紫杉类化疗药物抗肿瘤免疫调节的作用

总结国内外关于紫杉类化疗药物对肿瘤免疫调节作用的研究进展.方法:应用Medline和CHKD期刊全文数据库检索系统,以"紫杉醇/多西紫杉醇,免疫调节,免疫治疗,化疗,肿瘤"为关键词,检索1999-01-2009-04紫杉类化疗药与免疫及肿瘤免疫治疗相关的文献,其中英文146篇,中文11篇,根据研究内容为紫杉醇或多西紫杉醇的免疫影响以及在肿瘤免疫治疗中的作用对文献进行筛选,最后纳入20篇.结果:紫杉类化疗药物具有明显的免疫调节作用,其抗肿瘤免疫调节作用与剂量和细胞亚群及作用时间相关.当紫杉类化疗药物与疫苗合理联合应用时可产生明显的抗肿瘤协同效果,紫杉类化疗药物具体的作用机制尚未完全明确.结论:化疗联合免疫疗法为肿瘤治疗带来了新的思路及希望,但目前紫杉类药物联合免疫治疗的研究尚处于初期,具体的机制及理想的联合方式仍需进一步研究.     

红豆杉及紫杉醇研究的进展

近年来,新抗癌药紫杉醇及其类似物的研究引起广泛注意,临床报告紫杉醇对抗药的卵巢癌、乳腺癌、非小细胞肺癌等有突出疗效.本文对国内外关于紫杉醇及其类似物的化学、抗肿瘤作用、药理及临床研究作一介绍.     

抗癌新药-紫杉醇的临床研究进展

紫杉醇(Paclitaxel)是美国国立癌症研究所(NCI)在美国西北部的紫杉树皮中发现的一种具有独特作用机制的抗肿瘤新药，1971年美国北卡州三角研究所的WallMC等，确定了它的结构，1977年NCI选择Taxol进入临床研究，1993年FDA批准上市。紫杉醇是一种新型的抗肿瘤药物，本文对近年来紫杉醇的临床研究进展作一综述。     

Docetaxel的药理学研究进展

 Docetaxel是紫杉醇类抗肿瘤药物中的一个新的有代表性的化合物。其结构和药理与紫杉醇相似,二种药物都是紫杉的提取物：Docetaxel是欧洲紫杉的半合成品,而紫杉醇是太平洋紫杉的天然成分。     

多西他赛作为一线用药治疗卵巢癌研究进展

多西他赛是半合成的紫杉类药物,临床药理学研究证实,多西他赛的抗瘤活性强于紫杉醇,并和紫杉醇没有交叉耐药。已有的研究表明,多西他赛治疗铂类耐药和对紫杉醇耐药的卵巢癌有较好的疗效。近几年,很多研究评价了多西他赛作为一线药物治疗卵巢上皮癌的价值。Ⅰ期和Ⅱ期的临床研究证实,多西他赛联合铂类药物作为一线药物治疗卵巢癌有较好的有效率为58%～89%,而多西他赛联合卡铂化疗的毒副反应比多西他赛联合顺铂少,特别是神经毒性。Ⅲ期临床研究比较了多西他赛联合卡铂方案和目前作为治疗卵巢上皮癌标准一线化疗方案的紫杉醇联合卡铂方案治疗卵巢上皮癌的差别,发现两个方案有相同的有效率,分别为58.7%和59.5%,但是多西他赛联合卡铂化疗的神经毒性更低,所以推荐多西他赛加卡铂联合化疗方案作为卵巢上皮癌的一线化疗方案。     

多西他赛作为一线用药治疗卵巢癌研究进展

多西他赛是半合成的紫杉类药物,临床药理学研究证实,多西他赛的抗瘤活性强于紫杉醇,并和紫杉醇没有交叉耐药.已有的研究表明,多西他赛治疗铂类耐药和对紫杉醇耐药的卵巢癌有较好的疗效.近几年,很多研究评价了多西他赛作为一线药物治疗卵巢上皮癌的价值.Ⅰ期和Ⅱ期的临床研究证实,多西他赛联合铂类药物作为一线药物治疗卵巢癌有较好的有效率为58%～89%,而多西他赛联合卡铂化疗的毒副反应比多西他赛联合顺铂少,特别是神经毒性.Ⅲ期临床研究比较了多西他赛联合卡铂方案和目前作为治疗卵巢上皮癌标准一线化疗方案的紫杉醇联合卡铂方案治疗卵巢上皮癌的差别,发现两个方案有相同的有效率,分别为58.7%和59.5%,但是多西他赛联合卡铂化疗的神经毒性更低,所以推荐多西他赛加卡铂联合化疗方案作为卵巢上皮癌的一线化疗方案.     

紫杉醇注射液、紫杉醇脂质体以及多西他赛治疗乳腺癌的疗效及安全性北大核心CSCD

紫杉烷类化合物是最具有潜力的抗恶性肿瘤药物之一。紫杉醇属于紫杉烷类化合物,是目前被批准用于乳腺癌、卵巢癌、肺癌等恶性肿瘤的一线化疗药物。紫杉醇为从太平洋紫杉树皮中提取的二萜类化合物,其产量低、结构复杂、不易提取和合成以及不溶于水的特性大大限制了紫杉醇的临床应用研究。多西他赛是半合成紫杉醇类似物,水溶性略大于紫杉醇,是有潜力的细胞微管蛋白抑制剂,临床应用较多。传统的紫杉醇采用聚氧乙烯蓖麻油作为药物载体,会引起多种不良反应,限制了该药的使用。2003年我国研制成功的注射用紫杉醇脂质体（力扑素）     

抗肿瘤新药紫杉醇研究进展

抗肿瘤新药紫杉醇研究进展安徽省淮南职业医专祁向东，奇云，方坤美国ＦＤＡ已于１９９２年批准紫杉醇用于治疗晚期卵巢癌。本文回顾了紫杉醇的研究历史，并重点介绍国内外关于紫杉醇及其类似物的化学、抗肿瘤作用、药理及临床的研究结果。一、紫杉醇研究的历史美［ｊ４Ｒ...     

泰索帝治疗非小细胞肺癌

泰索帝是半合成的紫杉类抗肿瘤新药，本文在阐述泰索帝的化学结构、作用机制、药代动力学Ⅰ期临床试用结果的基础上，综述了泰索帝单药治疗非小细胞肺癌的疗效，与顺铂和去甲长春花碱等联合化疗治疗非小细胞肺癌的Ⅱ临床结果，以及主要的不良反应，提示泰索帝是一个很有前途的抗肿瘤新药。     

雷帕霉素联合多西紫杉醇诱导肺癌95D细胞凋亡的机制研究

目的:探讨哺乳动物雷帕霉素靶蛋白信号通路抑制剂雷帕霉素(rapamycin,Rapa)联合多西紫杉醇( docetaxel,DTX)对肺癌95D细胞系凋亡的影响.方法:流式细胞仪检测雷帕霉素及联合多西紫杉醇对95D细胞凋亡的影响,RT-PCR方法和Western blot检测凋亡基因survivin mRNA和蛋白的表达.结果:mTOR抑制剂雷帕霉素和多西紫杉醇单独处理组均能促进肺癌细胞的凋亡,下调凋亡基因survivin mRNA和蛋白的表达;联合应用雷帕霉素和多西紫杉醇促凋亡作用更强,survivin mRNA和蛋白的表达下降更明显.结论:雷帕霉素联合多西紫杉可以降低survivin的表达,从而起到促进肿瘤细胞凋亡的作用,为临床寻找新型抗肿瘤药物及治疗肺癌的新化学治疗方案提供了理论和实践基础.     

Targeting the microtubules in breast cancer beyond taxanes: the epothilones

Microtubule-targeting agents such as the taxanes are highly active against breast cancer and have become a cornerstone in the treatment of patients with early and advanced breast cancer. The natural epothilones and their analogs are a novel class of microtubule-stabilizing agents that bind tubulin and result in apoptotic cell death. Among this family of compounds, patupilone, ixabepilone, BMS-310705, ZK-EPO, and KOS-862 are in clinical development. Extensive preclinical studies have shown that epothilones are working through partially nonoverlapping mechanisms of action with taxanes. In the clinic, epothilones have been found in a series of phase I and phase II studies to be active even in patients who had recently progressed to taxanes. The toxicity profile of these agents consists mostly of sensory neuropathy, sometimes reversible. Neoadjuvant studies with epothilones have been conducted and a number of phase III studies in advanced breast cancer are either under way or have been recently completed. The results of these studies are eagerly awaited and it is anticipated that epothilones may become an important treatment option in patients with breast cancer.     

Epothilones: a novel class of microtubule-stabilizing drugs for the treatment of cancer

Microtubule-targeted anticancer drugs are effective in treating various cancers but are limited in use due to development of resistance and unacceptable toxicities. The epothilones are a novel class of microtubule-stabilizing anticancer drugs and may have a role in treating taxane-resistant cancers. Revised and updated data from several clinical studies for ixabepilone were recently published and subsequently resulted in ixabepilone becoming the first epothilone approved as monotherapy or in combination for treatment of locally advanced or metastatic breast cancer. BMS-310705, patupilone, KOS-862, KOS-1584 and ZK-EPO are epothilones that have been developed. Although peripheral sensory neuropathy and neutropenia are the dose-limiting toxicities for ixabepilone, these dose-limiting toxicities are ixabepilone specific. This review will discuss the current preclinical, clinical pharmacokinetic and pharmacodynamic, efficacy and toxicity data of the epothilones.     

New taxanes and epothilone derivatives in clinical trials

This review describes the experimental and clinical properties of new taxanes and epothilones. Six new taxanes are currently in clinical trials: BMS 184476, BMS 188797, BMS 275183, IDN 5109/BAY 598862, RPR 109881A et RPR 116258 All these derivatives share the same feature which is a decreased recognition by Pgp-170, the product of the MDR1 gene. This confers innovative properties such as in vitro and in vivo activities on tumors expressing the Pgp-170, activity by the oral route. Identification of other families of molecules bearing the same mechanism of action as taxol has been a goal pursued by many groups. The discovery of epothilones led to the pharmaceutical development of two molecules: EPO 906 (which corresponds to the natural compound epothilone B) and BMS 247550. Phase I clinical trials have established that all these investigational drugs (taxanes and epothilones) can be safely administered in patients, the limiting toxicity being most of the time febrile neutropenia. Many tumor responses have been noted.     

Ixabepilone: a novel antineoplastic agent with low susceptibility to multiple tumor resistance mechanisms

Tumor resistance to chemotherapeutic agents ultimately leads to treatment failure in the majority of cancer patients. The identification of new agents that are less susceptible to mechanisms of tumor resistance could, therefore, bring significant clinical benefits to patients with advanced cancer. One new drug class of great interest in this respect is the epothilones and their analogues, which are microtubule inhibitors with low susceptibility to several mechanisms of drug resistance. Ixabepilone is an analogue of natural epothilone B with activity against a wide range of tumor types, including drug-resistant tumors. This is consistent with the preclinical activity of ixabepilone against human cancer cell lines resistant to taxanes and other agents. Taxane resistance in these cells may be acquired or primary and results from several mechanisms, such as overexpression of multidrug-resistance proteins and the betaIII-tubulin isoform. Ixabepilone has demonstrated efficacy as monotherapy or in combination with capecitabine in anthracycline- and taxane-pretreated/resistant metastatic breast cancer (MBC), and has recently been approved for use in resistant/refractory MBC. Other epothilones, such as patupilone, KOS-1584, and ZK-EPO, are also being evaluated in drug-resistant cancers. Ixabepilone represents a new treatment option for MBC patients with cancers resistant to available chemotherapeutic agents.     

Clinical experience with epothilones in patients with breast cancer

The search for novel chemotherapeutic agents in the treatment of breast cancer with lower susceptibility to resistance mechanisms than current agents has led to the discovery of the epothilones and their analogues. Epothilones stabilize microtubules in a manner similar to taxanes but are structurally distinct. Ixabepilone, an epothilone B analogue, having demonstrated high antimicrotubule activity in preclinical studies, has shown notable efficacy in phase II trials in patients with early-stage and metastatic breast cancer. Of particular note, single-agent ixabepilone is effective in tumors resistant to anthracyclines, taxanes, and capecitabine, for which there is currently no recommended therapy. Different mechanisms of action and the non-overlapping toxicities of ixabepilone with other agents provide the rationale for ixabepilone in combination as a valid therapeutic approach. Phase II results assessing ixabepilone in combination with capecitabine in anthracycline- and taxane-pretreated patients are promising. The investigation of ixabepilone in the neoadjuvant setting has also revealed potential biomarkers to predict ixabepilone response. Ixabepilone has demonstrated activity in patients with tumors that are estrogen receptor-, progesterone receptor-, and HER2-negative. The safety profile throughout the trials has been manageable, with peripheral neuropathy as one of the more notable adverse events, which has been mostly reversible. A phase III trial comparing ixabepilone plus capecitabine versus capecitabine alone demonstrated significant prolongation of median progression-free survival and reduction in relapse risk. Additionally, other members of the epothilone family, such as patupilone, ZK-EPO, BMS-310705, and KOS-862, have demonstrated efficacy against breast cancer in phase I clinical trials. Ongoing phase II/III trials continue to assess ixabepilone and other members of the epothilone family in breast cancer, particularly in combination regimens, as being valid treatment options in multidrug-resistant breast cancer.     

The epothilones: new therapeutic agents for castration-resistant prostate cancer

The management of castration-resistant prostate cancer (CRPC) presents a clinical challenge because of limitations in efficacy and durability with currently available therapeutics. The epothilones represent a novel class of anticancer therapy that stabilizes microtubules, causing cell death and tumor regression in preclinical models. The structure of the tubulin-binding site for epothilones is distinct from that of the taxanes. Moreover, preclinical studies suggest nonoverlapping mechanisms of resistance between epothilones and taxanes. In early-phase studies in patients with CRPC, treatment with ixabepilone, a semisynthetic analog of epothilone B, induced objective responses and prostate-specific antigen declines in men previously progressing on docetaxel-based regimens. Clinical activity has been observed in nonrandomized trials for patients with CRPC using ixabepilone in the first- and second-line settings as a single agent and in combination with estramustine. Patupilone and sagopilone were also shown to have promising efficacy in phase II clinical trials of patients with CRPC. All three epothilones appear to be well tolerated, with modest rates of neutropenia and peripheral neuropathy. The lack of crossresistance between epothilones and taxanes may allow sequencing of these agents. Evaluating epothilones in phase III comparative trials would provide much-needed insight into their potential place in the management of patients with CRPC.     

Current perspectives of epothilones in breast cancer

Taxanes have been broadly used in the treatment of breast cancer. However, the majority of initially responsive breast cancer patients eventually develop resistance to taxanes (acquired resistance) and a non-negligible percentage of patients are primarily resistant to these agents (de novo resistance). Additionally, taxanes require pre-medication and may cause important side effects such as febrile neutropenia and neuropathy. Hence, new agents with better efficacy and/or a better toxicity profile and/or are easier to administer need to be developed. Epothilones are a novel class of microtubule-targeting agents sharing a similar mechanism of action to the taxanes and having a more potent antiproliferative activity in various tumour cells lines, particularly in cases of taxane-resistant breast cancer. This review will focus on clinical development of epothilones in breast cancer, particularly ixabepilone which is in the late stages of development, their potential impact in clinical practice, advantages and limitations.     

Epothilones: clinical update and future directions

Epothilones are cytotoxic compounds that function in a similar fashion to paclitaxel and show promise for the treatment of a variety of cancers by inducing microtubule bundling and apoptotic cell death. However, their mechanism of microtubule binding is different from that of paclitaxel, which makes epothilones an attractive drug class for patients with taxane-resistant malignancies. As taxane resistance remains a significant barrier in the treatment of a variety of cancers, it is important to understand epothilones and their indications. Several epothilone compounds, including ixabepilone (BMS-247550, aza-epothilone B, Ixempra), patupilone (EPO906, epothilone B), KOS-862 (desoxyepothilone B, epothilone D), BMS-310705, ZK-EPO (ZK-219477), nd KOS-1584, have been testedf or the treatment of a variety of solid tumor types. Recently, ixabepilone became the first epothilone to be approved by the US Food and Drug Administration, for the treatment of metastatic or locally advanced breast cancer as monotherapy or in combination with capecitabine (Xeloda) after other treatments have failed. This article reviews recent findings from clinical trials of epothilones and discusses future directions for the use of these agents in cancer therapy, with a focus on the two most-studied epothilones to date: ixabepilone and patupilone.     

Epothilones: mechanism of action and biologic activity.

Drugs that target microtubules are among the most commonly prescribed anticancer therapies. Although the mechanisms by which perturbation of microtubule function leads to selective death of cancer cells remain unclear, several new microtubule-targeting compounds are undergoing clinical testing. In part, these efforts focus on overcoming some of the problems associated with taxane-based therapies, including formulation and administration difficulties and susceptibility to resistance conferred by P-glycoprotein. Epothilones have emerged from these efforts as a promising new class of anticancer drugs. Preclinical studies indicate that epothilones bind to and stabilize microtubules in a manner similar but not identical to that of paclitaxel and that epothilones are effective in paclitaxel-resistant tumor models. Clinical phase I and early phase II data are available for BMS-247550, BMS-310705, EPO906, and KOS-862. The results suggest that these compounds have a broad range of antitumor activity at doses and schedules associated with tolerable side effects.     

Efficacy and safety of ixabepilone (BMS-247550), a novel epothilone B analogue

The epothilones are a new class of non-taxane tubulin polymerization agents obtained by natural fermentation of the myxobacteria Sorangium cellulosum. The cytotoxic activities of the epothilones, like those of the taxanes, have been linked to stabilization of microtubules, but they also have important differences. Among the epothilone family, ixabepilone (BMS247550) is a semisynthetic derivative of the natural product epothilone B. Ixabepilone was evaluated in vivo in a panel of human and rodent tumour models, the majority of which were chosen because of their known, well-characterized resistance to paclitaxel, and seems able to overcome the over-expression of multidrug resistance and to be unaffected by mutations in the beta tubulin gene. The interest of ixabepilone was clinically confirmed in clinical studies of phase II which demonstrated a strong activity at the patients with metastatic breast cancer resistant to taxanes and in patients suffering of other types of chemoresistant tumors.