奥沙利铂神经毒性的治疗研究进展

奥沙利铂（LOHP）属于新的铂类抗癌药,其铂原子与1,2-二氨环己烷及一个草酸基结合,是单一对映结构体,常用于转移性结直肠癌治疗,或辅助治疗原发性肿瘤完全切除后三期DukesC结肠癌。随着奥沙利铂在临床的应用日益广泛,其神经毒性反应越来越引起重视,如何预防和减轻奥沙利铂的神经毒性已成为研究重点之一。本文旨在对奥沙利铂神经毒性的治疗研究进展做一综述。     

奥沙利铂的神经毒性分析和预防措施

介绍奥沙利铂的神经毒性和预防措施,减轻累积性神经毒性症状的发生.     

中医药防治奥沙利铂所致神经毒性进展

奥沙利铂是第三代铂类广谱抗癌药,其疗效更好,毒性更低,已成为大肠癌辅助化疗的一线化疗药。近年来有关中医药防治奥沙利铂神经毒性的临床研究作一综述,供参考。     

中药治疗奥沙利铂神经毒性16例

奥沙利铂是继顺铂和卡铂第三代铂类抗癌药物，国内的多中心Ⅱ期临床试验结果，联合用药有效率为34．4％，成为初次化疗失败或复发转移大肠癌病人的一线治疗方案。此外，在胃癌的联合方案中，李桂生利用奥沙利铂联合方案治疗晚期胃癌，RR53．8％．MST12．5％个月。[第一段]     

奥沙利铂神经系统毒性与防治

奥沙利铂已经越来越多地应用于肿瘤的治疗,它属于三代铂制剂,抗癌谱广,疗效可靠,主要作用机制为通过与DNA形成加合物抑制细胞增殖,体内外试验显示对多种肿瘤细胞株有抑制作用,包括对顺铂和卡铂耐药的细胞株。对胃癌、大肠癌、肝癌、卵巢癌、淋巴瘤、非小细胞肺癌等均有较好的效果,也经历了多中心临床观察。但奥沙利铂的剂量相关性周围神经毒性影响了其临床应用和推广[1]。近年,国内外学者对防治措施做了大量研究,报告如下。1奥沙利铂神经毒性表现     

奥沙利铂神经毒性机制及防治新进展

摘 要奥沙利铂的神经毒性是其常见不良反应之一,具有独特的临床特征,其发生机制至今尚不清楚并且缺乏有效的防治方法。近年来的研究发现,瞬时受体电位通道、间隙连接通道、烟碱型乙酰胆碱受体等在介导奥沙利铂神经毒性中发挥了重要作用,基因多态性也与其显著相关。此外,研究者们利用锰福地吡、单唾液酸神经节苷脂和黄芪根提取物等药物在防治奥沙利铂的神经毒性中进行了探索,并显示出了良好的疗效。该文就近年来奥沙利铂神经毒性的发生机制及防治研究进展做一综述。     

奥沙利铂神经毒性机制及防治研究进展

奥沙利铂是第3代铂类抗癌药物,抗癌谱广、毒副反应轻微是其主要特点。但该药的外周神经毒性发生率却高达90%,是其剂量限制性毒性。现对奥沙利铂(乐沙定)神经毒性表现、分级、发生机制及防治策略进行综述,以便为奥沙利铂疗程持续和达到更好疗效、更小毒性提供依据。     

谷胱甘肽对奥沙利铂神经毒性的防治效果

目的　评价谷胱甘肽对奥沙利铂神经毒性的防治效果。方法　对 70例应用奥沙利铂经动脉插管化疗治疗患者进行回顾性分析。预防治疗组 :4 4例中 ,男 36例 ,女 8例 ;年龄 2 2～ 75岁 ,平均年龄 4 8岁。对照组 :2 6例中 ,男 2 0例 ,女 6例 ;年龄 1 9～ 70岁 ,平均年龄 4 5岁 ;预防治疗组介入前 2天开始使用还原型谷胱甘肽 ,每日 1 2 0 0 mg加入 5 %葡萄糖注射液 2 5 0 ml中静脉滴注 ,至介入后 3～ 5天。对照组只予以保肝、对症治疗 ,不用谷胱甘肽。结果　对照组奥沙利铂神经毒性的发生率为 4 6 .1 5 % (1 2 / 2 6 ) ,预防组 1 3.6 4 % (6 / 4 4 ) ,经 χ2检验 ,差异有非常显著性 (P<0 .0 1 )。结论　谷胱甘肽对预防奥沙利铂的神经毒性有较好的治疗效果 ,是预防奥沙利铂的神经毒性主要措施之一     

氨磷汀防治奥沙利铂神经毒性的临床研究

目的 研究氨磷汀防治奥沙利铂神经毒性的临床效果.方法 将80例奥沙利铂胃肠道肿瘤患者随机均分为试验组和对照组,所有患者均采用含奥沙利铂的FOLFOX4方案进行化学治疗,化学治疗前试验组使用昂丹司琼8 mg、地塞米松5 mg和氨磷汀500 mg/m2,对照组仅予昂丹司琼8 mg和地塞米松5 mg.每个治疗周期评估患者外周神经毒性.结果 6个周期的化学治疗后,氨磷汀组有22.50%的患者发生Ⅰ～Ⅱ度外周神经毒性,明显低于对照组的47.50%(P＜0.01),有7.50%的患者发生Ⅲ度外周神经毒性,显著低于对照组的17.50%(P＜0.05).其他化学治疗相关毒副反应发生率两组均无明显差别.结论 应用氨磷汀能预防奥沙利铂神经毒性的发生,并降低神经毒性的严重程度.     

奥沙利铂相关神经毒性及其影响因素分析

目的 探讨奥沙利铂致神经毒性的发生率及其高危因素,为奥沙利铂相关神经毒性的预防提供参考。方法 采用病例回顾性研究,对住院化疗期间使用奥沙利铂的患者进行数据采集,观察奥沙利铂致神经毒性的发生情况、发生程度与患者的一般状况、化疗前后临床检验指标的变化及与辅助用药的情况。采用统计学方法比较出现神经毒性组与未出现神经毒性组的组间差异,再对有显著性差异的观察指标进行logistic回归分析,筛选神经毒性的相关危险因素。结果 共纳入有效病例1 216例。发生奥沙利铂相关神经毒性817例(67.19%),其中临床诊断、疾病分期、体表面积、化疗次数、药物蓄积量、化疗前后白细胞变化、化疗前后淋巴细胞的变化、化疗前后血小板的变化、化疗前后钙的变化、使用钙镁补充剂等共12项指标有统计学差异(P<0.05)。化疗前后血小板的变化、疾病分期、药物蓄积量为神经毒性的影响因素。结论 奥沙利铂相关的神经毒性发生率较高,应引起临床足够重视。特别是化疗前后血小板的变化大、疾病分期晚、药物蓄积大的患者,应密切监护神经毒性的临床表现,积极采取预防措施,必要时给予停药及对症处理。     

Synthesis and cytotoxic activities of a series of novel N-methyl-bisindolylmaleimide amide derivatives

A novel series of N-methyl-bisindolylmaleimides were synthesized and evaluated for their inhibitory activities against nine tumor cell lines. Some of the compounds showed an interesting activity against the tested cell lines. The most potent compounds 5e and 5j displayed antiproliferative activity with 50% inhibitory concentration values in the μM range against some tested cell lines.     

Six new furostanol glycosides from Smilax glauco-china and their cytotoxic activity

Six new steroidal saponins, namely glauco-chinaosides A–F, and one known compound were isolated from the tubers of Smilax glauco-china. Their structures were elucidated by a combination of spectroscopic analysis and hydrolysis followed by spectral and chromatographic analysis. Compounds 1–7 were tested in vitro for their cytotoxic activities against four human tumor cell lines (SH-SY5Y, SGC-7901, HCT-116, and Lovo). Compounds 1, 2, and 5 exhibited cytotoxic activity against SGC-7901, with IC₅₀ values of 2.7, 11.5, and 6.8 μM, respectively.     

Total synthesis and cytotoxic activity of stellatin

Stellatin (3,4-dihydro-8-hydroxy-7-hydroxymethyl-6-methoxyisocoumarin) (8), an extrolite of fungal genera Emericella and Aspergillus, was synthesized. Thus, Vilsmeier–Haack formylation of methyl ester of 3,5-dimethoxy-4-methylphenylacetic acid (1) to afford the formyl ester (2) followed sulfamic acid–sodium chlorite oxidation of the aldehydic function to yield the carboxy ester (3). Chemoselective reduction of ester function in the latter using NaBH₄/THF/MeOH furnished the corresponding hydroxy acid (4) that on cyclodehydration afforded the 3,4-dihydro-6,8-dimethoxy-7-methylisocoumarin (5). Benzylic bromination of the C-7 methyl in 5 using NBS/benzoyl peroxide to give the 7-bromomethyldihydroisocoumarin (6) followed the nucleophilic substitution using aqueous acetone to provide 7-hydroxymethyl-dihydroisocoumarin (7). Finally, the regioselective demethylation of 8-methoxyl group using anhydrous magnesium iodide furnished the stellatin (8). The dihydroisocoumarins (5–8) were screened for cytotoxic activity against human keratinocyte cell line and were found to exhibit moderate to good activity.     

One pair of new cyclopentaisochromenone enantiomer from Alternaria sp. TNXY-P-1 and their cytotoxic activity

One pair of new cyclopentaisochromenone derivatives, (+)-(S)-6-hydroxy-1,8-dimethoxy-3a-methyl-3,3a-dihydrocyclopenta[c]isochromene-2,5-dione (1a) and (-)-(R)-6-hydroxy-1,8-dimethoxy-3a-methyl-3,3a-dihydrocyclopenta[c]isochromene-2,5-dione (1b), together with seven known analog 2?8, were isolated from a rice solid culture of the endophytic fungus Alternaria sp. TNXY-P-1, obtained from fresh leaf of Arisaema heterophyllum. Their structures were elucidated on the basis of detailed 1D, 2D NMR, and HRESIMS analysis. Among them, compounds 1a and 1b were enantiomers separated from 1 by chiral HPLC. The absolute configurations of 1a and 1b were assigned by quantum chemical calculations of the electronic circular dichroic spectra. All isolated compounds were evaluated for cytotoxic activities. Interestingly, enantiomers (+)-1a and (?)-1b showed distinct selective antitumor activities against HL-60 cell lines with IC₅₀ values of >200, 75.3 μM, respectively.     

Two new cytotoxic acetogenins from Annona squamosa

Two new annonaceous acetogenins named as squamostanin-A and squamostanin-B were isolated from 95% EtOH extract of the seeds of Annona squamosa. Their structures were determined by spectroscopic method, and their cytotoxicities were evaluated using MTT method.     

Garcixanthone A,a new cytotoxic xanthone from the pericarps of Garcinia mangostana

A new prenylated xanthone, garcixanthone A (5), together with eight known compounds, mangostanaxanthones I (1) and II (2), garcinone E (3), β-mangostin (4), 8-hydroxycudraxanthone G (6), garcinone C (7), cudraxanthone G (8), and (-)-epicatechin (9) were isolated from the EtOAc-soluble fraction of the air-dried pericarps of Garcinia mangostana (family Clusiaceae). Their structures were verified on the basis of spectroscopic data interpretation as well as comparison with the literature. The cytotoxic and antimicrobial activities of the new compound were assessed using sulforhodamine B (SRB) and agar disk diffusion assays, respectively. Compound 5 showed significant cytotoxic potential against epithelial lung carcinoma (A549) and breast carcinoma (MCF7) cell lines with IC₅₀s 3.0 and 4.2 μM, respectively, compared to doxorubicin (0.74 and 0.41 μM, respectively).     

Synthesis and evaluation of cytotoxic activities of artemisinin derivatives

Artemisinin is a naturally occurring antimalarial agent which has shown potent anticancer activity. In this work, new artemisinin derivatives with the piperazine group were synthesized. The cytotoxic activities of derivatives 5a – 5d were evaluated by MTT assay against ten cell lines. The results showed that 5a – 5d were more effective in inhibiting cancer cell growth than artemisinin. 5d was the most active against HepG2 and PLC‐PRF‐5 cells and presented no cytotoxicity on L‐02 cells. Hoechst 33342 staining and flow cytometry experiment revealed that 5d could induce HepG2 and PLC‐PRF‐5 cell apoptosis. Flow cytometry analysis showed that 5d induced the loss of mitochondrial membrane potential (MMP) and increased the levels of intracellular free calcium and reactive oxygen species. 5d also induced cell cycle arrest in G2/M phase in HepG2 cells. According to the results of Western blotting and caspase‐3 kit, 5d could significantly increase the content of p53, bax, Apaf‐1, and caspase‐3 and decrease the protein level of bcl‐2, pro‐caspase‐9, and pro‐caspase‐3 in HepG2 cells. These findings indicate that 5d activates the mitochondria‐mediated apoptotic pathway in HepG2 cells and may merit further investigation as a potential therapeutic agent for hepatocellular carcinoma.     

龙须菜的有机酸组成及其细胞毒活性

目的研究红藻龙须菜有机酸提取物的组成及其细胞毒活性。方法用MTT法测定有机酸提取物对HeLa细胞的生长抑制活性,并将有机酸甲酯化后,以GC-MS测定其组成及含量。结果龙须菜有机酸提取物对HeLa细胞显示出细胞毒活性,其IC50=6.5μg.mL-1。鉴定了甲酯化有机酸中的13个化合物,其主要成分为棕榈酸甲酯(61.34%)。各组分对应的有机酸主要是C16或C18脂肪酸和邻苯二甲酸类等化合物,其中的棕榈酸、硬脂酸、棕榈油酸、油酸和亚油酸据文献报道具有抗肿瘤活性。结论上述脂肪酸成分可能是龙须菜抗肿瘤活性成分之一。     

海洋蓝藻 Okeania hirsute 中的次级代谢产物及其细胞毒活性

目的 研究从海洋蓝藻 Okeania hirsute 中分离鉴定次级代谢产物并进行细胞毒活性评价。方法 三个天然产物(1~3)的结构确定是通过广泛的波谱数据,包括一维和二维核磁及质谱等。结果 化合物3对人大细胞肺癌细胞NCI-H460显示出强的细胞毒活性,IC₅₀值为0.384 μg/mL。结论 这是首次从Okeania属蓝细菌中分离获得化合物1~3。这些天然产物的发现表明Okeania属蓝细菌可以作为发现新颖化合物的重要来源。