FT-207软胶囊栓剂对消化道癌的临床药理学研究

呋氟脲嘧啶〔1-(2-4氢呋喃)-5-FU,FT-207〕是5-FU的衍生物,在体内缓慢地转化成具有抗癌作用的活性物质(5-FU、FUR、FUMP),为阻碍DNA合成的抗癌剂。术前给予FT-207栓剂,测定肿瘤组织、正常组织及末梢血中FT-207与5-FU的浓度,并对抗癌剂在组织内分布情况进行了研究。作者对11例消化道恶性肿瘤施行了切除手术,其中肠癌8例,胃癌3例。病理组织检查:腺癌10例,恶性淋巴瘤1例。术前3小时给予FT-207栓剂1000mg,在手术中采取肿瘤组织与正常组织各1g及采取血清1ml,冷冻保存在-20℃备检。用高速液相层析法测定FT-207浓度,用气相层     

大肠癌辅助疗CF+5-Fu方案与FT-207+L-OHP方案疗效比较

目的 比较Ⅱ-Ⅲ期大肠癌根治术后病人的辅助化疗CF+5-Fu与FT-207+L-OHP两种方案的远期疗效和毒性反应.方法 CF+5-Fu组58例,给予CF(200 mg)静脉滴注2h+5-Fu(375 mg-500 mg/m2)静脉滴注4-8 h,均为d1-5;FT-207+L-OHP组27例,FT-207(1g)静脉滴注d1-5+L-OHP(80 mg-120 mg/m2)静脉滴注d1.每例化疗三个周期以上,比较1年生存率、1年无病生存率、2年生存率、2年无病生存率及毒副反应.结果 CF+5-Fu与FT-207+L-OHP两组1年生存率分别为93.1%、88.9%,1年无病生存率分别为84.5%、81.5%,2年生存率分别为81.8%、82.6%,2年无病生存率分别为74.5%、73.9%,两组之间均没有统计学差异.两组毒性反应相比较,CF+5-Fu组高于FT-207+L-OHP组且有显著统计学差异的是静脉炎;在发生白细胞下降、血红蛋白下降、口腔溃疡、脱发方面两组无统计学差异;在血小板减少、恶心呕吐、乏力、腹痛腹泻、神经毒性方面,FT-207+L-OHP组均明显高于CF+5-Fu组,且有显著统计学差异.结论 Ⅱ-Ⅲ期大肠癌根治术后病人的辅助化疗CF+5-Fu与FT-207+L-OHP两种方案的远期疗效均较好,两组无统计学差异;CF+5-Fu组毒性反应明显较轻,疗效性价比更高.本文建议基层医院肿瘤科医生仍可优先选择CF+5-Fu方案来治疗Ⅱ-Ⅲ期大肠癌根治术后的病人.     

胃癌的化学药物治疗

一、常用化疗方案 1.单一用药 (一)呋喃氟脲嘧啶(FT-207)本药作用原理同氟脲嘧啶(5-FU),其特点是毒性低,口服或直肠给药吸收良好,化疗指数为5-FU的两倍。口服每日600～800mg,分3～4次,总量20～40g,有效率20％。副反应有食欲不振、恶心、呕吐。引起白细胞与血小板减少者不及10％。直肠给药每剂500mg,每日500～1000mg,总量20～60g,有效率26.0～33.3％,稍高于口服。消化道副反应少,血象影响轻。 (二)优福定(UFT)UFT每片含FT-207 50mg及尿嘧啶(Uracil)112mg。Uracil本身无抗癌作用,但可阻碍5-FU的分解代谢,使FT-207吸收后生成5-FU的浓度提高,不增加毒性。每日口服3次,每次     

Ⅲ期胃癌术后辅助免疫化疗的疗效观察

目的 探讨云芝多糖(PSK)+丝裂霉素(MMC)+氟脲嘧啶(FT-207)免疫化疗方案对Ⅲ期胃癌患者的术后辅助治疗效果。方法 将126例治愈根治性切除的Ⅲ期胃癌病例,术后随机分为两组:对照组(66例)术后辅助MMC+FT-207方案化疗,试验组(60例)术后辅助PSK+MMC+FT-207方案免疫化疗。分别观察患者一般状态、骨髓抑制、肝功能、T细胞亚群及生存率情况。结果 (1)治疗组全身乏力、面色苍白、食少纳差、恶心呕吐、腹胀、腹泻等症状明显好于对照组(P<0.05),同时治疗组化疗后外周血中白细胞减少及血小板减少均少于对照组,尤其是2级以上的的骨髓抑制也少于对照组。(2)化疗后对照组免疫功能略有下降,但试验组T细胞亚群不下降,反而略升高。同时对照组的丙氨酸转氨酶(ALT)和天冬氨酸转氨酶(AST)升高、总蛋白及白蛋白降低均较试验组高,说明PSK具有保护药物对肝的损伤作用。(3)试验组与对照组3年生存率分别为51.7％(31/60)和53.0％(35/66),差别不大。但前者5年生存率为46.7％(28/60),显著高于后者31.8％(21/66,P<0.05)。结论MMC+FT-207+PSK免疫化疗可提高胃癌患者对化疗的耐受性、改善生活质量及延长生存时间。     

FT-207栓剂治疗恶性肿瘤的经验

FT-207为5-氟脲嘧啶衍生物,结构为N_1(2′-四氢呋喃)-5氟脲嘧啶。其毒性为5-氟脲嘧啶的1/6,可缓缓释出活性型5-氟脲嘧啶,并长期维持其浓度,化疗指数提高2倍。作者用 FT-207栓剂治疗恶性肿瘤43例,其中40例为不能行根治术者或术后复发者;3例为根治术后辅助治疗。包括胃癌15例,结、直肠癌14例,乳癌6例,食管癌2例,十二指肠癌1例,胆道癌2     

UFT疗法的研究现状

氟尿嘧啶(5-FU)于1957年由Heidelberger等合成并进行了广泛的动物实验,以后很快进入临床,是常用的抗肿瘤药物之一。1968年Hiller合成了呋喃氟尿嘧啶(FT-207),这是一种需要经肝微粒体的药物代谢酶P450活化后才能起作用的所谓“潜伏化”型药物。由于FT-207口服后血中浓度持续较久,服用方便,毒性低于5-FU,因此在很多国家广泛应用。     

5’-去氧氟脲嘧啶核苷、呋喃氟脲嘧啶、和5-氟脲嘧啶免疫抑制效果的比较研究

5′一去氧脲嘧啶核苷(5′-DFUR)是由Cook 等于1979年合成的一种新的5-Fu 的衍生物。作者与其他实验室获得的结果表明:以化疗指数为指标,本药对各种不同肿瘤模型都优于5-Fu。本文对5′-DFUR 在小鼠细胞介导和体液免疫方面的抑制效应进行了实验,并与5-Fu 和呋喃氟脲嘧啶(FT-207)加以比较。1.对鸡红细胞(CRBC)的迟发型过敏反应:于BDF_1,小鼠左足底部注射10~8CKBC 致敏,4日后再用10~8CRBC 于右足底部攻击,所发生的迟发型过敏反应是计算攻击24小时后足底部增厚情况。在用CRBG     

新抗肿瘤药优福定(UFT)治疗晚期胃肠癌的临床观察

 优福定(UFT)是济南制药厂研制的以呋哺氟脲啼啶(FT-207)和脲嘧啶(Uracil)配伍的新型抗肿瘤药物。 我院自1985年1月至6月临床试用UFT治疗晚期胃肠癌25例, 现将近期疗效报道如下。     

奈达铂联合替加氟治疗晚期头颈部癌的临床研究

目的:观察奈达铂(NDP)联合替加氟(FT-207)治疗晚期头颈部癌的疗效及毒副反应.方法:对44例晚期头颈部癌患者给予NDP 80mg/m2～100mg/m2静脉滴注2小时以上,第1天,FT-207 600mg/m2,第1天～5天,静脉滴注8小时,每21天为一周期,至少应用2周期.结果:44例患者中可评价疗效42例,初治19例,CR 2例,PR 9例,有效率57.9%(11/19);复治23例,CR 1例,PR 8例,有效率39.1%(9/23);近期客观有效率47.6%(20/42),中位进展时间(TTP)5.1个月,中位生存时间(MST)10.5个月,主要毒副反应为骨髓抑制,恶心,呕吐,但患者均能耐受.42例可评价毒副反应的患者中,有3例(7.1%)出现Ⅲ度中性粒细胞降低,5例(11.9%)出现Ⅲ度～IV度血小板降低.结论:NDP联合FT-207化疗对晚期头颈部癌疗效较好,毒副反应较轻,可作为晚期头颈部癌的主要化疗方案.     

黄芪多糖对创伤应激小鼠胸腺、脾脏淋巴细胞中NF-κ BmRNA与IL-10mRNA表达影响的形态计量学研究

目的:探讨创伤应激状态下小鼠免疫功能变化及黄芪多糖(APS)对应激状态下机体免疫功能影响。方法:建立小鼠截肢应激模型,将50只Balb/c小鼠随机分为5组: 正常对照组(A);应激对照组(B);应激 黄芪多糖高(C)、中(D)、低(E)剂量组,每组10只。创伤后72小时称小鼠胸腺、脾脏湿重,用原位杂交检测胸腺、脾脏淋巴细胞中NF-κB mRNA、IL-10mRNA表达,计算机图像分析系统定量。结果:与正常对照组(A)比较,创伤后72小时应激对照组(B)小鼠胸腺、脾脏重量指数明显下降(P<0.01=;胸腺、脾脏淋巴细胞NF-κBmRNA、IL-10mRNA表达水平均明显升高(P<0.01);与创伤应激对照组(B)比较,应激 黄芪多糖高(C)、中(D)、低(E)剂量组小鼠胸腺、脾脏指数有不同程度的升高,胸腺、脾脏淋巴细胞中NF-κB mRNA、IL-10mRNA的表达受抑(P<0.01)。与正常对照组(A)比较,应激 APS高剂量组(C)小鼠胸腺、脾脏指数;胸腺、脾脏组织中NF-κB mRNA、IL-10mRNA的表达无显著性差异(P>0.01>0.05)。结论:创伤后小鼠免疫功能受抑;黄芪多糖体内应用可有效恢复其免疫功能。     

Metabolism of 1,3-bis(tetrahydro-2-furanyl)-5-fluorouracil in mice.

1,3-Bis(tetrahydro-2-furanyl)-5-fluorouracil (FD-1) is a new masked compound of fluorinated pyrimidine and a derivative of 1-(tetrahydro-2-furanyl)-5-fluorouracil (FT-207). The pharmacokinetics of FD-1 and FT-207 were compared in the livers and kidneys of control mice and in mice (DD males) pretreated with phenobarbital. The half-time in the liver of FD-1 orally administered was about 40 minutes, whereas that of FT-207 in the liver was about 3 hours. Hepatic concentrations of 5-fluorouracil (FUra) originating from FD-1 were three to five times as much as those originating from FT-207. FD-1 formed 3-(tetrahydro-2-furanyl)-5-fluorouracil (3-T-F-FU) and FT-207 by a ratio of about 3 to 10, respectively. Although FD-1 had a short period of half reduction, FT-207 and 3-T-F-FU had a half-time lasting for 3--4 hours. In contrast, the renal concentration of FD-1 was one-third that of FT-207. Oral administration of FD-1 to the mice pretreated with phenobarbital elevated the FT-207 and 3-T-F-FU levels in the livers to twice the levels in the control mice and further elevated the FUra levels in the livers to twice the levels in the controls. These results indicate that FD-1 is catabolized in the liver by microsomal enzymes (including cytochrome P450) faster than is FT-207, which consequently enlarges the hepatic pool of the intermediates on the way to FUra formation.     

西咪替丁与优福定合用的抗肿瘤作用

我们研究了西咪替丁与优福定并用对实验性肿瘤的效应及其作用机制。单用西咪替丁对移植于小鼠的实体型S—180和肝癌的生长有抑制作用。两药合用的抑瘤作用强于任一药物。西咪替丁能增强小鼠巨噬细胞的吞噬功能,并能对抗优福定对巨噬细胞的抑制作用。西咪替丁对优福定的有效组份呋哺氟尿嘧啶的药代动力学的影响表明西咪替丁能增加大鼠血清中呋哺氟尿嘧啶的峰浓度和AUC。     

Intraperitoneal administration of FT-207 for mouse peritonitis carcinomatosa

The peritoneal surface of the lesion was observed after treatment by scanning electron microscopy to evaluate the anticancer effect of FT-207. FT-207 (1.0 mg/day) was injected intraperitoneally to the DDN mice in which 3 X 10(7) MM2 tumor cells were inoculated the day before treatment. The anticancer effect was examined from 2nd to 7th consecutive day after tumor cell implantation, and the following results were obtained. 1) In the early phase after injection of FT-207, many macrophage-like cells were observed on the peritoneal surface. 2) Each MM2 tumor cell was covered by many macrophage-like cells, and these tumor cells were destroyed. 3) In the late phase after injection of FT-207, tumor cells were hyperplastic on the peritoneal surface, but less prominent than in the control group. 4) Effusion and adhesion in peritonitis carcinomatosa of FT-207 group were less than in the control group.     

N1-(2 tetrahydrofuryl)-5-fluorouracil (FT-207) in the postoperative adjuvant chemotherapy of gastric cancer. Delivery of a fat-emulsified agent to the lymph

The influence of fat emulsification of N1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207) on lymphatic transport was studied in seven postoperative gastric cancer patients. The water-in-oil-type of emulsion of FT-207 (FT-w/o), the oil-in-water-type emulsion of FT-207 (FT-o/w) and an enteric-coated granule of FT-207 (FT-G) each in 1-g doses, calculated in terms of FT-207, were administered orally. Lymph from a thoracic duct fistula, prepared in advance, and from the blood of a peripheral vein was collected simultaneously along a time course after administration to measure the concentrations of FT-207 and 5-fluorouracil (5-FU). For FT-w/o, FT-207, and 5-FU, concentrations were significantly higher, both in the lymph and in the blood, than those for FT-G and FT-o/w. However, no significant differences in FT-207 and 5-FU concentrations were observed between FT-o/w and FT-G. It was concluded that FT-w/o can be useful as an adjuvant chemotherapeutic drug in the postoperative treatment of gastric cancer.     

Relationship of chemotherapy on human cancer xenografts in nude mice to clinical response in donor patient

Responsiveness of experimental chemotherapy on human cancer xenografts in nude mice was directly compared with clinical response to the same chemotherapy in their donor patients. These xenografts were 1 line of rectal cancer (H-26), two lines of gastric cancer (H-08 and H-22), and 1 line of breast cancer (H-62). Experimental chemotherapies studied were single-drug FT-207 to four lines of xenografts and a combination of mitomycin C, 5-FU, and cytosine arabinoside (MFC) to a line of gastric cancer H-08. Single-drug treatment with FT-207 to H-26 resulted in remarkable retardation of the tumor growth. The comparative treatment with FT-207 suppository to the donor patient of H-26 showed appreciable response. All the other chemotherapies to three other lines (H-08, H-22, and H-62) induced no significant response, which was parallel to the corresponding clinical response in each donor patient. The sensitivity to chemotherapeutic drugs was thought to be still preserved in human cancer xenografts in nude mice.     

5-FU concentration in tissues of gastric cancer patients with preoperative administration of UFT--especially in comparison with FT-207

FT-207 or UFT was administered preoperatively to 74 patients with gastric cancer. The 5-FU and FT-207 concentrations in the serum and various tissues were investigated. The 5-FU concentration in various tissues was higher than in the serum after the administration of FT-207 or UFT. Especially it showed that 5-FU concentration in tumor was highest in other normal tissues. The 5-FU concentration in the tumor for the UFT group was higher than for the FT-207 group. There was a significant difference between the UFT and FT-207 groups (P less than 0.05). Levamisole had no influence on the concentration of 5-FU.     

Antitumor activity of a new fluoropyrimidine derivative, 5'-deoxy-5-fluorouridine, against murine and human experimental tumors

5'-Deoxy-5-fluorouridine (5'-DFUR) was evaluated for antitumor activity against four murine tumors (L1210 leukemia, P388 leukemia, Lewis lung carcinoma, and B16 melanoma) and a human mammary carcinoma (MX-1) xenografted in athymic mice. Intraperitoneal administration of 5'-DFUR was ineffective against B16 melanoma implanted intraperitoneally and showed less marked antitumor activity against P388 and L1210 leukemias implanted intraperitoneally or intravenously as compared with that of 5-fluorouracil (5-FU) or 1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207), while oral administration of 5'-DFUR showed a similar or superior antitumor activity to that of 5-FU or FT-207 against L1210 leukemia implanted subcutaneously. 5'-DFUR showed a marked antitumor activity against MX-1 implanted subcutaneously and also showed slight antitumor activity against Lewis lung carcinoma implanted subcutaneously, while 5-FU and FT-207 did not show any significant antitumor activity against these tumors. These results suggest that 5'-DFUR may be worthy of clinical trial against solid tumors, especially cancers of the breast.     

Clinical study on the permeability of FT-207 and 5-FU in primary lung cancer

Distribution of the FT-207 and 5-FU between plasma and lung tissue as well as tumor tissue was studied in 28 patients with lung cancer after administration of FT-207 preoperatively. Two methods of administration were employed, one is intravenous drip infusion (IV Group) (800 mg/day for three days) and the other is suppository (Supp Group) (750 mg 2/day for three days). The level of FT-207 was higher in plasma than in normal lung tissue or tumor tissue in IV Group. There was no difference in the level of FT-207 between plasma, normal lung tissue and tumor tissue in Supp Group. The level of 5-FU was higher in tumor tissue than in plasma both in IV Group and Supp Group. Furthermore, intravenous drip infusion was more effective method to give FT-207 because of higher level of 5-FU in tumor tissue than in normal tissue. Comparison of the tissue level in IV Group between two histologic types of tumor, i.e. squamous cell carcinoma and adenocarcinoma, disclosed that there was no significant difference in the concentration of FT-207 and 5-FU both in normal lung tissue and in tumor tissue.     

Long-term administration of tegafur in postoperative adjuvant chemotherapy in gastric cancer patients. Serial analysis of serum tegafur and 5-fluorouracil concentrations, and influence from PSK combination

We investigated the pharmacokinetics of long-term (2-year) daily oral administration of FT-207-E or UFT for postoperative adjuvant chemotherapy in 85 gastric cancer patients by measuring serum FT-207 and 5-FU concentration serially. There were no significant changes in serum FT-207.5-FU concentration during observation period between FT-207-E and UFT groups. There was different operative modality between partial gastrectomy (Billroth I) and total gastrectomy, but no significant difference in serum FT-207.5-FU concentration between the two groups, and no significant serial changes in serum FT-207.5-FU concentrations were observed in both groups. Conversion from FT-207 to 5-FU measured by serum concentration was not suppressed by combination with the biological response modifier PSK.     

Effect of FT-207 on bladder cancer in rats induced by BBN. II: The effect of oral administration of FT-207 during oncogenesis of bladder cancer

The effect of Tegafur (FT-207) by oral administration on the development of urinary bladder tumors in Wistar strain male rats induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) was studied. Urinary bladder tumors were induced in 18 of 20 rats (90.0%) when rats were given 0.05% BBN in the drinking water for 8 weeks and then given water without BBN for 12 weeks. When FT-207 100mg/kg B. W./day was given in their diet after treatment with 0.05% BBN for 8 weeks, tumors developed in the urinary bladder with low incidence (9 of 16 rats: 56.3%). Hematotoxicity was not observed in all animals treated with FT-207. These results shows that FT-207 also inhibited the development of urinary bladder tumors treated with BBN in rats by oral administration, which were similar those our previous results showed by intraperitoneal administration of FT-207.