Les antiangiogéniques : limites actuelles en oncologie thoracique

Antiangiogenic agents appear as major therapeutic options in renal, colorectal and breast cancer. Their part in thoracic oncology is still limited today except for bevacizumab. We review the current limits of antiangiogenic agents in terms of efficacy, activity, tolerance and therapeutic strategies. Problems about predictive biomarkers and cost-effectiveness of antiangiogenic agents in thoracic oncology are also mentioned.     

Drug hybridization strategies: before or after lead identification?

The molecular hybridization approach is one of the most valuable structural modification tools useful for the discovery of ligands and prototypes presenting either optimized affinity for one bioreceptor or the ability to modulate more than one bioreceptor associated with the target disease. The growing efforts to discover hybrid drugs resulting from the combination of pharmacophoric moieties of different known lead compounds have brought a new hope for the treatment of multifactorial diseases in recent years. This editorial describes possible ways of exploring molecular hybridization strategies to plan new effective dual or symbiotic drug candidates.     

Concatenation of molecular docking and molecular simulation of BACE-1, γ-secretase targeted ligands: in pursuit of Alzheimer’s treatment

IntroductionAlzheimer''s disease (AD), the most predominant cause of dementia, has evolved tremendously with an escalating frequency, mainly affecting the elderly population. An effective means of delaying, preventing, or treating AD is yet to be achieved. The failure rate of dementia drug trials has been relatively higher than in other disease-related clinical trials. Hence, multi-targeted therapeutic approaches are gaining attention in pharmacological developments.AimsAs an extension of our earlier reports, we have performed docking and molecular dynamic (MD) simulation studies for the same 13 potential ligands against beta-site APP cleaving enzyme 1 (BACE-1) and γ-secretase as a therapeutic target for AD. The In-silico screening of these ligands as potential inhibitors of BACE-1 and γ-secretase was performed using AutoDock enabled PyRx v-0.8. The protein-ligand interactions were analyzed in Discovery Studio 2020 (BIOVIA). The stability of the most promising ligand against BACE-1 and γ-secretase was evaluated by MD simulation using Desmond-2018 (Schrodinger, LLC, NY, USA).ResultsThe computational screening revealed that the docking energy values for each of the ligands against both the target enzymes were in the range of −7.0 to −10.1 kcal/mol. Among the 13 ligands, 8 (55E, 6Z2, 6Z5, BRW, F1B, GVP, IQ6, and X37) showed binding energies of ≤−8 kcal/mol against BACE-1 and γ-secretase. For the selected enzyme targets, BACE-1 and γ-secretase, 6Z5 displayed the lowest binding energy of −10.1 and −9.8 kcal/mol, respectively. The MD simulation study confirmed the stability of BACE-6Z5 and γ-secretase-6Z5 complexes and highlighted the formation of a stable complex between 6Z5 and target enzymes.ConclusionThe virtual screening, molecular docking, and molecular dynamics simulation studies revealed the potential of these multi-enzyme targeted ligands. Among the studied ligands, 6Z5 seems to have the best binding potential and forms a stable complex with BACE-1 and γ-secretase. We recommend the synthesis of 6Z5 for future in-vitro and in-vivo studies.     

抗肿瘤新药——培美曲塞

培美曲塞是一种作用于叶酸代谢过程中 多种靶点的抗肿瘤新药。临床前研究及临床研究证 实该药对多种实体肿瘤有明确的抗瘤活性,包括肺 癌、乳腺癌、胰腺癌、卵巢癌等,特别是对恶性胸膜间 皮瘤的治疗。药物的不良反应主要包括骨髓抑制和 皮疹,在补充叶酸和维生素B12的情况下,不良反应 明显减轻,病人耐受性良好。本文就近年来该药的 研究进展作一简要的介绍。     

Emerging drugs for non-small-cell lung cancer

Non-small-cell lung cancer (NSCLC) accounts for 80% of all lung cancer cases and is the leading cause of cancer mortality. Despite the optimization of chemotherapy regimens, treatment outcomes for advanced disease are still disappointing. The EGFR tyrosine kinase inhibitor, erlotinib, and the recombinant monoclonal antibody against the VEGF, bevacizumab, have proven active in NSCLC. In the BR.21 trial, a 2-month benefit in overall survival was observed for previously treated NSCLC patients who received erlotinib versus placebo. The combination of chemotherapy plus bevacizumab yielded superior overall survival or progression-free survival in one randomized trial in advanced non-squamous NSCLC patients. However, despite the introduction of more effective agents, new treatment strategies are clearly needed in lung cancer management.

The review focuses on a number of new targeted agents/chemotherapy drugs now in clinical trials directed at improving NSCLC management. Mature results regarding their activity and usefulness can be expected in the near future.     

略论分子靶向治疗与中医抗肿瘤理念

目的：探讨分子靶向治疗与中医抗肿瘤理念的相关性。方法：对＂带瘤生存＂＂多靶点治疗＂＂生活质量评估＂等方面进行理论分析。结果：分子靶向治疗与中医药治疗,不宜严格按照传统的疗效标准来评价,而需要建立一个基于循证医学的包含生命质量（QOL）的疗效评价体系。在此评价体系下,客观指标（如瘤体大小和数目,肿瘤标记物）和主观感受（自觉症状、心理状态）均能够运用恰当的参数进行描述和统计,最终全面而客观地反映抗肿瘤治疗的疗效。结论：分子靶向治疗与中医抗肿瘤理念有许多共同之处,值得进一步研究和探索。     

多靶点抗肿瘤天然产物研究进展

天然产物及其衍生物是抗肿瘤药物的重要组成部分.目前在临床上应用的天然产物来源的抗肿瘤药物以传统细胞毒类药物或靶向某一特定靶点的分子靶向药物为主,其应用受限于药物相关不良反应和肿瘤耐药.近年的研究表明,抗肿瘤活性天然产物往往能够靶向肿瘤细胞的多个靶点,影响肿瘤发生发展中的多个过程.由于肿瘤是一种多因素诱发的系统性疾病,多...     

肿瘤干细胞多靶点联合治疗效果分析

[目的]探讨有效的肿瘤生物治疗新思路,用肝癌细胞系Bel7402-V3为细胞模型检测联合单克隆抗体9A9和15D2对其干性功能（自我更新、侵袭和耐药）的影响。[方法]采用活细胞流式免疫荧光术检测单独抗体、联合抗体与肿瘤干细胞标志物ESA在Bel7402-V3亲本及sphere细胞中的表达;甲基纤维素成球实验和Transwell小室侵袭实验分别检测抗体对Bel7402-V3亲本细胞成球能力和侵袭能力的影响;CCK8法及IC50法检测联合抗体对Bel7402-V3亲本细胞耐药能力的影响。[结果]流式荧光结果显示：标志物ESA、单抗15D2、单抗9A9所识别的细胞比例在Bel7402-V3 sphere细胞中比在亲本细胞中分别富集了2.6倍、4.1倍、2.0倍;在Bel7402-V3亲本和sphere细胞中,联合单抗与标志物共染比例（9A9＋15D2与ESA）大于单抗分别与标志物共染比例之和[（9A9＋ESA）＋（15D2＋ESA）];单抗9A9与15D2联合时对Bel7402-V3亲本细胞的成球抑制率和侵袭抑制率均明显高于等浓度的单种单抗对Bel7402-V3亲本细胞的功能抑制;经联合单抗处理的Bel7402-V3亲本细胞耐药能力较经等浓度单种单抗处理的细胞耐药能力显著降低[9A9＋15D2：IC50为0.32μg/ml,9A9：IC50为0.58μg/ml,15D2：IC50为0.56μg/ml。[结论]肿瘤干细胞中存在不同亚群,其在不同的信号通路或基因水平上发挥了不同的作用。联合多靶点的抗体治疗能显著提高疗效。     

Multi-Target Cytotoxic Actions of Flavonoids in Blood Cancer Cells

To date, cytotoxic effects of flavonoids in various cancer cells are well accepted. However, the intracellularsignaling cascades triggered by these natural compounds remain largely unknown and elusive. In this minireview,the multiplicity of molecular targets of flavonoids in blood cancer cells is discussed by demonstrating theinvolvement of various signaling pathways in induction of apoptotic responses. Although these data reveal a greatpotential of flavonoids for the development of novel agents against different types of hematological malignancies,the pleiotropic nature of these compounds in modulation of cellular processes and their interactions certainlyneed unraveling and further investigation.     

作用于多靶点的组蛋白去乙酰化酶抑制剂结构设计的研究进展

目的 肿瘤产生机制的复杂性,要求对多种促肿瘤发生发展机制同时抑制,才能有效阻止肿瘤生长。组蛋白去乙酰化酶抑制剂(HDACi)作为一种新型抗肿瘤药物,能诱导肿瘤细胞凋亡, 阻止癌细胞增长。利用结构的多样性和变通性设计新颖的作用于多靶点的HDACi。方法 分类总结大量已被报道的多靶点组蛋白去乙酰化酶抑制剂。结果 多靶点抑制剂在临床实验中表现出了较好的抗肿瘤活性。结论 多靶点单一分子的HDACi的研究日益引起人们的重视,具有广阔的研发前景。