表达蛋白质组学在抗肿瘤药物研发中的应用

表达蛋白质组学主要对正常、疾病或药物处理细胞或亚细胞中的所有蛋白质进行定性或定量研究。近年来表达蛋白质组学对抗肿瘤药物的研发起到了一定的推动作用。本文通过检索相关数据库文献,对其进行梳理、总结和归纳,阐述了表达蛋白质组学在抗肿瘤药物研发中的应用,包括抗肿瘤药物靶点发现、药物作用机制阐明、临床诊断以及基于网络药理学的药物研发理念的实现等。尽管表达蛋白质组学本身还存在一些缺陷,但随着其技术的不断发展,必将进一步促进抗肿瘤创新药物的研发。     

天然抗肿瘤药物有效成分及其作用机理的探讨

目的探讨天然药物抗肿瘤的有效成分及其作用机理,为进一步开发天然抗肿瘤药物提供理论基础。方法通过收集和查找近年来有关天然药物在抗肿瘤方面的报道和研究,整理和总结出天然药物在抗肿瘤方面的有效成分和作用机制。结果天然药物抗肿瘤成分主要有生物碱类,中药多糖类,萜类,醌类,蛋白质类等;对抗肿瘤主要作用机制有对肿瘤细胞的直接杀灭作用;干扰细胞周期;诱导肿瘤细胞的分化;逆转多药耐药性肿瘤细胞的抗凋亡作用;诱导肿瘤细胞凋亡;提高机体免疫力来抗肿瘤等方面进行。结论天然抗肿瘤药物的有效成分类别有多样性,但主要为生物碱类,多糖类等为主;作用机制为直接对肿瘤细胞杀灭作用,干扰细胞生长的各个周期及提高机体免疫力等方面。     

诱导细胞凋亡的抗肿瘤抗生素

细胞凋亡是肿瘤防治的一个非常重要的机制，诱导细胞凋亡的抗肿瘤抗生素的面世开辟了肿瘤化疗药物研发的新途径。概述诱导细胞凋亡的抗肿瘤抗生素种类、来源、抗肿瘤谱及实验研究，并对其作用机制进行探讨。     

肿瘤化学治疗的毒性反应和护理

近30年来，肿瘤化学治疗已从辅助治疗地位发展成治疗恶性肿瘤的三大手段之一。抗肿瘤药物通过在体内直接与DNA结合，干扰RNA和蛋白质的合成，或改变机体的内分泌环境，达到抑制或杀灭肿瘤细胞的目的。现用于临床的抗肿瘤药物有60余种，但多种缺少选择抑制肿瘤的作用，在杀伤肿瘤细胞的同时，对增殖旺盛的正常细胞如造血系统、     

透明质酸及其衍生物在药物递送系统中的研究进展

透明质酸(hyaluronic acid,HA)是一种天然多糖,具有良好的生物相容性和可降解性。天然HA对强酸、强碱、热、自由基及透明质酸酶敏感,对其进行修饰可克服以上问题并获得具有各种优良特性的衍生物。HA及其衍生物可作为药物的缓释载体,能够延缓药物的释放,发挥长效作用,可用于多种药物的递送,如蛋白质、核酸及抗肿瘤药物等。HA及其衍生物可与细胞表面多种受体(CD44,RHAMM,LYVE-1,HARE)特异性结合,可用于靶向药物递送,尤其是抗肿瘤药物的递送。     

板栗中蛋白质的分离鉴定及活性研究

目的探讨板栗中蛋白质的分离纯化及其促肾细胞生长作用和抗肿瘤作用及机制。方法从板栗中提取出的水溶性蛋白质,经鉴定是欧栗球蛋白(CAS)。利用MTT法检测该蛋白对正常肾细胞和肝癌细胞HepS,小鼠肉瘤S180腹水型肿瘤细胞增殖的影响;检验其对小鼠T细胞和B细胞增殖作用的影响;用DNA电泳方法检测该蛋白诱导HepS细胞凋亡的作用。结果 CAS在体外对正常肾细胞的增殖有促进作用,对试验的肿瘤细胞的增殖均有抑制作用,对T细胞和B细胞的增殖有促进作用,对HepS细胞具有诱导凋亡的作用。结论 CAS具有促肾细胞生长和抗肿瘤作用,其抗肿瘤作用机制可能通过提高机体免疫力和诱导细胞凋亡来实现。     

自噬激活与抗肿瘤药物的作用

自噬是一种在正常细胞和病态细胞中普遍存在的生理机制。某些肿瘤细胞中自噬活动低下与肿瘤的发生有一定的关系。抗肿瘤药物可以诱导细胞产生自噬,并参与了自噬的分子调控,同时它也可能导致细胞凋亡。自噬在抗肿瘤药物中作用与给药浓度及细胞的类型等因素有关。抗肿瘤药物引起的细胞自噬对肿瘤细胞产生正负两方面的影响,将自噬途径作为抗肿瘤药物的靶点有着广阔的前景。     

抗体偶联药物研究进展

靶向治疗已成为肿瘤治疗新趋势。抗肿瘤靶向药物与传统的细胞毒性化疗药物相比具有特异性高、选择性强和非细胞毒性等优点,抗体偶联药物（ ADC）属于抗肿瘤靶向药物,由抗体、“弹头”药物（细胞毒性药物）通过链分子连接而成。 ADC 将抗体的靶向性与细胞毒性药物的抗肿瘤作用相结合,可以降低细胞毒性抗肿瘤药物的不良反应,提高肿瘤治疗的选择性,还能更好地应对靶向单抗的耐药性问题。     

热休克蛋白90抑制剂的研究进展

热休克蛋白90（heat shock protein90，Hsp90）是生物进化过程中高度保守的一类蛋白质，参与很多生理过程，在信号转导中起重要作用。Hsp90抑制剂与Hsp90结合，抑制Hsp90活性，诱导Hsp90作用蛋白降解，从而阻断细胞的增殖生长，是一类具有开发前景的抗肿瘤、抗病毒药物。现对Hsp90的结构和作用机制以及4类Hsp90抑制剂——格尔德霉素及其衍生物、根赤壳菌素、新生霉素及以嘌呤结构为基础的抑制剂的研究现状进行综述。     

右旋糖酐—药物结合物在抗肿瘤药物给药系统中的应用

右旋糖酐在临床上用作血浆体积扩张剂已有50多年的历史，近年来用作大分子载体的研究报道不断出现，将合适的药物与右旋糖酐形成大分子结合物后，能起到延长药效、减少毒性、增强靶向性及降低免疫原性等作用，已知可载运的有抗肿瘤药、抗生素、抗炎药、蛋白质类药物等，其中在抗肿瘤药方面的研究前景尤为可观。本文综述了抗肿瘤药的大分子结合物近年来的发展情况，并重点介绍了目前研究较多的水溶性大分子载体右旋糖酐用于抗肿瘤药物方面的设计思路、研究现状、存在问题及发展方向等。     

Bortezomib as an antitumor agent

The ubiquitin-proteasome pathway (UPP) is the major non-lysosomal proteolytic system in the cytosol and nucleus of all eukaryotic cells. Bortezomib (also known as PS-341 and Velcade) is a proteasome inhibitor, a novel class of cancer therapies. Bortezomib blocks multi-ubiquitinated protein degradation by inhibiting 26S proteasome activity, including regulating cell cycle, anti-apoptosis, and inflammation, as well as immune surveillance. In multiple myeloma (MM) cells, bortezomib directly induces cell stress response followed by activation of c-Jun NH(2) terminal kinase (JNK)/stress-activated protein kinase (SAPK), and triggers caspase-dependent apoptosis of tumor cells. Recent clinical studies demonstrated that bortezomib had remarkable anti-tumor activity in refractory and relapsed MM, providing the basis to approval by FDA. Its anti-tumor activities earlier in the course, in combination therapies, and in other malignancies is ongoing.     

A new tick Kunitz type inhibitor, Amblyomin-X, induces tumor cell death by modulating genes related to the cell cycle and targeting the ubiquitin-proteasome system

The aim of this study was to evaluate the anti-tumor activity of Amblyomin-X, a serine protease Kunitz-type inhibitor. Amblyomin-X induced tumor mass regression and decreased number of metastatic events in a B16F10 murine melanoma model. Alterations on expression of several genes related to cell cycle were observed when two tumor cell lines were treated with Amblyomin-X. PSMB2, which encodes a proteasome subunit, was differentially expressed, in agreement to inhibition of proteasomal activity in both cell lines. In conclusion, our results indicate that Amblyomin-X selectively acts on tumor cells by inducing apoptotic cell death, possibly by targeting the ubiquitin-proteasome system.     

Bortezomib in the treatment of cancer

Bortezomib (Velcade, formerly PS-341) represents the first proteasome inhibitor to have shown anti-tumor activity in both solid and haematological malignancies. It blocks activation of nuclear factor-kappa B (NF-kB), resulting in increased apoptosis, decreased angiogenic cytokine production, and inhibition of tumor cell adhesion to stroma. Additional mechanisms of action include c-Jun N-terminal kinase activation, effects on growth factor expression and anti-angiogenic properties. Multiple myeloma is the prototype of cancer where bortezomib has shown marked in vitro activity, which was followed by rapid translation to phase I, II and III clinical trials, and resulted in accelerated approval by the FDA for the treatment of patients with relapsed refractory disease. Different clinical trials are currently ongoing in multiple myeloma as well as in many others haematologic and solid tumors (mantle cell and follicular non-Hodgkin's lymphoma; peripheral T-cell lymphoma; Waldenstr?m's macroglobulinemia, chronic lymphocytic leukemia; head and neck / gastroesophageal junction / stomach /colo-rectal / prostate / non-small cell lung cancer). This reviews focuses on the proteasome inhibition exerted by bortezomib, the first proteasome inhibitor to have shown anti-cancer activity in both solid and haematologic malignancies.     

The combination of proteasome inhibitors bortezomib and gambogic acid triggers synergistic cytotoxicity in vitro but not in vivo

The proteasome inhibitor-based combinational therapy has been reported to be an efficient cancer treatment. Our recent studies demonstrated that the natural compound gambogic acid (GA) is a tissue-specific proteasome inhibitor, comparable to bortezomib (Bor), and sensitizes malignant cells to the proteasome inhibitor MG132/MG262 both in vitro and in vivo. The aim of this study was to further extend our investigation by combining GA with the clinically used proteasome inhibitor Bor to test their combined efficacy against human hepatoma HepG2 and mouse hepatoma H22 cells. GA and Bor synergistically induced cytotoxicity and cell death in human HepG2 and mouse H22 cells, and accelerated proteasome inhibition, endoplasmic reticulum (ER) stress and caspase activation in HepG2 cancer cells. However, unexpectedly, GA did not enhance or even antagonized Bor-induced tumor growth inhibition in H22 allograft and HepG2 xenograft tumor models. These findings demonstrated that GA increased Bor activity in vitro but limited the efficacy of Bor in vivo. We suggest that the combination of GA and Bor be avoided when administering these drugs to patients.     

Phase 1 clinical trial of the novel proteasome inhibitor marizomib with the histone deacetylase inhibitor vorinostat in patients with melanoma, pancreatic and lung cancer based on in vitro assessments of the combination

Purpose Combining proteasome and histone deacetylase (HDAC) inhibition has been seen to provide synergistic anti-tumor activity, with complementary effects on a number of signaling pathways. The novel bi-cyclic structure of marizomib with its unique proteasome inhibition, toxicology and efficacy profiles, suggested utility in combining it with an HDAC inhibitor such as vorinostat. Thus, in this study in vitro studies assessed the potential utility of combining marizomib and vorinostat, followed by a clinical trial with the objectives of assessing the recommended phase 2 dose (RP2D), pharmacokinetics (PK), pharmacodynamics (PD), safety and preliminary anti-tumor activity of the combination in patients. Experimental Design Combinations of marizomib and vorinostat were assessed in vitro. Subsequently, in a Phase 1 clinical trial patients with melanoma, pancreatic carcinoma or Non-small Cell Lung Cancer (NSCLC) were given escalating doses of weekly marizomib in combination with vorinostat 300?mg daily for 16?days in 28?day cycles. In addition to standard safety studies, proteasome inhibition and pharmacokinetics were assayed. Results Marked synergy of marizomib and vorinostat was seen in tumor cell lines derived from patients with NSCLC, melanoma and pancreatic carcinoma. In the clinical trial, 22 patients were enrolled. Increased toxicity was not seen with the combination. Co-administration did not appear to affect the PK or PD of either drug in comparison to historical data. Although no responses were demonstrated using RECIST criteria, 61% of evaluable patients demonstrated stable disease with 39% having decreases in tumor measurements. Conclusions Treatment of multiple tumor cell lines with marizomib and vorinostat resulted in a highly synergistic antitumor activity. The combination of full dose marizomib with vorinostat is tolerable in patients with safety findings consistent with either drug alone.     

硼替佐米在恶性血液病中的作用机制

硼替佐米作为一种蛋白酶抑制剂,对多发性骨髓瘤细胞表现出抑制细胞生长、诱导肿瘤细胞凋亡、抑制细胞粘附、抑制肿瘤血管生成等作用,同时对血液系统其他恶性肿瘤具有显著的作用。本文就硼替佐米在恶性血液病中的作用机制作一综述。     

新一类蛋白酶体抑制剂bortezomib

综述了bortezomib的药理作用、药动学及临床评价.本品是一种新型的蛋白酶体抑制剂,临床上用于复发性和难治性多发性骨髓瘤的治疗.     

Research progress of microtubule inhibitor-induced tumor cell mitotic catastrophe北大核心CSCD

Microtubule inhibitor has been a hot area of anticancer drugs research. Microtubule inhibitor exert an anti-tumor effect by promoting or inhibiting the microtubule aggregation to break the dynamic balance of microtubule, hindering the spindle formation of tumor cells, and then blocking the process of cell division. Mitotic catastrophe is a cell death phenomenon that is caused by abnormal cell division and damage of spindle structure in cell mitosis phase. In recent years more and more attention has been paid to mitotic catastrophe cell death because it has been confirmed clinically that microtubule inhibitors can induce mitotic catastrophe death of tumor cells. This paper reviews the latest research progress of microtubule inhibitors, and discusses the molecular mechanisms of mitotic catastrophe cell death tumor cells induced by microtubule inhibitors.