Cetuximab enhances the efficiency of irinotecan through simultaneously inhibiting the MAPK signaling and ABCG2 in colorectal cancer cells

BackgroundThe present study sought to investigate the combined effects of cetuximab and irinotecan on colorectal cancer cells as well as the mechanisms underlying their anti-cancer effects.Material and methodsHigh performance liquid chromatography, Hoechst staining assay, and western blotting analysis were used to detect intracellular drug concentrations, cell apoptosis, and protein expression in the presence of cetuximab, irinotecan, and the combination of both.ResultsCetuximab was found to increase intracellular concentrations of irinotecan as well as cytotoxicity by inhibiting the epidermal growth factor receptor and, by extension, the downstream RAS-RAF-MEK-ERK signaling pathway. Cetuximab therefore induced apoptosis and improved the effect of irinotecan in colorectal cancer cells. It was also shown that cetuximab inhibited the drug efflux activity of ABCG2. In combination with irinotecan, cetuximab can both significantly induce cell apoptosis by inhibiting the RAS-RAF-MEK-ERK signaling pathway and improve the effects of irinotecan by decreasing drug efflux through the inhibition of ABCG2.ConclusionThese features contribute to its anti-cancer potential.     

Optimization of Hyperthermic Intraperitoneal Chemotherapy With Oxaliplatin Plus Irinotecan at 43°C After Compete Cytoreductive Surgery: Mortality and Morbidity in 106 Consecutive Patients

Background Peritoneal carcinomatosis (PC), which has hitherto been regarded as a lethal entity, can now be cured with surgery (treating macroscopic tumor seeding) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) (treating residual microscopic disease). The purpose of this study was to analyze the morbidity and mortality of a particular approach associating optimal (R0–R1) cytoreduction, optimal HIPEC combining oxaliplatin and irinotecan, and an optimal homogeneous intraperitoneal temperature of 43°C. Methods A total of 106 consecutive patients were included in this prospective phase 2 study. After complete resection of the PC, HIPEC was performed by the Coliseum technique with oxaliplatin (360 mg/m²) combined with irinotecan (360 mg/m²) in 2 L/m² of 5% dextrose, over 30 minutes at a real intraperitoneal temperature of 43°C. During the hour preceding HIPEC, patients received 5-fluorouracil (400 mg/m²) and leucovorin (20 mg/m²) intravenously, resulting in tritherapy. Results Postoperative mortality and morbidity rates were 4% and 66%, respectively. The most frequent complications were digestive fistula (24%), lung infection (16%), and severe hematological toxicity (11%). Statistical correlation was evidenced between morbidity and the carcinomatosis score (P = .0008), the number of resected organs (P = .0001), the duration of surgery (P = .0001), and blood loss (P = .0001). Conclusions This new approach, optimized in three respects (complete cytoreduction, combination oxaliplatin with irinotecan, and high temperature) has resulted in a relatively high but acceptable incidence of adverse events considering the expected advantage for survival.     

A phase II study of irinotecan in combination with doxifluridine, an intermediate form of capecitabine, in patients with metastatic colorectal cancer

The purpose of this study was to examine the efficacy of a combination treatment of sequential irinotecan and doxifluridine, an intermediate of capecitabine, evaluated by the response rate and safety in patients with metastatic colorectal cancer. In all, 60 metastatic colorectal cancer patients with measurable disease were enrolled. The schedule of the treatment consisted of a 90 min intravenous (IV) infusion of irinotecan 150 mg/m² for on days 1 and 15, and 600–1,000 mg/body of oral doxifluridine on days 3–14 and 17–28. Cycles were repeated every 35 days. A median of three cycles of the combination therapy (range 1–14 cycles) was administered. A total of 57 patients (95%) completed at least two cycles of the therapy without any dose reductions. There was one complete response and 23 partial responses with an overall response rate of 40% [95% confidence interval (CI): 28–53%]. A total of 19 patients had stable disease, 43(72%) achieved disease control. The median time to progression was 5.9 months and the median overall survival was 20.5 months. Ten (17%) and 17 (28%) patients developed Grade 3–4 leukopenia and neutropenia, respectively. Grade 3–4 fatigue was observed in 7(12%) patients, nausea in five (8%), vomiting in four (7%), and diarrhea,in three (5%) patients. No treatment-related deaths were noted during the study. From these results, the combination of sequential irinotecan and doxifluridine is considered to be an effective, easy-to-administer regimen with acceptable tolerability.     

伊立替康对食管癌细胞放射增敏作用及核因子κB活性的影响研究

目的 探讨伊立替康（CPT-11）对食管癌EC109细胞的放射增敏作用及核因子（NF）κB活性的影响。方法 采用MTT法观察不同浓度CPT-11（20、50、100、200 μmol／L）作用24、48及72 h后的细胞存活率以筛选低细胞毒性药物浓度进行后续实验;根据实验设计分为对照组、单纯照射组和CPT-11+照射组,采用克隆形成实验检测经不同剂量X线（0、2、4、6、8和10 Gy）的存活分数（SF）并通过单击多靶模型拟合细胞存活曲线计算增敏比（SER）,采用流式细胞技术检测各组处理48 h后的凋亡率和caspase-3活化率,Foci焦点形成实验检测各组的DNA损伤情况,Western blotting检测各组NF-κB p65和IκB α的蛋白水平,实时定量PCR（qPCR）检测各组的Rad51水平。结果 在20～200 μmol／L范围内,随CPT-11浓度增加,EC109细胞的增殖抑制率升高,抑制效应呈浓度和时间依赖方式,差异有统计学意义（P＜0.05）。选取与CPT-11 20%抑制浓度（IC₂₀）接近的浓度（25 μmol／L）进行增敏实验。CPT-11+照射组的SF低于单纯照射组,且CPT-11+照射组的D0为1.39±0.14,单纯照射组的D0为2.46±0.17,SER为1.77。与对照组和单纯照射组比较,CPT-11+照射组的凋亡率、caspase 3活化率及Foci焦点数目均升高,而Rad51水平降低,差异有统计学意义（P＜005）。CPT-11+照射组的NF-κB p65水平低于其余两组,且IκB-α水平高于其余两组（P＜0.05）。结论 CPT-11可抑制食管癌EC109细胞增殖并具有放射增敏作用,同时诱导凋亡,可能与抑制NF-κB途径有关。     

UGT1A在伊立替康治疗转移性结直肠癌中的疗效与不良反应预测价值

化疗是转移性结直肠癌（mCRC）的主要治疗手段,伊立替康是mCRC的重要药物,但其存在治疗有效率有限、毒副反应个体差异大的问题。因此需要寻找有效的生物学标志物,筛选出对治疗反应性好、耐受性好的个体以指导临床治疗。尿苷二磷酸葡萄糖醛酸转移酶1A（UGT1A）的基因多态性与伊立替康的毒性及疗效均密切相关,但现有研究结果不一致,预测作用存在争议。本文通过Pubmed检索基因多态性与伊立替康相关性的有关文献,综合分析了UGT1A预测伊立替康毒性局限性的原因,可能与人种差异、药物使用剂量不同及与其他化疗药物或靶向药物联合使用有关。UGT1A多位点基因多态性的检测或与羧酸酯酶（CES）、ATP结合盒子（ABC）转运体、CYP3A4、SCOL等多个基因多态性的联合检测可能是提高伊立替康毒性和疗效预测水平的方式之一。     

Irinotecan,a key chemotherapeutic drug for metastatic colorectal cancer

Irinotecan hydrochloride is a camptothecin derivative that exerts antitumor activity against a variety of tumors. SN-38 produced in the body by carboxylesterase is the active metabolite of irinotecan. After irinotecan was introduced for the treatment of metastatic colorectal cancer(CRC) at the end of the last century,survival has improved dramatically. Irinotecan is now combined with 5-fluorouracil,oxaliplatin and several molecularly-targeted anticancer drugs,resulting in the extension of overall survival to longer than 30 mo. Severe,occasionally life-threatening toxicity occurs sporadically,even in patients in relatively good condition who have a low risk of chemotherapyinduced toxicity,often causing the failure of irinotecanbased chemotherapy. Clinical pharmacological studies have revealed that such severe toxicity is related to exposure to SN-38 and genetic polymorphisms in UDPglucuronosyltransferase 1A1 gene. The large interand intra-patient variability in systemic exposure to SN-38 is determined not only by genetic factors but also by physiological and environmental factors. This review first summarizes the roles of irinotecan in chemotherapy for metastatic CRC and then discusses the optimal dosing of irinotecan based on the aforementioned factors affecting systemic exposure to SN-38,with the ultimate goal of achieving personalized irinotecan-based chemotherapy.     

FOLFOX和FOLFOXIRI方案在结直肠癌肝转移术后患者中的应用

目的 比较FOLFOXIRI（folinic acid, 5-fluorouracil, oxaliplatin and irinotecan）和FOLFOX（folinic acid, 5-fluorouracil and oxaliplatin）两种化疗方案在肠癌肝转移同期手术切除患者中的有效性及安全性。方法 回顾性分析2008年1月至2011年7月结直肠癌伴肝转移同期手术切除患者60例,分为两组,分别接受FOLFOXIRI或FOLFOX两种化疗方案,观察不良反应以及1、2、3年无病生存期（DFS）和总生存期（OS）,采用Kaplan-Merier进行生存分析。结果 接受FOLFOXIRI或FOLFOX两种化疗方案的60例患者,不良反应包括白细胞下降、血小板下降、贫血、恶心呕吐、腹泻、肝肾功能损害、神经毒性、口腔黏膜炎、脱发,FOLFOXIRI组在白细胞减少及腹泻方面有更高的不良事件发生率,其余不良反应与FOLFOX组相仿。两组患者1、2、3年无病生存率分别为73.3%、43.3%、26.7%和60%、13.3%、10%,其中2、3年DFS存在统计学差异。两组患者1、2、3年总生存率分别为86.7%、73.3%、36.7%和83.3%、50%、13.3%,其中3年OS差异有统计学意义（P=0.024）。结论 FOLFOXIRI和FOLFOX两种化疗方案安全有效,FOLFOXIRI组在白细胞减少及腹泻方面有更高的不良事件发生率,但更具远期生存优势。     

Effect of kaempferol on lipid peroxidation and antioxidant status in 1,2-dimethyl hydrazine induced colorectal carcinoma in rats

Colorectal cancer, a common cause of cancer related deaths in both sexes in western population is often due to persistent oxidative stress leading to DNA damage. Antioxidants scavenge free radicals and inhibit neoplastic process. Kaempferol, a flavonol widely distributed in tea, broccoli, grape fruit, brussel sprouts and apple and is claimed to have chemopreventive action in colon cancer. The aim of our study was to evaluate the effect of kaempferol on tissue lipid peroxidation and antioxidant status in 1,2-dimethyl hydrazine induced colorectal cancer in male wistar rats and to compare its efficacy with irinotecan. Experimental colon cancer induced by 1,2-dimethyl hydrazine in rats mimic human colon cancer and therefore is an ideal model for chemoprevention studies. The rats were divided into six groups. Group 1 served as control. Group 2 received 1,2-dimethyl hydrazine (20 mg/kg body weight) subcutaneously once a week for four weeks. Group 3 received irinotecan (100 mg/kg body weight) intravenously once a week for four weeks with 1,2-dimethyl hydrazine. Groups 4 to 6 were given a daily oral dose of 50, 100, 200 mg/kg body weight of kaempferol with 1,2-dimethyl hydrazine. The total study period was 16 weeks. Kaempferol supplementation lowered 1,2-dimethyl hydrazine induced erythrocyte lysate and liver thiobarbituric acid reactive substances level and rejuvenated anti oxidant enzymes catalase, super oxide dismutase and glutathione peroxidase. The recovery of enzyme status was maximum at the dose of 200 mg/kg body weight and was comparable to irinotecan. Our study reveals that kaempferol could be safely used as a chemopreventive agent in colorectal cancer.