In Vitro Evaluation of Rigosertib Antitumoral and Radiosensitizing Effects against Human Cholangiocarcinoma Cells

Cholangiocarcinoma is the first most common cancer of the biliary tract. To date, surgical resection is the only potentially curative option, but it is possible only for a limited percentage of patients, and in any case survival rate is quite low. Moreover, cholangiocarcinoma is often chemotherapy-resistant, and the only drug with a significant benefit for patient’s survival is Gemcitabine. It is necessary to find new drugs or combination therapies to treat nonresectable cholangiocarcinoma and improve the overall survival rate of patients. In this work, we evaluate in vitro the antitumoral effects of Rigosertib, a multi-kinase inhibitor in clinical development, against cholangiocarcinoma EGI-1 cell lines. Rigosertib impairs EGI-1 cell viability in a dose- and time-dependent manner, reversibility is dose-dependent, and significant morphological and nuclear alterations occur. Moreover, Rigosertib induces the arrest of the cell cycle in the G2/M phase, increases autophagy, and inhibits proteasome, cell migration, and invasion. Lastly, Rigosertib shows to be a stronger radiosensitizer than Gemcitabine and 5-Fluorouracil. In conclusion, Rigosertib could be a potential therapeutic option, alone or in combination with radiations, for nonresectable patients with cholangiocarcinoma.     

Low-Molecular-Weight Fucoidan as Complementary Therapy of Fluoropyrimidine-Based Chemotherapy in Colorectal Cancer

This study investigated the roles of low-molecular-weight fucoidan (LMWF) in enhancing the anti-cancer effects of fluoropyrimidine-based chemotherapy. HCT116 and Caco-2 cells were treated with LMWF and 5-FU. Cell viability, cell cycle, apoptosis, and migration were analyzed in both cell types. Potential mechanisms underlying how LMWF enhances the anti-cancer effects of fluoropyrimidine-based chemotherapy were also explored. The cell viability of HCT116 and Caco-2 cells was significantly reduced after treatment with a LMWF-–5FU combination. In HCT116 cells, LMWF enhanced the suppressive effects of 5-FU on cell viability through the (1) induction of cell cycle arrest in the S phase and (2) late apoptosis mediated by the Jun-N-terminal kinase (JNK) signaling pathway. In Caco-2 cells, LMWF enhanced the suppressive effects of 5-FU on cell viability through both the c-mesenchymal–epithelial transition (MET)/Kirsten rat sarcoma virus (KRAS)/extracellular signal-regulated kinase (ERK) and the c-MET/phosphatidyl-inositol 3-kinases (PI3K)/protein kinase B (AKT) signaling pathways. Moreover, LMWF enhanced the suppressive effects of 5-FU on tumor cell migration through the c-MET/matrix metalloproteinase (MMP)-2 signaling pathway in both HCT116 and Caco-2 cells. Our results demonstrated that LMWF is a potential complementary therapy for enhancing the efficacies of fluoropyrimidine-based chemotherapy in colorectal cancers (CRCs) with the wild-type or mutated KRAS gene through different mechanisms. However, in vivo studies and in clinical trials are required in order to validate the results of the present study.     

Smart Vitamin Micelles as Cancer Nanomedicines for Enhanced Intracellular Delivery of Doxorubicin

Chemotherapy is one of the most effective treatments for cancer. However, intracellular delivery of many anticancer drugs is hindered by their hydrophobicity and low molecular weight. Here, we describe highly biocompatible and biodegradable amphiphilic vitamin conjugates comprising hydrophobic vitamin E and hydrophilic vitamin B labeled with dual pH and glutathione-responsive degradable linkages. Vitamin-based micelles (vitamicelles), formed by self-assembly in aqueous solutions, were optimized based on their stability after encapsulation of doxorubicin (DOX). The resulting vitamicelles have great potential as vehicles for anticancer drugs because they show excellent biocompatibility (>94% after 48 h of incubation) and rapid biodegradability (>90% after 2.5 h). Compared with free DOX, DOX-loaded vitamicelles showed a markedly enhanced anticancer effect as they released the drug rapidly and inhibited drug efflux out of cells efficiently. By exploiting these advantages, this study not only provides a promising strategy for circumventing existing challenges regarding the delivery of anticancer drugs but also extends the utility of current DOX-induced chemotherapy.     

奥沙利铂联合氟尿嘧啶亚叶酸钙一线治疗转移性大肠癌2周方案与3周方案的对比研究

目的:比较奥沙利铂(L-OHP)联合5-氟尿嘧啶/亚叶酸钙(5-FU/CF)的2周方案与3周方案一线治疗转移性结直肠癌的临床疗效及不良反应。方法:66例转移性结直肠癌患者随机接受治疗。A 组, 予L-OHP 85 mg/m², 第1天, 静脉滴注2h, 同时或之后予CF 200 mg/m², 静脉滴注2h,续5-FU 400 mg/m², 静脉推注, 600 mg/m² 持续静脉滴注22h, 次日重复CF 与5-FU 。每2周重复1次, 每2次计为1周期。B 组, 予L-OHP130 mg/m², 第1天, 静脉滴注2h, CF 200 mg/m²,静脉滴注2h, 续5-FU 375～425 mg/m² 静脉滴注4～6h, 连用5d, 每3周重复1次, 每次计为1周期。结果:A 、B 两组疗效相近, RR 分别为42.9%和38.7%(P>0.05)。两组病例不良反应发生率相似, 主要表现为消化道反应、神经系统毒性和脱发。结论:L-OHP 联合5-FU/CF 的2周方案与3周方案均可作为晚期转移性大肠癌一线治疗的选择之一。     

真实世界中R0切除术后结直肠癌患者接受卡培他滨为基础辅助化疗的预后影响因素及安全性探讨

目的:卡培他滨为基础的辅助化疗显著降低R0切除术后结直肠癌患者的术后复发风险。本研究旨在探讨真实世界中R0切除术后结直肠癌患者接受卡培他滨为基础辅助化疗的预后影响因素及安全性。方法:本研究从2010年1月到2017年12月,纳入279例R0切除术后接受卡培他滨为基础辅助化疗的结直肠癌患者。通过医院的病例系统整理患者基线临床资料。前期随访为患者在医院接受固定周期的辅助化疗期间的随访。后期对预后的随访为电话随访,每3个月一次。随访患者出现复发后接受治疗的情况,重点询问死亡状态和死亡的日期。用Kaplan-Meier生存分析方法分析患者的无疾病生存期（DFS）和总生存期（OS）。不良反应的评价标准依据CTCAE 4.0的标准进行。记录2级以上不良反应发生情况。结果:纳入研究的279例患者的中位年龄51岁,范围为19～82岁。男性167例（59.86%）。ECOG评分中0分患者180例（64.52%）。结肠癌和直肠癌分别173例和106例。肿瘤分化方面,分化较好、分化中等、分化较差患者分别为58例,192例和17例。肿瘤分期上,II期患者58例,III期患者221例。错配修复基因（MMR）状态上,错配修复基因缺失（dMMR）患者19例,错配修复基因存在（pMMR）患者176例,未做检测患者84例。T1-2和T3-4的患者分别为73例和206例。辅助化疗方面,接受卡培他滨单药辅助化疗患者71例,接受卡培他滨联合奥沙利铂辅助化疗患者208例。纳入研究的279例患者均可评价预后,整体人群的中位DFS为4.7年（95% CI:4.12～5.33）,中位OS为6.6年（95% CI:5.74～7.27）。在针对OS的多变量Cox分析中年龄、ECOG评分和病理分期对OS具有独立的影响意义。不良反应方面,2级以上不良反应发生率较高的为中性粒细胞减少,手足综合征,腹泻等。总体不良事件安全可控。结论:R0切除术后的结直肠癌患者接受卡培他滨为基础辅助化疗具有较好的预后和安全性。     

5-氟尿嘧啶、表阿霉素、丝裂霉素单用及合用时对胰腺癌细胞Aspc-1 和Bxpc-3 的抑制作用

目的 观察5-氟尿嘧啶(5-FU)、表阿霉素(EADM)和丝裂霉素(MMC) 体外对胰腺癌细胞(Aspc-1及Bxpc-3) 的作用和药物联合应用时的相互作用。 方法 采用MTT 测定法观察5-FU、E-ADM 和MMC 单用及合用时对细胞的抑制作用, 并应用中效原理判定药物合用的效果。 结果 单用或者合用时随着药物浓度的增加其对细胞的抑制作用也增加, 5-FU 和MMC 合用于Aspc-1 细胞株, 当效应为0.84 时CI 为1, 大剂量时(效应大于0.84) 是协同作用(CI <1), 小剂量时(效应小于0.84) 是拮抗作用(CI >1)。MMC和E-ADM 合用时表现为轻度的拮抗作用。5-FU 和MMC、MMC 和E-ADM 合用于Bxpc-3, 当效应分别为0.49、0.62 时CI 为1, 大于此效应表现为轻度拮抗(C >1), 小于此效应则相反。5-FU 和E-ADM 合用对两株细胞量效曲线图的形态相似表现为轻度的拮抗作用, 随着效应的增加拮抗作用略有下降。 结论 药物的相互作用与药物浓度有关, 药物及细胞株的不同其量效曲线存在较大差异。通过动脉灌注或保留导管持续灌注以提高化疗药物局部浓度能够改善胰腺癌的化疗效果。     

黛力新在含顺铂方案化疗后呕吐的精神抑郁患者中的应用

目的探讨黛力新对含顺铂方案化疗后呕吐的精神抑郁患者的应用价值。方法将58例有精神抑郁并经顺铂方案化疗后有呕吐反应的恶性肿瘤患者按随机数字表法分为2组,分别接受常规止吐（RA组,n=26）及常规止吐加黛力新（RD组,n=32）治疗,观察2组的止吐效果、抑郁状况及生活质量。结果 RD组止吐疗效、抑郁状况、部分生活质量指标（食欲、睡眠、日常生活及精神状态）改善均显著优于RA组;RD组治疗前后Hamilton抑郁量表（HAMD）评分下降≥3分的患者止吐疗效显著优于HAMD下降〈3分者（均P〈0.05）。结论黛力新可改善含顺铂方案化疗后呕吐的精神抑郁患者的抑郁状况,提高常规止吐治疗的疗效,改善其生活质量,且抑郁状况改善显著者止吐效果亦得到更好的改善。     

Syndecan-1在结直肠癌中的表达与EGFR表达、K-Ras突变及化疗疗效相关性分析

目的: 探讨结直肠癌中Syndecan-1的表达与表皮生长因子受体(epidermal growth factorreceptor,EGFR)表达、K-Ras基因突变及化疗疗效的关系。方法: 利用免疫组织化学法检测160例晚期结直肠癌患者中Syndecan-1的表达情况,分析其与患者临床病理特征、分子标志物及FOLFOX方案化疗疗效的相关性。结果: 所有患者中有41例(25.6%)Syndecan-1表达阳性,111例(69.4%)EGFR表达阳性;Syndecan-1的表达与EGFR表达显著相关（P<0.05）;与K-Ras基因突变无相关性（P>0.05）;Syndecan-1表达阳性患者的化疗有效率56.1%,阴性患者为40.3%（P<0.05）,Syndecan-1表达阳性患者的中位无疾病进展时间为8.8个月,而阴性患者为7.2个月（P<0.05）。结论: Syndecan-1的表达对结直肠癌进展及判断预后有一定的临床价值,且与常用FOLFOX化疗方案的疗效有相关性。     

靶向抑制肠道菌β-葡萄糖醛酸苷酶在肿瘤预防和治疗中的应用

肠道菌β-葡萄糖醛酸苷酶（BGUSs）是肠道菌群产生的一类重要水解酶,其通过水解内源性和外源性葡萄糖醛酸苷影响肿瘤发生发展以及化疗药物的疗效（药效/毒性）。近年来,越来越多的研究尝试通过抑制肠道BGUSs降低患癌风险和减轻化疗药物引起的毒副作用。但由于BGUSs具有基因和结构的多样性、生理病理功能的复杂性以及对特定抑制剂响应的差异性,表征介导特定疾病或药物不良反应的BGUSs并发展有效的选择性抑制剂面临巨大的挑战。本文概述了BGUSs的结构和功能的最新进展,汇总了近年来在BGUSs介导的致癌物和肿瘤化疗药物代谢方面的发现、BGUSs抑制剂的研发及其预防肿瘤和缓解化疗药物不良反应的临床前研究结果,并讨论了将抑制BGUSs作为肿瘤预防和药物治疗新策略的前景。     

Molecular encapsulation of thalidomide with sulfobutyl ether-7 beta-cyclodextrin for immediate release property: enhanced in vivo antitumor and antiangiogenesis efficacy in mice

Thalidomide's reported ability to inhibit tumor angiogenesis has led to clinical trials determining its effectiveness in combating various types of cancer. Since thalidomide exhibits low oral bioavailability due to limitations in solubility, inclusion complexation using sulfobutyl ether-7 β-cyclodextrin was used to improve the delivery of thalidomide. Our main goals were to increase the solubility, bioavailability as well as chemical stability of thalidomide through complexation with anionic β-cyclodextrin, to characterize the complex in solid state using differential scanning calorimetry, X-ray powder diffractometry, and to explore thalidomide's antitumorigenic and antiangiogenesis potential when administered orally as free and in combination with cyclodextrin to experimental animals. The aqueous solubility and aqueous alkaline stability of thalidomide was markedly increased by the SBE7βCD complexation. Thalidomide administered orally in combination with SBE7βCD, led to a significant delay in tumor formation as a result of improved cellular drug absorption, distribution through solubilization in experimental animals. The improved pharmacological efficacy of the thalidomide-cyclodextrin complex compared to free thalidomide in mouse melanoma model suggest that such a delivery system may be useful for the improved therapeutics of thalidomide, in vivo.