肿瘤的中医药多靶点治疗

本文综述了国内外学者用现代技术方法及指标,研究并证明多类中药能诱导细胞凋亡、逆转细胞多药耐药,抑制肿瘤新生血管生长、调整细胞信号转导、调整机体免疫功能、对化疗药物增效增敏解毒、抗肿瘤转移,旨在说明中医药具有多环节、多靶点治疗肿瘤的作用.     

中西医结合肿瘤研究思路与治疗方法的探讨

对目前中西医结合肿瘤基础研究方法与临床治疗模式进行了剖析,提出了中药抗肿瘤有效成份的提取是中西医结合肿瘤研究的主要方向,诱发肿瘤细胞凋亡、诱导肿瘤细胞分化、逆转肿瘤细胞多药耐药等是中医药研究的新思路;在辨证理论指导下进行方药加减变化、剂型改革及扩大给药途径是提高中西医结合治疗肿瘤疗效的关键环节,并强调在晚期肿瘤综合治疗中,尤应充分发挥中药不良反应小,遣方用药灵活的优势,同时指出中药在四种结合模式中发挥着重要作用,其运用的最佳时机、周期或疗程应以具体病情而定.     

分子靶向抗肿瘤药物临床应用

分子靶向抗肿瘤药物有独特的靶向抗肿瘤作用,在当前临床治疗中已发挥一定作用,并显示出良好的应用前景.主要有抗信号转导药物、抗血管生成药物、肿瘤耐药逆转剂及以细胞膜分化抗原为靶点的药物等.现就这些分子靶向药物的临床应用与目前研究进展作一综述.     

中西医结合肿瘤研究思路与治疗方法的探讨

对目前中西医结合肿瘤基础研究方法与临床治疗模式进行了剖析，提出了中药抗肿瘤有效成份的提取是中西医结合肿瘤研究的主要方向，诱发肿瘤细胞凋亡，诱导肿瘤细胞分化，逆转肿瘤细胞多药耐药等是中医药研究的新思路；在辨证理论指导下进行方药加减变化，剂型改革及扩大给药途径是提高中西医结合治疗肿瘤疗效的关键环节，并强调在晚期肿瘤综合治疗中，尤应充分发挥中药不良反应小，遣方用药灵活的优势，同时指出中药在四种结合模式中发挥着重要作用，其运用的最佳时机、周期或疗程以具体病情而定。     

分子靶向抗肿瘤药物临床应用

分子靶向抗肿瘤药物有独特的靶向抗肿瘤作用，在当前临床治疗中已发挥一定作用，并显示出良好的应用前景。主要有抗信号转导药物、抗血管生成药物、肿瘤耐药逆转剂及以细胞膜分化抗原为靶点的药物等。现就这些分子靶向药物的临床应用与目前研究进展作一综述。     

槲皮素逆转肿瘤多药耐药机制的研究进展

恶性肿瘤已成为当今威胁人类健康的重大疾病.目前,肿瘤的治疗主要是以手术为主的综合治疗,其中化疗药物的应用可明显抑制肿瘤生长、改善患者预后,但肿瘤的多药耐药严重阻碍了其治疗效果.槲皮素是广泛存在于植物中、具有生物活性的黄酮类化合物,具有抗肿瘤等多种药理学作用.目前,槲皮素逆转肿瘤多药耐药作用已引起广泛关注.研究发现,其可通过抑制多种耐药相关蛋白、诱导细胞凋亡、抑制热休克蛋白功能、逆转上皮间质转化等作用,从而逆转肿瘤多药耐药.本文主要综述槲皮素逆转肿瘤多药耐药的分子机制及其临床应用前景,以期为逆转肿瘤多药耐药的基础及临床研究提供新思路.     

槲皮素抗肿瘤作用机制

槲皮素能抑制多种肿瘤细胞的增殖,诱导细胞凋亡,干扰细胞信号传导,逆转肿瘤细胞的多药耐药和增强其他药物的抗肿瘤作用.随着分子生物学技术的不断发展,槲皮素抗肿瘤的分子机制逐渐被阐明,将为肿瘤的预防和治疗提供更好的理论依据.     

靶向谷胱甘肽抗氧化系统逆转肿瘤耐药的研究进展*

谷胱甘肽（glutathione,GSH ）是维持生物体内氧化还原平衡状态最为重要的小分子活性寡肽,具有抗氧化和调节机体巯基平衡的作用,并通过参与谷胱甘肽化修饰调控众多信号转导分子及氧化还原敏感转录因子的活性。研究显示,在多种肿瘤中GSH 水平明显增高,通过消除ROS 、解毒药物或参与DNA 修复过程等机制促进肿瘤细胞耐药。GSH 系统代谢酶在耐药肿瘤细胞中亦呈高表达,调控肿瘤细胞对药物的治疗反应。耗竭GSH 或下调GSH 系统代谢酶可有效逆转肿瘤耐药,使耐药肿瘤细胞恢复化疗敏感性,表明GSH 抗氧化系统是促使肿瘤耐药的关键性因素之一。近年来,GSH 抗氧化系统作为潜在的抗肿瘤治疗和耐药逆转靶点正备受关注。本文就GSH 抗氧化系统参与肿瘤耐药的作用及GSH 抗氧化系统靶向药物作一综述。      

高通量分析技术在肿瘤MDR中的研究进展

高通量分析技术是近年来肿瘤研究新平台,肿瘤多药耐药(MDR)和耐药逆转药物研究在肿瘤化疗领域亟需解决。现综述基因芯片、蛋白质芯片、组织芯片三大高通量微阵列技术在肿瘤MDR机制、筛选耐药逆转靶点和逆转药物及指导临床个体化治疗等方面的应用。     

高通量分析技术在肿瘤MDR中的研究进展

高通量分析技术是近年来肿瘤研究新平台，肿瘤多药耐药（MDR）和耐药逆转药物研究在肿瘤化疗领域亟需解决。现综述基因芯片、蛋白质芯片、组织芯片三大高通量微阵列技术在肿瘤MDR机制、筛选耐药逆转靶点和逆转药物及指导临床个体化治疗等方面的应用。     

Molecular targeting therapy of cancer: drug resistance,apoptosis and survival signal

Recent progress in the development of molecular cancer therapeutics has revealed new types of antitumor drugs, such as Herceptin, Gleevec, and Iressa, as potent therapeutics for specific tumors. Our work has focused on molecular cancer therapeutics, mainly in the areas of drug resistance, apoptosis and apoptosis resistance, and survival-signaling, which is related to drug resistance. In this review, we describe our research on molecular cancer therapeutics, including molecular mechanisms and therapeutic approaches. Resistance to chemotherapeutic drugs is a principal problem in the treatment of cancer. P-Glycoprotein (P-gp), encoded by the MDR1 gene, is a multidrug transporter and has a major role in multidrug resistance (MDR). Targeting of P-gp by small-molecular compounds and/or antibodies is an effective strategy to overcome MDR in cancer, especially hematologic malignancies. Several P-gp inhibitors have been developed and are currently under clinical phased studies. In addition to the multidrug transporter proteins, cancer cells have several drug resistance mechanisms. Solid tumors are often placed under stress conditions, such as glucose starvation and hypoxia. These conditions result in topo II poison resistance that is due to proteasome-mediated degradation of DNA topoisomerases. Proteasome inhibitors effectively prevent this stress-induced drug resistance. Glyoxalase I, which is often elevated in drug- and apoptosis-resistant cancers, offers another possibility for overcoming drug resistance. It plays a role in detoxification of methylglioxal, a side product of glycolysis, which is highly reactive with DNA and proteins. Inhibitors of glyoxalase I selectively kill drug-resistant tumors that express glyoxalase I. Finally, the susceptibility of tumor cells to apoptosis induced by antitumor drugs appears to depend on the balance between pro-apoptotic and survival (anti-apoptotic) signals. PI3K-Akt is an important survival signal pathway, that has been shown to be the target of various antitumor drugs, including UCN-01 and geldanamycin, new anticancer drugs under clinical evaluation. Our present studies provide novel targets for future effective molecular cancer therapeutics.     

Molecular and pharmacological strategies to overcome multidrug resistance

Multidrug resistance is a major obstacle to the effective treatment of cancer. Despite vast improvements in our understanding of the mechanisms of drug resistance, relatively few significant advances have been made towards effectively circumventing it in a clinical setting. The ability to modulate multidrug resistance has been complicated by the fact that many human tumors simultaneously exhibit multiple resistance mechanisms. In order to effectively overcome multidrug resistance it will be necessary to design new strategies that combine multiple modulating agents and approaches. This review provides an overview of the major causes of multidrug resistance and summarizes many of the current approaches being taken to overcome it. We also describe how liposomal drug delivery systems can be utilized to aid in achieving these goals.     

Molecular and pharmacological strategies to overcome multidrug resistance

Multidrug resistance is a major obstacle to the effective treatment of cancer. Despite vast improvements in our understanding of the mechanisms of drug resistance, relatively few significant advances have been made towards effectively circumventing it in a clinical setting. The ability to modulate multidrug resistance has been complicated by the fact that many human tumors simultaneously exhibit multiple resistance mechanisms. In order to effectively overcome multidrug resistance it will be necessary to design new strategies that combine multiple modulating agents and approaches. This review provides an overview of the major causes of multidrug resistance and summarizes many of the current approaches being taken to overcome it. We also describe how liposomal drug delivery systems can be utilized to aid in achieving these goals.     

A novel doxorubicin-mitomycin C co-encapsulated nanoparticle formulation exhibits anti-cancer synergy in multidrug resistant human breast cancer cells

Anthracycline-containing treatment regimens are currently the most widely employed regimens for the management of breast cancer. These drug combinations are often designed based on non-cross resistance and minimal overlapping toxicity rather than drug synergism. Moreover, aggressive doses are normally used in chemotherapy to achieve a greater therapeutic benefit at the cost of more acute and long-term toxic effects. To increase chemotherapeutic efficacy while decreasing toxic effects, rational design of drug synergy-based regimens is needed. Our previous work showed a synergistic effect of doxorubicin (DOX) and mitomycin C (MMC) on murine breast cancer cells in vitro and improved efficacy and reduced systemic toxicity of DOX-loaded solid polymer–lipid hybrid nanoparticles (PLN) in animal models of breast cancer. Herein we have demonstrated true anticancer synergy of concurrently applied DOX and MMC, and have rationally designed PLN to effectively deliver this combination to multidrug resistant (MDR) MDA435/LCC6 human breast cancer cells. DOX–MMC co-loaded PLN were effective in killing MDR cells at 20–30-fold lower doses than the free drugs. This synergistic cell killing was correlated with enhanced induction of DNA double strand breaks that preceded apoptosis. Importantly, co-encapsulation of dual agents into a nanoparticle formulation was much more effective than concurrent application of single agent-containing PLN, demonstrating the requirement of simultaneous uptake of both drugs by the same cells to enhance the drug synergy. The rationally designed combination chemotherapeutic PLN can overcome multidrug resistance at a significantly lower dose than free drugs, exhibiting the potential to enhance chemotherapy and reduce the therapeutic limitations imposed by systemic toxicity.     

Overcoming drug efflux-based multidrug resistance in cancer with nanotechnology

Multidrug resistance(MDR),which significantly decreases the efficacy of anticancer drugs and causes tumor recurrence,has been a major challenge in clinical cancer treatment with chemotherapeutic drugs for decades.Several mechanisms of overcoming drug resistance have been postulated.Well known P-glycoprotein(P-gp) and other drug efflux transporters are considered to be critical in pumping anticancer drugs out of cells and causing chemotherapy failure.Innovative theranostic(therapeutic and diagnostic) strategies with nanoparticles are rapidly evolving and are anticipated to offer opportunities to overcome these limits.In this review,we discuss the mechanisms of drug efflux-mediated resistance and the application of multiple nanoparticle-based platforms to overcome chemoresistance and improve therapeutic outcome.     

Reversal of multidrug resistance by lipophilic drugs

The phenomenon of multidrug resistance implies that a wide spectrum of structurally and functionally unrelated chemotherapeutic drugs are recognized and processed by the molecular system which protects multidrug-resistant (MDR) cells against lipophilic cytotoxic drugs. This suggests that lipophilic agents with low toxicity may also be recognized and processed by this molecular system. At high concentrations these agents might saturate the system, thereby reversing multidrug resistance. In support of this hypothesis, 19 (73%) of 26 arbitrarily chosen lipophilic drugs were in this study found to increase the accumulation of actinomycin D in MDR WEHI 164 cells. The most potent of these drugs were also shown to sensitize these cells to the cytotoxic effect of actinomycin D and doxorubicin. There was a good correlation between the ability of the lipophilic drugs to induce an increased accumulation of actinomycin D in MDR cells and their ability to sensitize these cells to the cytotoxic effect of chemotherapeutic drugs. The ability to reverse drug resistance appeared to be additive, since increased accumulation of actinomycin D was also obtained by combining low concentrations of various lipophilic drugs. This may be a way to reduce the in vivo toxic effect of the lipophilic drugs yet still obtain a reversal of drug resistance. When MDR cells were exposed to lipophilic drugs which reversed drug resistance, the synergistic cytotoxic effect of actinomycin D and tumor necrosis factor was obtained at reduced actinomycin D concentrations.     

Death by design: where curcumin sensitizes drug-resistant tumours

Chemotherapy remains the core of anticancer treatment. However, despite the tremendous strides made in the development of targeted anticancer therapies, emergence of resistance to chemotherapeutic drugs is still a major obstacle in the successful management of resistant tumours. Therefore, profound investigation into the in-depth molecular mechanisms of drug resistance is essential and may hopefully translate into effective therapies that can flip the switch from drug resistance to susceptibility. Mechanistically, resistance phenomena may be explained by (i) overexpression of drug efflux pumps, (ii) enhanced drug detoxification, (iii) rapid DNA repair efficiency, (iv) defects in apoptosis regulation, and (v) active cell survival signals. Several adverse effects associated with multidrug resistance and the need for safe multi-targeted anticancer drugs instigated the use of the phytochemical, curcumin, the yellow pigment of the spice turmeric, which has pleotropic activities. We performed a structured literature review using PubMed and Medline searches with secondary review of cited publications, identifying studies on the role of curcumin in conquering drug resistance in cancer. This review describes how curcumin sensitizes cancer cells through regulation of multiple multidrug resistance pathways, thus employing one drug for multiple targets. Curcumin helps the cancer cells to regain their 'forgotten' apoptosis, modulates drug-target interaction at different levels, restrains survival pathways when their proteins are overexpressed, and finds an alternate way to carry forward the process of sensitization of different resistant tumours. Additionally, the review dissects the role of curcumin, if any, in targeting the major culprit of drug resistance, cancer stem cells (CSC), thereby circumventing resistance. Taken together, this review strongly suggests that curcumin is a promising chemosensitizing agent and that the unique properties of curcumin may be exploited for successful management of resistant tumours.     

Novel application of metformin combined with targeted drugs on anticancer treatment

The success of targeted drug therapies for treating cancer patients has attracted broad attention both in the academic community and social society. However, rapidly developed acquired resistance is becoming a newly recognized major challenge to the continuing efficiency of these therapies. Metformin is a well‐known natural compound with low toxicity derived from the plant French lilac. Our previous work has highlighted research progress of the combination of clinically applied chemotherapies and metformin by different mechanisms. We have also launched a study to combine metformin with the small molecule targeted drug gefitinib to treat bladder cancer using intravesical administration. Thus, in this minireview, we summarize recent achievements combining metformin with various targeted therapies. This work directs the potential clinical future by selecting available cancer patients and providing precise medicine by the combination of metformin and targeted drugs to overcome resistance and enhance therapeutic efficacies.     

益肠促愈方辅助西药治疗宫颈癌放疗后放射性肠炎疗效观察

目的:探讨益肠促愈方辅助西药治疗宫颈癌放疗后放射性肠炎临床疗效。方法:研究对象选取我院2015年7月至2017年7月收治宫颈癌放疗后放射性肠炎患者共100例,以随机数字表法分为对照组（50例）和中西医组（50例）,分别给予西药单用和在此基础上加用益肠促愈方辅助治疗,比较两组综合疗效,内镜疗效,治疗前后主要证候评分、日常生活质量评分、转化生长因子β1（transforming growth factor β1,TGF-β1）水平及药物毒副反应发生率。结果:中西医组综合疗效和内镜疗效均显著优于对照组（P<0.05）;中西医组治疗后主要证候评分显著低于对照组、治疗前（P<0.05）;中西医组治疗后EORTC QOL-C30量表评分均显著高于对照组、治疗前（P<0.05）;中西医组治疗后TGF-β1水平显著低于对照组、治疗前（P<0.05）;同时两组药物毒副反应发生率比较差异无统计学意义（P>0.05）。结论:益肠促愈方辅助西药治疗宫颈癌放疗后放射性肠炎可有效减轻消化道和全身症状,促进肠黏膜损伤修复,调节TGF-β1水平。