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1.
热休克蛋白70(heat shock protein 70,Hsp70)是一种在应激条件下诱导表达的伴侣蛋白,能帮助细胞内新生蛋白折叠,蛋白细胞内运输、蛋白装配和降解,并能在应激状态下维持蛋白质构象。研究表明,Hsp70与许多疾病有关,如癌症、神经退行性疾病、异源移植的排斥、感染等,有望成为新的药物作用靶点。本文综述了Hsp70的结构、家族成员、协同伴侣(co-chaperones)成员及其功能研究进展,并介绍Hsp70抑制剂的研究现况。 相似文献
2.
目的:分析吉非替尼治疗非小细胞肺癌的临床疗效。方法:调查我院2005年1月到2006年12月患非小细胞肺癌的住院病人40例,给予吉非替尼250 mg,每日1次口服。结果:总有效率为35.0%(完全缓解1例,部分缓解13例),疾病控制率为82.5%(完全缓解1例,部分缓解13例,基本稳定19例)。其中男性病人29例,女性病人11例,有效率分别为55.2%和36.4%(P<0.05)。主要不良反应是恶心呕吐37%、厌食25%、皮疹18%等。结论:吉非替尼治疗非小细胞肺癌有较好的疗效,不良反应较轻,可以提高大多数病人的生活和生存质量。 相似文献
3.
目的 研究非小细胞肺癌(non-small cell lung cancer,NSCLC)的四种不同化疗方案的药物经济学效果和流行病学临床评价.方法 采用回溯法筛选了129例非小细胞肺癌病例,分成4组,分别为Ⅰ组NP方案(长春瑞滨NVB 顺铂DDP);Ⅱ组GP(吉西他滨GEM 顺铂DDP);Ⅲ组NPA方案(长春瑞滨NVB 顺铂DDP 艾迪AIDI);Ⅳ组NPK(长春瑞滨NVB 顺铂DDP 薏苡仁提取物(康莱特KLT)).运用药物流行病学的疗效比较和药物经济学的成本-效果分析方法进行研究.结果 4组疗效分别为31.43%,36.36%,41.94%,53.33%.不良反应Ⅳ和Ⅲ组低于Ⅰ和Ⅱ组.生活质量Ⅳ>Ⅲ>Ⅱ>Ⅰ组.成本效果比分别为550.22、556.48、641.43、511.58元.结论 NP方案总成本最低但疗效也最低,NPK方案疗效最好,并且每提得一个疗效百分点其花费最小,最具经济学意义. 相似文献
4.
Introduction: Heat shock protein 90 (HSP90) serves as a critical facilitator for oncogene addiction. There has been augmenting enthusiasm in pursuing HSP90 as an anticancer strategy. In fact, since the initial serendipitous discovery that geldanamycin (GM) inhibits HSP90, the field has rapidly moved from proof-of-concept clinical studies with GM derivatives to novel second-generation inhibitors. Areas covered: The authors highlight the current status of the second-generation HSP90 inhibitors in clinical development. Herein, the authors note the lessons learned from the completed clinical trials of first- and second-generation inhibitors and describe various assays attempting to serve for a more rational implementation of these agents to cancer treatment. Finally, the authors discuss the future perspectives for this promising class of agents. Expert opinion: The knowledge gained thus far provides perhaps only a glimpse at the potential of HSP90 for which there is still much work to be done. Lessons from the clinical trials suggest that HSP90 therapy would advance at a faster pace if patient selection and tumor pharmacokinetics of these drugs were better understood and applied to their clinical development. It is also evident that combining HSP90 inhibitors with other potent anticancer therapies holds great promise not only due to synergistic antitumor activity but also due to the potential of prolonging or preventing the development of drug resistance. 相似文献
5.
Introduction: Nanoparticle albumin-bound paclitaxel (nab-paclitaxel), a microtubule inhibitor, has demonstrated clinical efficacy in the treatment of advanced non-small cell lung cancer (NSCLC) either as monotherapy or in combination. Nab-paclitaxel was developed to reduce the toxicities associated with solvent-bound paclitaxel (sb-paclitaxel). Areas covered: This review first focuses on the clinical trials evaluating the efficacy and tolerability of nab-paclitaxel in NSCLC at different settings. The approval of nab-paclitaxel in combination with carboplatin at the front-line setting for advanced NSCLC was based on the key phase III study, which showed that nab-paclitaxel/carboplatin was associated with superior overall response rate and favorable toxicity profile compared to sb-paclitaxel/carboplatin. The review also addresses the nab-paclitaxel pharmacology, other combinations (e.g. immunotherapy with PD-1/PD-L1 inhibitors), potential biomarkers (e.g. caveolin-1), and special subgroups (e.g. the elderly, squamous histology). Expert opinion: Existing data has established the role of nab-paclitaxel in the management of advanced NSCLC. Emerging evidence, such as preliminary results from Keynote-407 and IMpower 131 studies, indicates that novel combinations of nab-paclitaxel/carboplatin and PD-1/PD-L1 inhibitors could further improve clinical benefits with manageable toxicity. Nevertheless, in order to better position nab-paclitaxel and to improve patient selection, future studies are warranted to further understand its mechanism of action, predictive biomarkers, and potential synergism with other agents. 相似文献
6.
Introduction: Heat shock proteins (Hsps) are part of a complex network of chaperone proteins that are critically involved in the conformational maturation of intracellular proteins and regulate their degradation via the proteasome system Hsps (especially Hsp70 and Hsp90) are upregulated in many cancers and are potentially attractive therapeutic targets. Ganetespib is a potent non-geldanamycin analogue, and avoids the toxicities associated with older analogues due to its small molecular weight, lipophilicity and the absence of the benzoquinone moiety; strong pre-clinical data support its evaluation in lung cancer, especially small cell lung cancer (SCLC). Areas covered: The chemical structure of ganetespib, the biology of Hsp90 in cancer and the pharmacokinetic and pharmacodynamic data related to ganetespib are summarized; data from preclinical studies and multiple Phase I-III clinical trials, with a focus on its evaluation in SCLC are reviewed. Expert opinion: Recent progress made in the treatment of refractory SCLC with immune checkpoint inhibitors and DLL3-directed antibody-drug conjugate have made the development of ganetespib particularly challenging in SCLC. Hsp90 remains a critical therapeutic target. Hsp90 inhibitors with a wider therapeutic index and combinations with drugs targeting iHsp90 co-chaperones such as Cdc37 or Protein Kinase 2 may need to be explored in the future. 相似文献
7.
抗肿瘤新药是当前新药研发的热点。为获得更大的临床获益,积极探索不同形式的联合用药方案,是抗肿瘤药物研发的必然方向。本文将从技术审评角度,阐述当前开展抗肿瘤药物申报联合用药早期临床试验的申报要求与审评考虑。 相似文献
8.
Introduction: Acute myeloid leukemia (AML) is the most common myeloid malignancy in adults. Despite recent discoveries of targeted therapies, the frontline therapy consisting of chemotherapy remains unchanged for the past four decades. Like other cancers, AML is characterized by deranged DNA damage repair (DDR) pathway. Although impaired DDR may contribute to the pathogenesis of AML it also allows leukemia cells with damaged DNA to attempt repair resulting in resistance. CHK1 inhibitors reverse the cell cycle arrest, disallowing the cell to repair the chemotherapy-induced DNA damage, driving the cell to enter into mitotic catastrophe. Areas covered: This paper reviews the preclinical and clinical development of CHK1 inhibitors and we discussed their promising role as a potential addition to the therapeutic arsenal of AML. Expert opinion: Targeting the cell cycle checkpoints is an intriguing approach to treat cancer in general and AML in particular. CHK1 inhibitors in combination with chemotherapy have the potential of improving outcome in high-risk AML characterized by DDR activation. 相似文献
9.
Endothelin-1 (ET-1) is enhanced and has been demonstrated to be a prognostic marker in patients with advanced stages of heart failure, acute ischaemic syndromes, myocardial infarction and pulmonary hypertension. Activation of the endothelin (ET) system is associated with adverse haemodynamic consequences in patients with congestive heart failure and results in coronary vasoconstriction in patients with coronary artery disease (CAD). Moreover, ET-1 raises blood pressure, induces vascular and myocardial hypertrophy and acts as the natural counterpart of nitric oxide (NO), which exerts vasodilating, antithrombotic and antiproliferative effects. This article reviews recently completed and ongoing clinical trials examining the effects of ET receptor antagonists in patients with heart failure, CAD, arterial hypertension and pulmonary hypertension. 相似文献
10.
Introduction: Crizotinib is a first-in-class ALK tyrosine kinase inhibitor (TKI), which has proven its superiority over standard platinum-based chemotherapy for the first-line therapy of ALK-rearranged non-small cell lung cancer (NSCLC) patients. The development of acquired resistance to crizotinib represents an ongoing challenge with the central nervous system being one of the most common sites of relapse. Ceritinib and alectinib are approved second-generation ALK TKIs. Several novel ALK inhibitors, more potent and with different selectivity compared to crizotinib, are currently in development. Areas covered: This review will focus on new ALK inhibitors, currently in phase 1 or 2 clinical studies. We will also comment on the mechanisms of resistance to ALK inhibition and the strategies to delay or overcome resistance. Expert opinion: The therapeutic management of ALK-rearranged NSCLC has been greatly improved. Next-generation ALK inhibitors have shown differential potency against ALK rearrangements and ALK resistance mutations. The molecular profile of the tumor at the time of disease progression to crizotinib is crucial for the sequencing of novel ALK TKIs. Ongoing clinical studies will address key issues, including the optimal therapeutic algorithm and whether combinational approaches are more effective than single ALK inhibition for the outcome of ALK-rearranged NSCLC patients. 相似文献
11.
Colorectal cancer is one of the most common cancers worldwide. Through well-designed clinical trials, advances have been made in the treatment of localised and advanced colorectal cancer. It has been established that 6 months of 5-fluorouracil-based chemotherapy will improve overall survival in patients with stage III colon cancer. The role of adjuvant chemotherapy in stage II colon cancer remains an unresolved issue. Recent studies have demonstrated an improved survival with the addition of irinotecan to 5-fluorouracil and leucovorin for the treatment of advanced colorectal cancer. Immunotherapy, molecular targeted therapy and liver-directed therapy, in addition to new chemotherapy combinations, are all being evaluated for the treatment of localised and advanced colorectal cancer. Ongoing and proposed studies are incorporating the identification of genetic and molecular abnormalities, which may provide prognostic information as well as direct treatment decisions. 相似文献
12.
Introduction: More than 424 million adults have diabetes mellitus (DM). This number is expected to increase to 626 million by 2045. The majority (90–95%) of people with DM has type 2-diabetes (T2DM). The continued prevalence of DM and associated complications has prompted investigators to find new therapies. One of the most recent additions to the anti-diabetic armamentarium are inhibitors of sodium-glucose co-transporters 1 and 2 (SGLT1, SGLT2). Areas covered: The authors review the status of SGLT2 inhibitors for the treatment of T2DM and place an emphasis on those agents in early phase clinical trials. Data and information were retrieved from American Diabetes Association, Diabetes UK, ClinicalTrials.gov, PubMed, and Scopus websites. The keywords used in the search were T2DM, SGLT1, SGLT2, and clinical trials. Expert opinion: The benefits of SGLT inhibitors include reductions in serum glycated hemoglobin (HbA1c), body weight, blood pressure and cardiovascular and renal events. However, SGLT inhibitors increase the risk of genitourinary tract infections, diabetic ketoacidosis, and bone fractures. The development of SGLT inhibitors with fewer side effects and as combination therapies are the key to maximizing the therapeutic effects of this important class of anti-diabetic drug. 相似文献
13.
Of all cancers, > 50% currently occur in individuals ≥ 65 years of age and this figure is expected to rise to 70% by 2030, due to a progressive expansion of the older population [1]. Clinical trials are needed in order to establish the benefits and risks of antineoplastic treatment in older individuals. It is reasonable to expect that the costs of these trials may be higher than in younger individuals, as older patients are more vulnerable to therapeutic complications and may need more supportive care, and the benefits of treatment may be less because of a reduced life-expectancy and competitive causes of death [2]. This article explores a cost-effective approach to clinical trials in older individuals, after reviewing the basic concepts of economic analysis and unique aspects of geriatric oncology that may affect the cost of treatment. In the process, the cost differences of cancer treatment in younger and older patients will be explored. 相似文献
14.
目的探讨培美曲塞二钠联合顺铂方案一线治疗失败的晚期非小细胞肺癌的疗效和毒性。方法15例既往化疗或靶向治疗失败的晚期非小细胞肺癌患者接受培美曲塞二钠联合顺铂方案化疗,其中培美曲塞二钠500mg/m2加入0.9%氯化钠注射液100ml静脉点滴超过10min;顺铂75mg/m^2。每21d重复,2周期评价疗效。结果15例患者中,部分缓解(PR)1例,进展(SD)8例,PD6例,总有效率6.6%,毒性反应主要为疲乏无力,占53.3%。白细胞下降占46.6%,恶心、呕吐占33.3%。结论培美曲塞二钠联合顺铂方案是一线治疗失败的晚期非小细胞肺癌的理想方案之一。 相似文献
15.
Summary
Background: The new intercalative agent Mitonafide was shown in early clinical trials to be toxic to the central nervous system when administered as a short intravenous infusion, but not when given as a 120-hour continuous infusion. Thus, clinical development in different tumor types was pursued using only this administration schedule,
Patients and methods: Forty-nine patients with previously untreated non-small cell lung cancer(NSGLC) and at least one measurable site received Mitonafide as a 120-hour continuous (5 days) infusion every 3 weeks. The starting dose was 170 mg/m 2/day × 5 in the first 26 patients and 200 mg/m 2/day × 5 in the remainder. Patients were evaluated for toxicity after each course and for response every two courses and remained on treatment until excessive toxicity or disease progression were observed. A special test, the Mini-mental state, was used to assess patients' cognitive functions.
Results: Of the 49 patients entered, 42 were evaluable for response and toxicity. Toxicity consisted mainly of myelosuppression and no neurologic side effects were observed. Only one patient presented a partial response.
Conclusions: Although definitively safe with this schedule of administration, Mitonafide is not active in NSCLC. 相似文献
16.
目的:对接受紫杉醇联合顺铂3周方案的非小细胞肺癌患者药代动力学差异进行研究,分析非小细胞肺癌患者中紫杉醇关键药代动力学参数Tc>0.05(血浓度0.05μM以上时间)与临床毒性的相关性,为紫杉醇的治疗药物监测提供依据。方法:应用纳米增强免疫比浊法检测非小细胞肺癌患者紫杉醇化疗后(24±6)h的血药浓度,采用群体药物动力学模型计算出Tc>0.05值,同时观察化疗后出现的不良反应,按照NCI-CTC v4.0毒副反应评价标准进行分级、结果:全组16例患者共进行32次化疗,有效周期29次(可测算出Tc>0.05),共发生不良反应25例次,包括骨髓抑制、胃肠道反应,无因不良反应而中断治疗者。将患者按照紫杉醇在体内暴露情况分为两组:正常暴露组和高暴露组。骨髓抑制的发生率在两组中存在显著差异(P=0.003),恶心呕吐的发生率无显著性差异(P=0.483)。对两组Ⅲ度以上骨髓抑制的发生率进行比较,发现两组间存在差异,但无统计学意义(P=0.052)。结论:通过测算紫杉醇Tc>0.05值可以了解紫杉醇在患者体内的暴露情况,从而判断患者发生骨髓抑制的风险。但由于本研究中样本量有限,尚需大样本的临床研究进一步证实上述结论。 相似文献
17.
目的:探讨临床药师参与非小细胞肺癌患者药学监护的模式与效果。方法:临床药师通过参与试验组患者化疗方案制定、护士给药指导、并对患者用药后的疗效和不良反应进行跟踪处理后,比较试验组和对照组患者的不良反应发生情况。结果:临床药师主要通过治疗方案确定、护士给药指导以及药学监护三个方面介入治疗;试验组明显减少患者化疗辅助用药;临床药师介入的试验组不良反应发生率显著减少,恶心、呕吐(p<0.001),骨髓抑制(p=0.002)和肝功能损伤(p=0.014),具有统计学差异。结论:临床药师介入非小细胞肺癌治疗的干预措施有效可行,促进临床化疗方案有效执行,提高改善化疗效果和患者生活质量。 相似文献
18.
表皮生长因子受体酪氨酸激酶抑制剂(epithelial growth factor receptor tyrosine kinase inhibitors,EGFR-TKI)引领EGFR突变的晚期非小细胞肺癌精准治疗十多年,EGFR-TKI对EGFR常见突变的晚期非小细胞肺癌的疗效已得到明确的证实。然而对于EGFR罕见突变,EGFR-TKI的疗效在临床上存在众多争议。本文列举了目前已经进入临床阶段的EGFR-TKI类药物在EGFR突变阳性晚期非小细胞肺癌中的中位无进展及总生存期并进行比较,增加了EGFR罕见突变对EGFR-TKI疗效的相关研究,以期为临床EGFR-TKI的合理使用提供参考。 相似文献
19.
Introduction: Idiopathic pulmonary fibrosis (IPF) is an age-associated, progressive, and irreversible fatal interstitial lung disease. Although many drugs have failed in clinical trials, these failures improved the understanding of the pathogenesis of IPF. Currently, there are two drugs approved for IPF that slow the progression of the disease. However, the prognosis for patients with IPF remains poor and the search continues for drugs that inhibit the pathogenic pathways active in IPF to further reduce or even halt the progression of the disease. Areas covered: We highlight the recent information on the therapeutic targets currently explored in early stage clinical trials and discuss the potential for new therapy and the limitation of basic research in the treatment of IPF. Expert opinion: A key challenge in the coming years will lie in deciding which compounds to combine and how to evaluate combination therapies in clinical trials. The drugs most likely to provide additive efficacy when used in combination with one of the approved therapies are those with alternative, complementary, or synergistic mechanisms of action. 相似文献
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