物经济学角度对治疗晚期非小细胞肺癌的3种表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）的临床疗效和成本原效果进行评价和分析,为临床合理用药提供参考。方法118例一线采用EGFR-TKI 治疗的晚期非小细胞肺癌患者分为3组：厄洛替尼组（38例）,吉非替尼组（43例）和埃克替尼组（37例）,均在治疗后评价疗效和药物不良事件,并运用药物经济学的成本原效果分析法进行研究。结果厄洛替尼组、吉非替尼组、埃克替尼组的有效率分别为71.05%、74.42%和67.57%（P >0.05）;药物不良事件发生率比较差异均无统计学意义（P 均>0.05）。3组的成本原效果比分别为268.30、201.63、182.28,埃克替尼组显著低于厄洛替尼组、吉非替尼组。结论本研究的3种 EGFR-TKI 用于晚期非小细胞肺癌的治疗均具有较好的治疗效果和安全性,其中埃克替尼是最经济的。     

探索并验证治疗转移性前列腺癌的化学药物

目的:运用生物信息学技术探索转移性前列腺癌的关键基因及作用于关键基因的化学药物,并通过实验验证化学药物的治疗效果。方法:使用生物信息学技术及相关工具对GEO数据集GSE27616、GSE38241、GSE168718中转移性前列腺癌和非转移性前列腺癌的基因表达数据进行差异表达分析,使用STRING数据库、Cytoscape软件和人类蛋白表达图集（HPA）获取较差预后相关的关键基因,使用比较毒理学数据库（CTD）对关键基因的互作化学药物进行集合重叠分析。使用CCK-8法、平板克隆形成实验验证关键化学药物的效果。结果:差异表达分析获得差异表达基因共105个,其中下调基因79个,上调基因26个。 STRING数据库、 Cytoscape软件、人类蛋白表达图集（HPA）生存分析结果显示6个基因在前列腺癌组织中高表达且与较差预后有关（P＜0.05）。 使用CTD数据库分析较差预后相关基因,得出8个关键化学药物,通过CCK-8法、平板克隆形成实验最终证实1,2,4-苯三酸酐、环氧化苯并芘、达沙替尼、曲格列酮和舒尼替尼5种药物具有抑制转移性前列腺癌细胞系增殖的作用。结论:1,2,4-苯三酸酐、环氧化苯并芘、达沙替尼、曲格列酮和舒尼替尼5种化学药物能够抑制转移性前列腺癌细胞的增殖,为临床治疗转移性前列腺癌提供候选药物。     

口服抗肿瘤药物在吞咽困难患者中的合理使用

目的∶探索口服抗肿瘤药物制备口服混悬剂在吞咽困难患者中的合理使用。方法∶检索 SCI.GeenMedical. PubMed.ClinicaITnals.中国知网.万方数据库.查询口服抗肿瘤药物制备成口服混悬液方法的相关文献并进行汇总整
理。结果;可以制备成口服混悬液使用的药物有∶白消安.卡培他滨.苯工酸氮芥。羟基服 硫票险 替草唑胺 恭吉奥、长春瑞滨、达沙替尼、厄洛替尼、吉非替尼、伊马替尼、索拉非尼、舒尼替尼、克唑替尼、阿来替尼.奥希替尼,达拉非尼、曲美替尼、维莫非尼、塞瑞替尼、拉帕替尼、甲地孕酮、他莫昔芬,不建议制备成口服混悬液使用的药物有∶美法仑、尼洛替尼、培唑帕尼。结论;对于吞咽困难患者,部分口服抗肿瘤药物可以制备成口服混悬液给药,提高患者依从性。     

伊马替尼治疗慢性粒细胞白血病患者在生育时中断药物治疗对胎儿和患者自身的影响

目的:分析伊马替尼治疗慢性粒细胞白血病（chronic myeloid leukemia,CML）患者在生育时中断药物治疗对胎儿和患者自身的影响。方法:回顾性分析本科室21例CML合并妊娠患者在接受伊马替尼治疗后的影响。结果:21名接受伊马替尼治疗的CML患者中有6名为意外怀孕,15名为计划怀孕。有生育意愿的女性患者需达到血液学或细胞学缓解至少两年,在受孕前1个月和孕期前3个月停服伊马替尼,男性患者则在生育前一个月停止接受伊马替尼的治疗。所有意外受孕的患者在孕期均未停止服用伊马替尼。21名患者共生产9名男婴和7名女婴（其中1名尿道下裂,1名轻度脑水肿）,其余有2名自然流产,3名选择性流产。结论:鼓励接受伊马替尼治疗的CML患者有计划的生育,对于治疗期间意外怀孕的患者,伊马替尼则会导致自然流产或先天性异常。     

肺癌相关酪氨酸激酶抑制剂的药物相互作用

近年来,酪氨酸激酶抑制剂（TKI）开始应用于肺癌治疗领域。随着此类新药物的广泛应用,药物相互作用风险也在增加,亟需个体化用药。该类药物均为口服给药,吸收受胃液 pH 值影响,体内分布广泛、蛋白结合率高,多为转运体 ATP 结合盒（ABC）B1／G2作用底物,经细胞色素 P450（CYP450）同工酶代谢,同时多个 TKI 为 CYP450同工酶及转运体的抑制剂或诱导剂,存在巨大的药物相互作用风险。     

纳米递药系统负载奥希替尼抗非小细胞肺癌的研究进展

奥希替尼是不可逆的第三代表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）,用于治疗经典EGFR突变和T790M耐药突变的非小细胞肺癌（NSCLC）。然而,与其他EGFR-TKIs一样,奥希替尼不可避免地存在获得性耐药、水溶性差、肿瘤累积率低等问题,限制了其治疗效果。纳米递药系统可增加药物的溶解度和稳定性,延长药物血液循环时间,提高细胞摄取率,增加在肿瘤组织中的聚集改善药物耐药问题,已成为解决传统靶向药物弊端的有效手段。本文综述了第三代EGFR-TKI奥希替尼的作用机制,重点阐述了奥希替尼纳米递药系统抗NSCLC的研究进展,并对该领域面临的挑战和未来发展方向进行了展望。     

非小细胞肺癌靶向治疗药物的研究进展

以吉非替尼（gefitinib）和埃罗替尼（erlotinib）为代表的小分子表皮生长因子受体酪氨酸激酶抑制剂治疗非小细胞肺癌是近年研究的热点,部分患者对药物反应良好,但几项大规模临床研究并没有得出这类药物可延长生存期的结论。研究表明,西妥昔单抗（cetuximab）和贝伐单抗（bevacizumab）等单克隆抗体可能提高患者的治疗反应率,延长生存期。不同人种、不同发病机制肿瘤的药物作用靶点不同,因此应根据临床状态、病理分型等影响因素指导患者接受个体化靶向药物治疗。     

膀胱癌的靶向药物治疗

全身化疗是能够改善膀胱癌生存的主要治疗方法,然而疗效有限,因此靶向药物治疗在膀胱癌中的应用逐渐引人关注.目前针对膀胱癌的靶向药物包括贝伐珠单抗、西妥昔单抗、舒尼替尼、吉非替尼、依维莫司和程序性死亡受体1及其配体抑制剂,其为晚期膀胱癌的治疗提供了新的方向.     

一氧化氮前体药物与前列腺癌的研究进展

前列腺癌是男性最常见的肿瘤之一。一氧化氮（nitric oxide, NO）作为生物信使或效应分子在体内发挥重要的生理作用,且其体内水平异常与多种疾病的发生和发展密切相关。因此,一氧化氮前体型药物的研究备受关注。一些NO前体药物已被证实具有良好的抗肿瘤活性,显示出广泛的临床应用潜力和价值。目前,NO前体药物中显示出显著抗肿瘤效应的主要有有机硝酸酯、硝普盐、S-亚硝基硫醇和偶氮二醇烯鎓盐等。一氧化氮前体药可通过靶向释放NO,直接杀伤肿瘤细胞、诱导肿瘤细胞凋亡、增强免疫系统作用、削弱肿瘤细胞增殖及侵袭能力,并抑制其转移,提高肿瘤细胞对放化疗的敏感度,从而发挥抗肿瘤作用。本文就近年来NO前体药物对前列腺癌作用的研究进展作一综述。     

Cytostatic drugs in infants: a review on pharmacokinetic data in infants

Below a certain age protocols in pediatric oncology on cytostatic drug therapy advise use, of other parameters such as weight for dosing; this instead of the most conventional parameter, i.e. body surface area. In infants it is not uncommon that additional reductions are put on top of this for each cytostatic drugs to be administered. The rationale behind this is often lacking. Differences related to the ontogeny of absorption, distribution, metabolism and excretion are often not mentioned. Considering characteristics, such as lipophilia, ionization in relation to pH and size of the molecule and linking these characteristics with age related shifts in the gastrointestinal tract, composition of the body and renal function; predictions on pharmacokinetics (PK) in these infants can to a certain extent be made. More difficult are the shifts in activity of phase I and II enzymes, which are often not known for a specific product. In this review data on the ontogeny of relevant pharmacokinetic pathways in relation to the various cytostatic drugs and data from pharmacokinetic (PK) studies in infants are presented.This review shows that the administration of cytostatic drugs in infants is often based on limited or even no data at all. Based on such a lack of evidence on treatment of infants with cancer; it should be mandatory that in each infant treated with cytostatic drugs pharmacokinetic data are collected. Compiling these data in a global database would enable evidence-based drug therapy in infants with malignancies, resulting in a more effective treatment with less toxicity in this vulnerable population.     

肺癌基因异常表达与化疗药物的相关性分析

Objective To explore the relationship between aberrantly expressed genes in lung cancer genesand after chemotherapy by gene expression profi le. Methods In this article, expression profi le of lung cancertissue and normal lung tissue were compared to screen out the differentially expressed genes by statisticalmethod. The aberrant expressed genes of lung cancer cells were clarifi ed. Then the up-regulated aberrantlyexpressed genes were upregulated by the chemotherapy drugs were selected by association analysis. Finally,the genes which could correspond to many chemotherapy drugs were screened and analyzed by networkregulation, to clarify the possible regulation relationship between these genes. Results Three hundred andninety-seven up-regulated aberrantly expressed genes induced by 6 kinds of related chemotherapy drugs inlung cancer tissue were screened out. Among them, TOP2A,MAD2L1,BIRC5 corresponded to manychemotherapy drugs and MAD2L1 may control the biological function of TOP2A and BIRC5 through P53.Conclusion The up-regulated expression genes, TOP2A,MAD2L1 and BIRC5, may have correlation withthe effect of chemotherapy of lung cancer. MAD2L1 may infl uence the biological function of TOP2A andBIRC5.     

Possible Mechanisms of Acquired Resistance to Anti-angiogenic Drugs: Implications for the Use of Combination Therapy Approaches

The ultimate target of anti-angiogenic drugs is the genetically stable, activated endothelial cell of a newly forming tumor blood vessel, rather than the genetically unstable tumor cell population per se. This led to the notion that acquired resistance to such drugs may not develop as readily, if at all. While there is some evidence that this lack of resistance development may be the case for some direct-acting angiogenesis inhibitors, it is becoming apparent that resistance can develop over time to many types of angiogenesis inhibitors including, possibly, some direct inhibitors, especially when used as monotherapies. Possible mechanisms for such acquired or induced resistance include: (i) redundancy of pro-angiogenic growth factors when the drug used targets a single such growth factor or its cognate endothelial cell-associated receptor tyrosine kinase; (ii) the anti-apoptotic/pro-survival function of growth factors such as VEGF, which, in high local concentrations, can antagonize the pro-apoptotic effects of various angiogenesis inhibitors; (iii) epigenetic, transient upregulation, or induction, of various anti-apoptotic effector molecules in host-endothelial cells; and (iv) heterogeneous vascular dependence of tumor cell populations. It is suggested that long-term disease control with anti-angiogenic drugs can be best achieved by judicious combination therapy. In this regard, the great molecular diversity of anti-angiogenic drug targets, in contrast to chemotherapy, makes this a particularly attractive therapeutic option, especially when approved, commercially available drugs considered to have anti-angiogenic effects are used in such combination treatment strategies.     

异博定等药物对人卵巢癌耐药细胞系多药耐受的逆转作用

用已建立的耐长春新碱人卵巢癌的耐药细胞做实验,应用ＭＴＴ法证实：异博定、潘生丁、黄体酮、环孢菌素Ａ和他莫西芬等药,能不同程度的逆转耐药细胞对长春新碱的耐受;高效液相色谱仪测定进一步证实了上述逆转药可保持或增加耐药细胞内长春新碱的药物浓度。该作用系由于逆转药使耐药细胞表达的大量Ｐ糖蛋白功能失活,通过增加细胞摄取药物量或延长药物在细胞内滞留时间形成的。     

常见植物药对结肠癌的防治作用及其作用机制

植物药对结肠癌具有良好的防治作用。姜黄素、多糖(苹果多糖、香菇多糖)、皂苷(重楼皂苷、人参皂苷)、白藜芦醇、槲皮素等植物药可通过不同信号通路抑制结肠癌细胞的增殖,促进细胞凋亡。此外,植物药还具有抗炎、抗氧化、抗血管生成、减轻化疗药物不良反应、逆转肿瘤细胞耐药等作用。了解植物药对结肠癌的防治作用及其可能的作用机制,能为结肠癌的临床防治提供更多的理论依据及治疗思路。     

多肽作为抗肿瘤药物载体的研究进展

多肽作为抗肿瘤药物的纳米载体,能够对药物进行修饰、包裹,在实现靶向性给药、缓释药物、提高药物水溶性及生物利用度、降低药物的毒副作用等方面表现出良好的应用前景,因而也成为近年来药剂学领域的研究热点之一。本文综述了近年来出现的纳米药物载体的种类,并详细阐述了各类载体的特点和优点,为其进一步应用提供理论依据。     

顺铂等化疗药物对胃癌细胞端粒酶活性的影响

目的：探讨端粒酶作为化疗敏感性指标的可行性。方法：选择IC50剂量的顺铂，丝裂霉素C，阿霉素及5－氟脲嘧啶和甲酰四氢叶酸处理胃癌细胞，采用半定量TRAP－银染法检测药物处理前后胃癌细胞端粒酶活性。并应用流式细胞学检测细胞周期和细胞凋亡率。结果：顺铂，丝裂霉素C和阿霉素在诱导两细胞凋亡的同时，下调端粒酶活性，且其抑制作用呈时间依赖关系；5－氟脲嘧啶和甲酰四氢叶酸对胃癌细胞端粒酶活性无明显抑制作用，结论：化疗前后细胞端粒酶活性的变化，可作为化疗敏感性指标。     

The Effect of Anticonvulsant Drugs on Blood Levels of Methotrexate

The reduced bioavailability of chemotherapeutic agents is one of the reasons that explains the limited efficacy of adjuvant chemotherapy in high grade glioma patients. We report how even the results of high dose sequential chemotherapy can be influenced by antiepileptic drugs.     

Fungistatic Activity of Miconazole against Candida albicans in Relation to pH and Concentration of Nonprotonated Drug

At less than 10(-5) M, miconazole (MCZ) exerts a fungistatic effect on Candida albicans, presumably by interfering with ergosterol biosynthesis. The imidazole moiety of MCZ is subject to protonation (pKa approximately 6.5). Based on pKa and greater water solubility of protonated (MCZH+) versus nonprotonated (MCZo) drug, fungistatic action ought to be markedly affected by environmental pH, but apparently it is not. In this report growth phase, pH, and concentrations of MCZ and MCZo have been studied in relation to fungistasis. Yeasts were grown in a synthetic liquid medium and MCZ effects were monitored by viability determinations. Results showed that fungistatic activity is little affected by growth phase and is largely independent of drug concentration and pH. Antagonism of fungistasis by low pH was demonstrated only at less than 10(-7) M MCZ. Data supported earlier proposals that MCZo is required for biological activity and suggested that target sites are saturated at very low levels of drug.