胰岛素增强5-氟尿嘧啶对体外结肠癌细胞的细胞毒作用

目的 观察胰岛素增强5-氟尿嘧啶(5-Fu)对结肠癌HCT-8细胞株和HT-29细胞株的细胞毒作用,探讨其增效作用机制.方法 采用四甲基偶氮唑蓝(MTT)法检测胰岛素和5-Fu联合应用对HCT-8细胞和HT-29细胞的生长抑制率,流式细胞仪分析胰岛素对HCT-8细胞和HT-29细胞周期的影响.结果 于5.Fu应用前0-8h加入胰岛素,对结肠癌细胞的生长抑制率显著高于单用5-Fu组(P<0.01),以在5-Fu应用前4h加入胰岛素对细胞的生长抑制率最高,HCT-8细胞和HT-29细胞的生长抑制率分别为71.27%和70.71%.胰岛素浓度在0.8 mU/ml以上时,与5-Fu联用,对结肠癌细胞的生长抑制率高于单用5-Fu组(P<0.01).胰岛素浓度在0.8-8 mU/ml之间,细胞生长抑制率随着胰岛素剂量的增加而增高;但当胰岛素浓度在8-200 mU/ml之间时,细胞生长抑制率并未随胰岛素剂量的增加而增高,而是稳定在一定的水平.胰岛素作用于结肠癌HCT-8细胞和HT-29细胞后,各时点G_0/G_1期细胞百分比均明显低于对照组(P<0.01).胰岛素作用6、12和24h,HCT-8细胞和HT-29细胞s期百分比明显增高(P<0.01),其中以作用6h最高(HCT-8细胞和HT-29细胞分别为39.18%和36.42%),之后逐渐降低.结论 胰岛素可以增强5-Fu对结肠癌细胞的细胞毒作用.胰岛素作用细胞后使S期细胞增多.是其增强5-Fu细胞毒作用的主要机制之一.     

胰岛素增强5-氟脲嘧啶对H22肝癌移植瘤的抑制作用及其机制

目的: 建立裸鼠H22肝癌移植瘤模型,观察胰岛素是否增强5-氟脲嘧啶(5-FU)对裸鼠移植瘤的化疗疗效并探讨其机制。 方法: 免疫组织化学方法检测肿瘤组织中细胞周期蛋白D(CyclinD)的表达。用流式细胞仪检测肿瘤组织细胞周期改变。 结果: 大、中、小剂量胰岛素(0.09,0.06,0.03U/20g)联合5-FU均能增加单用5-FU时的抑瘤作用,大剂量胰岛素联合5-FU组对H22肝癌移植肿瘤生长抑制率达51.35%,明显高于单用5-FU组的27.93%(P<0.05)。大剂量胰岛素组H22肝癌移植瘤组织中CyclinD的阳性表达率为62%,明显高于对照组的30%(P<0.05)。大剂量胰岛素组G1期和S期所占比例分别为53.87%和46.13%,与对照组的61.37%和38.25%相比,G1期细胞明显减少,S期细胞显著增多(P<0.05)。 结论: 在裸鼠H22肝癌移植瘤模型中,胰岛素能增强5-FU对H22肝癌移植瘤的化疗疗效。推测胰岛素可以通过或者至少是部分通过增加CyclinD蛋白的表达而使大量肿瘤细胞处于S期,此时加入S期特异性化疗药物5-FU能够更加有效地杀伤肿瘤细胞。     

5-氟尿嘧啶化疗诱发心绞痛发作1例分析

患者男,58岁,主因上腹部疼痛20d于2012年3月27日入院。无高血压及心脏病史,无糖尿病、高脂血症、吸烟等心血管病危险因素。胃镜及病理活检示:贲门腺癌。诊断:贲门腺癌Ⅳ期（T₄N₂M₀）。给予DCF方案化疗:多西紫杉醇120 mg第1日静脉输注,顺铂30 mg第1～4日,1次/d静脉输注,5-氟尿嘧啶（5-FU）3 000 mg持续48h静脉输注。5-FU持续静脉输注约38 h时,患者开始出现发作性胸痛症状,立即停药。心电图检查显示明显ST-T动态改变,心肌酶正常。遂终止化疗,经心内科医师会诊,考虑变异性心绞痛,予抗心绞痛药物治疗。发作性胸痛于化疗终止5d后完全消失。5月2日患者行第2次化疗,仍给予DCF方案,患者于5-FU持续静脉输注约38 h再     

5-氟尿嘧啶引起心绞痛1例

蒽环类抗癌药物导致心脏损伤已引起广大临床医师的重视 ,而 5 氟尿嘧啶 (5 Ｆｕ)致心脏损伤临床上少见。Ｌａｂｉａｎｃａ等综述 1 0 0 0例使用 5 氟尿嘧啶的病人 ,有 1 6 %出现心脏毒性。原先有缺血性心脏病史者 ,心脏毒性发生率增加到 4 5 %。我科曾收治 1例因使用 5 氟尿嘧啶引起心绞痛患者 ,报告如下 :患者女性、44岁、因右乳癌行改良根治术后 2 0天于 1 996年 1 0月 2 8日入院、体检 :一般情况好 ,全身浅表淋巴结不肿大 ,右胸壁手术疤痕约 1 5厘米 ,中段未完全愈合 ,心肺无异常。辅助检查 :血常规、肝肾功能、心电图均正常。诊断为右…     

龙力胶囊对 S180 荷瘤小鼠化疗的增效减毒作用

目的:观察龙力胶囊(Longli capsule,LLC)在荷瘤小鼠化疗中的增效减毒作用.方法:以S180荷瘤小鼠为模型.实体瘤和腹水型小鼠各分为荷瘤模型组、LLC组、5-氟尿嘧啶(5-fluorouracil,5-FU)组、5-FU+LLC组,另设正常对照组,连续给药10d.观察各组小鼠抑瘤率、生命延长率和不良反应;检测各组小鼠体重、肿瘤质量、外周血白细胞数、骨髓有核细胞数、脾指数和胸腺指数;观察小鼠腹腔巨噬细胞吞噬能力,分析LCC对5-FU的增效减不良反应.结果:5-FU+LLC组小鼠体重增加明显高于5-FU单药组.与5-FU组比较,5-FU+LLC组S180荷瘤小鼠生存时间明显延长(P<0.05).5-FU,LCC和5-FU+LLC均可抑制S180荷瘤小鼠移植瘤的生长,其抑瘤率分别为40.34%,36.25%和47.46%.LCC可明显增强5-FU抑制肿瘤生长的作用(P<0.05).与5-FU组比较,LCC组及LCC+5-FU组外周血白细胞数、骨髓有核细胞数、脾指数、胸腺指数、以及腹腔巨噬细胞吞噬能力均明显增高.结论:LLC对5-FU具有一定的增效减不良反应.     

阿魏蘑菇提取物对5-氟尿嘧啶疗效的影响

背景与目的:研究阿魏蘑菇(pleurotas sapidus,PS)提取物对5-氟尿嘧啶(5-Fu)化疗效果的影响,并分析其作用机制.材料与方法:建立移植性人宫颈癌BALB/c(nu/nu)裸鼠模型,并随机分为模型对照组、5-Fu组、PS组、5-Fu+PS组4组,分别给予不同的药物干预,14 d后结束实验,检测各项指标.结果:模型组裸鼠体内瘤体积、瘤重明显高于各干预组(P＜0.01),5-Fu+PS处理组荷瘤裸鼠体内瘤重和瘤体积分别为(0.19±0.03)g,(0.134±0.016)cm3低于5-Fu处理组[(0.30±0.03)g,(0.210±0.018)cm3];5-Fu组外周血白细胞数(3.52±0.43)×10 9/L明显低于5-Fu+PS组(5.00±0.74)×10 9/L和模型组(5.51±0.50)×109/L;5-Fu+PS组瘤组织Bax基因和caspase-3蛋白表达水平强于5-Fu组(P＜0.05).结论:阿魏蘑菇具有增强5-Fu对肿瘤生长的抑制作用,和减轻5-Fu抑制白细胞增殖的功效,其机制可能与其激活Bax/caspase3途径有关.     

龙力胶囊对S（180）荷瘤小鼠化疗的增效减毒作用

目的：观察龙力胶囊（Longli capsule,LLC）在荷瘤小鼠化疗中的增效减毒作用。方法：以S180荷瘤小鼠为模型。实体瘤和腹水型小鼠各分为荷瘤模型组、LLC组、5-氟尿嘧啶（5-fluorouracil,5-FU）组、5-FU＋LLC组,另设正常对照组,连续给药10d。观察各组小鼠抑瘤率、生命延长率和不良反应;检测各组小鼠体重、肿瘤质量、外周血白细胞数、骨髓有核细胞数、脾指数和胸腺指数;观察小鼠腹腔巨噬细胞吞噬能力,分析LCC对5-FU的增效减不良反应。结果：5-FU＋LLC组小鼠体重增加明显高于5-FU单药组。与5-FU组比较,5-FU＋LLC组S180荷瘤小鼠生存时间明显延长（P〈0.05）。5-FU,LCC和5-FU＋LLC均可抑制S180荷瘤小鼠移植瘤的生长,其抑瘤率分别为40.34%,36.25%和47.46%。LCC可明显增强5-FU抑制肿瘤生长的作用（P〈0.05）。与5-FU组比较,LCC组及LCC＋5-FU组外周血白细胞数、骨髓有核细胞数、脾指数、胸腺指数、以及腹腔巨噬细胞吞噬能力均明显增高。结论：LLC对5-FU具有一定的增效减不良反应。     

胰岛素对人乳腺癌细胞株化疗增效作用的体外研究

目的:探讨用胰岛素提高癌细胞生长代谢水平及其对化疗敏感性的影响。方法:选用人乳腺癌细胞株(MDA-MB-543)为靶细胞,以胰岛素为细胞生长代谢促进剂,采用MTT比色法,分析细胞活力及细胞代谢。结果:MTT比色分析法发现,胰岛素(4.0~32.0mU/ml,8~18小时)使MDA-MB-543细胞株的细胞总数,细胞活力增加,可增加5-Fu(28.0μg/ml)及阿霉素(0.36μg/ml)的细胞毒作用。结论:初步证实提高癌细胞的生长代谢水平,继之给予化疗,可提高化疗药物的细胞毒作用。     

Effects of the Plasma Concentration of 5-Fluorouracil and the Duration of Continuous Venous Infusion of 5-Fluorouracil with an Inhibitor of 5-Fluorouracil Degradation on Yoshida Sarcomas in Rats

The correlations of the 5-fluorouracil (5-FU) level in the plasma and the duration of continuous 5-FU infusion with the antitumor activity of 5-FU on Yoshida sarcomas in rats were examined. The circadian variation in the plasma level of 5-FU during continuous infusion was prevented by treatment with 3-cyano-2,6-dihydroxypyridine (CNDP), which strongly inhibits 5-FU degradation. On continuous venous infusion of 2 to 30 mg/kg of 5-FU over 24 h with CNDP at a molar ratio of 1:10 into normal rats, the 5-FU level in the blood was linearly proportional to the dose of 5-FU. The optimum schedule for antitumor activity on Yoshida sarcomas in rats was found to be infusion of 5-FU at 5 mg/kg over 24 h for 6 consecutive days, which gave a plasma 5-FU level of 176 ng/ml. Continuous infusion of 5-FU to give a plasma level of 300 ng/ml for 6 consecutive days from day 5 after implantation of tumor cells, when the tumors weighed about 1.0 g, resulted in complete regression of the tumors in all rats.     

5-Fluorouracil cardiotoxicity induced by alpha-fluoro-beta-alanine

Cardiotoxicity is a rare complication occurring during 5-fluorouracil (5-FU) treatment for malignancies. We herein report the case of a 70-year-old man with 5-FU-induced cardiotoxicity, in whom a high serum level of alpha-fluoro-beta-alanine (FBAL) was observed. The patient, who had unresectable colon cancer metastases to the liver and lung, was referred to us for chemotherapy from an affiliated hospital; he had no cardiac history. After admission, the patient received a continuous intravenous infusion of 5-FU (1000 mg/day), during which precordial pain with right bundle branch block occurred concomitantly with a high serum FBAL concentration of 1955 ng/ml. Both the precordial pain and the electrocardiographic changes disappeared spontaneously after the discontinuation of 5-FU. As the precordial pain in this patient was considered to have been due to 5-FU-induced cardiotoxicity, the administration of 5-FU was abandoned. Instead, oral administration of S-1 (a derivative of 5-FU), at 200 mg/day twice a week, was instituted, because S-1 has a strong inhibitory effect on dihydropyrimidine dehydrogenase, which catalyzes the degradative of 5-FU into FBAL. The serum FBAL concentration subsequently decreased to 352 ng/ml, the same as the value measured on the first day of S-1 administration. Thereafter, no cardiac symptoms were observed. The patient achieved a partial response 6 months after the initiation of the S-1 treatment. The experience of this case, together with a review of the literature, suggests that FBAL is related to 5-FU-induced cardiotoxicity. S-1 may be administered safely to patients with 5-FU-induced cardiotoxicity.     

5-Fluorouracil plus 5-methyltetrahydrofolate in advanced pancreatic cancer

A total of 20 patients with advanced pancreatic adenocarcinoma were enrolled in a phase II trial testing the activity of 5-fluorouracil given at 370 mg/m² as a rapid i. v. bolus for 5 consecutive days, preceded by a rapid i. v. bolus of 200 mg/m² 5-methyltetrahydrofolic acid. The treatment was repeated every 4 weeks. The median age of the patients was 68 years and their median Eastern Cooperative Oncology Group (ECOG) performance status was 1. There were 7 patients with locally advanced disease and 13 with distant metastases (median, 2 sites). A median of 3 monthly cycles of treatment (range, 1–7) were given, with a corresponding dose intensity of 396 mg/m² per week (86% of that planned). No complete response, 1 partial response, and 8 cases of disease stabilization were obtained. In general the regimen was well tolerated, with only 2 patients suffering from grade 3 stomatitis or diarrhea; the most common toxicity was nausea, which was experienced by almost 50% of the patients. The combination of 5-methyltetrahydrofolate plus 5-fluorouracil appears as little effective in this disease as 5-fluorouracil plus 5-formyltetrahydrofolate (leucovorin). It is suggested that bolus 5-fluorouracil is so inactive as an effector agent against pancreatic cancer that its biochemical modulation with exogenous high-dose reduced folates cannot improve the therapeutic outcome produced by the fluoropyrimidine in these patients.Abbreviations FUra 5-fluorouracil - LV 5-formyltetrahydrofolic acid - ME-THF 5-methyltetrahydrofolic acid Supported by CNR grant 92.01289.PF70, 92.02271.PF39 and AIRC 1994. A Guglielmi is a fellow of the Associazione Italiana Ricerca Cancro     

5-Fluorouracil and dihydropyrimidine dehydrogenase

Dihydropyrimidine dehydrogenase (DPD) is a rate-limiting enzyme of (fluorinated) pyrimidine degradation that plays a significant role in the pharmacokinetics of 5-fluorouracil (5-FU). In addition, a catabolite of 5-FU induces a certain toxicity, and the sensitivity of 5-FU is determined by DPD activity in tumors. DPD is thus important clinically. Drugs have been developed that control variations of the pharmacokinetics of 5-FU by controlling or inhibiting DPD, thereby reducing toxicity and improving sensitivity. These fluorinated pyrimidines with DPD-inhibiting activity, called DPD-inhibitory fluoropyrimidines, contribute to oral therapy with 5-FU for cancer. This paper summarizes the important role of DPD in cancer chemotherapy with 5-FU.     

Pharmacokinetic Modulation of Plasma 5-Fluorouracil Concentrations to Potentiate the Antitumor Activity of Continuous Venous Infusion of 5-Fluorouracil

Methods for pharmacokinetic modulation of the plasma 5-fluorouracil (5-FU) level to increase antitumor activity during continuous venous infusion (CVI) of low doses of 5-FU were examined in Yoshida sarcoma-bearing rats. These methods were additional infusion of 5-FU for a short period (4 h) or oral administration of LIFT or Tegafur during long-term CVI of 5-FU that alone gave a plasma 5-FU level of about 50 ng/ml. The antitumor effect on Yoshida sarcoma was markedly potentiated when an additive dose of 5-FU combined with 3-cyano-2,6-dihydroxypyridine (CNDP), a potent inhibitor of 5-FU degradation, giving a plasma level of about 500 ng/ml, was infused for 4 h. A similar increase in the antitumor effect was observed with oral administration of a conventional dose of UFT during CVI of 5-FU without CNDP, giving a plasma level of 30 to 60 ng/ml. These results suggest that the antitumor effect of CVI of 5-FU can be potentiated by pharmacokinetic modulation of the 5-FU concentration in the blood.     

多西紫杉醇联合氟尿嘧啶及顺铂治疗晚期胃癌

 目的 观察国产多西紫杉醇（TAT）联合亚叶酸钙／5-氟尿嘧啶（CF／5Fu）及顺铂（DDP）治疗晚期胃癌的临床疗效与不良反应。方法 41例晚期胃癌患者接受TAT与CF／5-Fu及DDP联合化疗：TAT75mg／m2，静滴1h，d1；CF100mg，静滴2h，d1-5；5-Fu500mg／m2，22h微泵持续静滴，d1-5；DDP25mg／m2，静滴，d，1-3。28天为一个周期。治疗2个周期后评价疗效和不良反应。结果 41例患者均可评价疗效。完全缓解2例，部分缓解23例，有效率61．0％。中位疾病进展时间7．5个月，中位生存期10．6个月，1年生存率41．5％。主要不良反应为骨髓抑制，脱发和周围神经炎。结论 国产多西紫杉醇联合亚叶酸钙／5-氟尿嘧啶及顺铂治疗晚期胃癌缓解率高，毒副反应可以耐受。     

Comparative Antitumor Activity of 5-Fluorouracil and 5'-Deoxy-5-fluorouridine in Combination with Radiation Therapy in Mice Bearing Colon 26 Adcnocarcinoma

The present study compared the antitumor activities of chemotherapy with 5-fluorouracil (5-FU) and with its prodrug 5'-deoxy-5-fluorouridine (5'-DFUR) in combination with radiotherapy on a solid colon 26 adenocarcinoma in the mouse. A single administration of 5'-DFUR immediately after local irradiation on day 10 after tumor inoculation produced more than additive antitumor effects, while only an additive effect was observed in the combined treatment with 5-FU and radiation. This over-additive effect of 5'-DFUR was more obvious in a fractionated-dose treatment schedule, where the same combined modality treatment was given three times on days 6, 10 and 14 after inoculation of the tumor cells. 5'-DFUR enhanced the radiation effects on the tumor in terms of the delay in tumor growth as well as the increase in the survival time. 5-FU produced only a marginal additive antitumor effect. Furthermore, radiation damage to normal tissues (skin damage by local irradiation and bone marrow and spleen damage by whole-body irradiation) was not enhanced by 5'-DFUR, though radiation damage to the thymus was additive. On the other hand, 5-FU produced toxic effects that were additive for all normal tissues tested. Thus, at doses that were the most effective against tumors, relative therapeutic gain factors (the ratio of the effect on tumors to that on the bone marrow) of 5'-DFUR and 5-FU were 1.24 and 0.49, respectively. These results suggest that 5'-DFUR will have a greater potential than 5-FU in combined modality treatment of cancer patients.     

基因修饰对消化道肿瘤细胞化疗药敏感性的影响

目的：探讨UPRT基因修饰消化道肿瘤细胞后对5-氟脲嘧啶(5-FU)杀伤效应的增强作用。方法：采用PCR技术从大肠杆菌K12菌株基因组中扩增UPRT基因，并构建pLXSN逆转录病毒表达载体，进一步转染人胃癌细胞株SCG7901、大肠癌细胞株Lovo以及肝癌细胞株7721。采用MTT法检测转导UPRT基因前后，肿瘤细胞对5-FU敏感性的变化。结果：通过逆转录病毒载体介导UPRT基因修饰肿瘤细胞，体外MTT法检测结果显示，转导UPRT基因后可使SCG7901、Lovo及7721对5-FU的敏感性分别提高约21．07、30．25及35．19倍。结论：UPRT基因修饰肿瘤细胞，能明显提高其对5-FU杀伤的敏感性，增强5-FU的抗瘤效应。     

复方氟脲嘧啶脂质体治疗晚期消化系统肿瘤的疗效观察

目的　观察复方氟脲嘧啶脂质体治疗晚期消化系统肿瘤的临床疗效及毒副反应。方法　 10 6例Ⅲ～Ⅳ期消化道肿瘤 ,其中胃癌 42例 ,食管癌 43例 ,原发性肝癌 2 1例。以复方氟脲嘧啶脂质体或氟脲嘧啶为主 ,单药或联合DDP的方案化疗 ,均化疗 2个周期以上。每个周期间隔 2 1～ 2 8天。结果　复方氟脲嘧啶脂质体组治疗胃癌、食管癌 ,原发性肝癌有效率 (CR PR)分别为 :3 6 4%、40 0 %、10 % ,有轻度的消化道反应、骨髓抑制。氟脲嘧啶组治疗的有效率 (CR PR)分别为 :3 5 .0 %、3 9.1%、9.1%。而毒副作用较大。结论　以复方氟脲嘧啶脂质体为主的联合化疗治疗晚期消化系统肿瘤副反应小 ,疗效可 ,值得推广应用。