Eicosanoid-mediated Cl− secretion induced by the antitumor drug,irinotecan (CPT-11), in the rat colon

Irinotecan (CPT-11) is active against a broad range of human cancer. One of the side-effects of irinotecan is a strong diarrhoea. In order to investigate the mechanism underlying this diarrhoea, the effect of irinotecan on anion secretion across the isolated rat distal colon was studied. Irinotecan caused a concentration-dependent increase in short-circuit current (Isc). The increase in Isc was completely dependent on the presence of Cl^– ions and was supressed by furosemide and the Cl^– channel blocker NPPB (5-nitro-2-(3-phenylpropylamino)-benzoate), indicating that it is caused by a Cl^– secretion. The secretory response was inhibited by indomethacin, 1-benzylimidazole, a thromboxane synthase inhibitor, and SK&F 88046 ((N,Nbis-[7-(3-Chlorobenzeneaminosulfonyl)-1,2,3,4-tetrahydroisoquinolyl)disulfonylimide), a thromboxane A₂ receptor blocker. In isolated crypts irinotecan had no effect on the membrane potential. Consequently, the secretion induced by irinotecan is an indirect one, caused by the stimulation of eicosanoid production, e.g. thromboxane A₂, in the subepithelial tissue.     

In vitro schedule-dependent interaction between paclitaxel and SN-38 (the active metabolite of irinotecan) in human carcinoma cell lines

Paclitaxel and irinotecan are important new anticancer agents. The combination of these two agents has been considered for use against a variety of advanced solid tumors. Since the schedule-dependent effects of this combination may be crucial to its use, we studied the interaction of paclitaxel and SN-38 (the active metabolite of irinotecan) in various schedules in four human cancer cell lines in culture. Cell growth inhibition after 5 days was determined using an MTT assay. The effects of drug combinations at the IC₈₀ level were analyzed by the isobologram method. Simultaneous exposure to paclitaxel and SN-38 for 24 h produced antagonistic (subadditive and protective) effects in the human lung cancer cell line A549, the breast cancer cell line MCF7, and the colon cancer cell line WiDr, and produced additive effects in the ovarian cancer cell line PA1. Sequential exposure to paclitaxel for 24 h followed by SN-38 for 24 h, and the reverse sequence, produced additive effects in all four cell lines. These findings suggest that sequential administration, not simultaneous administration, may be the appropriate schedule for the therapeutic combination of paclitaxel and irinotecan. Continued preclinical and clinical studies should provide further insights and assist in determining the optimal schedule for this combination in clinical use. Received: 25 February 1997 / Accepted: 6 November 1997     

伊立替康对结肠癌Th1和Th2类细胞因子的影响

目的:观察和评价伊立替康联合5-FU/LV与单用5-FU/LV对结肠癌患者Th1和Th2类细胞因子基因表达水平的影响。方法:采用逆转录聚合酶链反应(RT-PCR)技术,检测结肠癌患者化疗前后外周血单个核细胞(PBMC)Thl和Th2类细胞因子mRNA表达水平。比较伊立替康联合5-FU/LV与单用5-FU/LV化疗对结肠癌患者细胞因子的影响。结果:结肠癌化疗3周期后,IL-6和IL-10阳性表达均较化疗前显著降低(P<0.05);IL-2和IL-12阳性表达均较化疗前显著升高(P<0.05)。伊立替康联合5-FU/LV组较单用5-FU/LV组能更好的降低结肠癌患者的IL-6、IL-10表达,提高IL-2、IL-12的表达(P<0.05)。结论:结肠癌患者细胞免疫受抑,Thl和Th2类细胞因子表达失衡,化疗可使结肠癌患者Th2类细胞因子的强势表达向Thl类逆转。伊立替康合并5-FU/LV能更好的改善患者的免疫状况,有助于机体的预后和康复。     

伊立替康联合化疗方案治疗原发性肝癌的临床研究

[目的]探讨伊立替康联合化疗治疗原发性肝癌的疗效和毒性反应。[方法]2004年9月-2007年3月于大连医科大学第二临床学院肿瘤科确诊为原发性肝癌的患者21例,采用依立替康（CPT-11）联合5-FU、DDP化疗,其中A组11例,CPT-11100 mg,DDP 60 mg,5-FU1000 mg,1次/d,经肝动脉灌注,B组10例,CPT-11100 mg,第1、8、15天,DDP75 mg/m^2,静脉滴注,5-FU300 mg/d,1次/d,连续7 d,持续静脉灌注,全部21-28 d为1周期。评价指标：有效率、临床获益率（完全缓解＋部分缓解＋稳定）,AFP下降情况、mTTP、毒性反应。[结果]A组疗效均为稳定,临床获益率100%,AFP下降者占50%,mTTP为5个月,B组1例部分缓解（10%）,5例稳定（50%）,临床获益率60%,AFP下降者20%,mTTP为5个月。毒性反应主要表现为骨髓毒性、肝功能毒性、迟发性腹泻。[结论]CPT-11联合化疗对于原发性肝癌有一定的疗效,与常规治疗相比,疗效相当,但在临床获益率和中位肿瘤进展时间方面显示一定的优势,毒性反应较轻微。其中,肝动脉灌注给药较静脉给药临床获益率较高,毒性反应较低,中位肿瘤进展时间相当,初步认为肝动脉灌注化疗优于静脉全身化疗。但对于无肝动脉灌注治疗指征或已出现血行转移的原发性肝癌患者采用静脉化疗,亦可获得一定的有效率,中位肿瘤进展时间延长,患者可明显获益。     

伊立替康单药二线治疗进展期结直肠癌的疗效观察

目的探讨伊立替康单药二线治疗进展期结直肠癌的临床效果。方法选取2011年1月～2013年1月本院收治的进展期结直肠癌患者50例,给予伊立替康90mg／mz,静脉滴注,第1、8天,每21天重复。2个疗程后评价治疗效果。化疗前常规止吐。结果本组50例患者,无完全缓解（CR）患者,其中,部分缓解（PR）12例（24％）,稳定（SD）26例（52％）,进展（PD）12例（24％）,总有效（CR＋PR）率为24％,疾病控制（CR＋PR＋SD）率为76％。均未出现药物所致死亡及严重不良事件,其中血液学毒性为骨髓抑制I＋Ⅱ度中性粒细胞减少症29例（58％）,Ⅲ＋Ⅳ度中性粒细胞减少症7例（14％）;非血液学毒性为I＋Ⅱ度迟发性腹泻18例（36％）,Ⅲ＋Ⅳ度迟发性腹泻3例（6％）,I＋Ⅱ度恶心呕吐29例（58％）,Ⅲ＋IV度恶心呕吐4例（8％）。结论伊立替康单药二线治疗进展期结直肠癌,效果显著．不良反应轻微。     

高效液相色谱法测定盐酸伊立替康注射液的含量

目的建立测定盐酸伊立替康注射液中盐酸伊立替康含量的高效液相色谱法。方法采用Agilent HC-C_（18）柱（250 mm×4.6 mm,5μm）,以磷酸盐缓冲液（称取无水磷酸二氢钠2.43 g和辛烷磺酸钠1.66 g,溶于1 000 mL水中）-甲醇-乙腈（57：25：18）为流动相,柱温为40℃,流速为1.5 mL/min,检测波长为255 nm。结果盐酸伊立替康质量浓度在0.1831~1.464 7 g/L范围内与峰面积呈良好线性关系（r=0.9994,n=7）,平均回收率为100.33%,RSD=0.46%（n=9）。结论该法准确、简便、重复性好,可用于盐酸伊立替康注射液的含量测定。     

Effects of Shengjiangxiexin decoction on irinotecan-induced toxicity in patients with UGT1A1*28 and UGT1A1*6 polymorphisms

OBJECTIVE

To evaluate the efficacy of Shengjiangxiexin decoction (SXD), prepared with a formula from Traditional Chinese Medicine (TCM), in reducing irinotecan-induced hematological and gastrointestinal toxicities in patients with UDP-glucuronosyltransferase (UGT) 1A1*28 and UGT1A1*6 polymorphisms.

伊立替康治疗结直肠癌相关胆碱能综合征89例

目的:观察和分析伊立替康治疗结直肠癌相关胆碱能综合征的发生情况.方法:应用2种FOLFIRI方案治疗转移性结直肠癌患者89例,观察和记录胆碱能综合征发生情况,并将其与患者临床资料、其他不良反应和所应用的治疗方案进行相关性分析.结果:53例(59.6%)患者发生胆碱能综合征,中位发生时间为伊立替康开始滴注后150min(30min-25h),绝大多数在用药后24h内逐渐消退,预防性应用阿托品可以有效预防胆碱能综合征发生;≥60岁老年患者胆碱能综合征明显高发(75.9%vs51.7%,P=0.029),未发现其与性别、ECOG评分等临床特征有关;出现胆碱能综合征患者迟发性腹泻有减少趋势(52.8%vs34.0%,P=0.077),未发现胆碱能综合征与其他不良反应相关;采用高剂量氟尿嘧啶治疗方案患者黏膜炎明显高发(50.0%vs27.5%,P=0.029).结论:伊立替康相关胆碱能综合征高发,应引起临床医生重视;胆碱能综合征对后续可能发生的迟发性腹泻和/或骨髓抑制无预测作用.     

The antioxidants,vitamin A and E but not vitamin C and melatonin enhance the proapoptotic effects of irinotecan in cancer cells in vitro

Irinotecan is one of the camptothecin analog which has been shown to have a broad spectrum of antitumor activities against various malignancies. The aim of this study was to evaluate the effect of vitamin A, C, E and melatonin on proapoptotic activity of irinotecan in human cancer cells in vitro. We observed that irinotecan induced apoptosis in all types of analyzed cell lines when used as a single agent. Combination of selected antioxidants with various doses of irinotecan (7.5–60 μM) resulted in significant increase in apoptotic cell death in A549 and HT29 cancer cell lines. The highest killing efficiency was observed after co-incubation of the cells with irinotecan and vitamin A (10 μM), or vitamin E (25 μM), respectively. The addition of vitamin C and melatonin to irinotecan treatment did not promote increase in killing of cancer cells. Our results indicate that some antioxidants can enhance the proapoptoic activity (properties) of irinotecan in human cancer cells in vitro. These findings may be supportive for the optimization of therapeutic efficacy of irinotecan treatment.