TNP-470联合5-FU抑制结肠癌肝转移的研究

目的:研究血管生成抑制剂TNP-470联合5-FU对结肠癌肝转移的抑制作用。方法:将结肠癌LOVO细胞注入裸鼠脾脏,建立结肠癌肝转移模型。将裸鼠随机分为联合治疗组、TNP-470组、5-FU组和对照组4组。治疗4周后,处死裸鼠,计数肝转移率和肝转移结节数。采用免疫组化SABC法和图像分析系统对肝转移肿瘤组织的微血管密度(MVD)和血管内皮生长因子(VEGF)的表达进行定量分析。结果:TNP-470 5-FU组和TNP-470组与对照组比较,肝转移率显著下降(P<0.01,P<0.01);TNP-470 5-FU组和5-FU组与对照组相比,VEGF表达量明显下降(P相似文献   

TNP-470抑制小鼠恶性腹腔积液形成的实验研究

目的 :研究血管生成抑制剂TNP 4 70对小鼠恶性腹腔积液形成的抑制作用。方法 :将小鼠肝癌腹水型细胞系Hca F2 5接种于小鼠腹腔 (2× 10 5/鼠 )。将 10 0只小鼠随机分成对照组 (0 9%NS) ,化疗组 (DDP 1mg/kg) ,TNP 4 70低、中、高剂量组 (30mg/kg、6 0mg/kg、90mg/kg)。自第 2天起分别腹腔内给药 (0 2ml/鼠 ) ,隔日给药 ,共 7次。第 15天处死部分小鼠测各项指标 ,余小鼠观察生存期。结果 :化疗组 ,TNP 4 70低、中、高剂量组的腹水抑制率分别为 74 77% ,5 2 33%、80 11%和 92 89% ;腹膜瘤结节的形成率分别为 10 0 % ,70 %、80 %、5 0 %和 30 %。在生存时间上 ,各治疗组较对照组明显延长生存期 (P <0 0 5 )。结论 :TNP 4 70具有抑制小鼠恶性腹腔积液的形成和延长小鼠生存时间的作用。     

血管生成抑制剂TNP-470抑制肝癌生长和转移的实验研究

目的　研究血管生成抑制剂TNP 470对肝细胞癌生长和转移的抑制作用。方法　把高转移人肝癌模型(LCI D2 0 )的肿瘤组织小块种植于裸鼠皮下 ,将 2 4只裸鼠随机分成对照组、治疗组。第 2天起分别给予溶剂 ( 3%酒精 )、TNP 470 ( 30mg kg)隔天皮下注射 ,共 8次。 结果　对照组、治疗组皮下瘤重分别为 ( 2 0 4± 0 34)g、( 0 98± 0 34) g(P<0 0 0 1) ;两组AFP分别为 ( 76 8 6± 2 82 3) μg L ,( 93 4±5 8 6 ) μg L (P <0 0 0 1) ,两组肺转移率分为5 0 % ( 6 12 )、8 3 % ( 1 12 ) (P <0 0 5 )。结论　血管生成抑制剂TNP 470能显著抑制肝细胞癌的生长和转移     

TNP-470和丝裂霉素联用对肝癌生长和转移抑制作用的实验研究

目的 :为了验证O (氯乙酰 氨甲酰基 )烟曲霉醇 (TNP 470 )和丝裂霉素 (MMC)联用的增效作用。方法 :将 40只荷有高转移肝癌的裸鼠随机分成 4个组 :①对照组 ;②TNP 470组 (30mg/kg,qod× 8次 ) ;③MMC组 (2mg/kg ,biw× 6次 ) ;④联合用药组 (TNP 470 30mg/kg ,qod× 8次 +MMC 2mg/kg ,biw× 6次 )。结果 :4个组瘤重分别为 2 0 0± 0 2 5 ,0 83±0 40 ,0 92± 0 2 5 ,0 5 6± 0 2 7克。统计学分析表明 :在瘤重方面 ,TNP 470组、MMC组和对照组比较差异具有显著性 (P <0 0 5 ) ,联合用药组和其他 3组比较均有显著性差异 (P <0 0 5 )。各组肺转移率分别为 5 0 % (5 / 10 ) ,10 % (1/ 10 ) ,0 % (0 /10 ) ,0 % (0 / 10 )。治疗各组裸鼠活动良好 ,无明显体重减轻。结论 :TNP 470、MMC对肝癌的生长和转移都有明显的抑制作用 ;TNP 470和MMC联用能起增效作用 ;MMC并未加重TNP 470引起的体重减轻等毒副作用。     

三氧化二砷联合TNP-470抑制鸡胚尿囊膜血管生成的研究

目的观察和比较三氧化二砷(As2O3)和O-(氯乙酰甲酰)夫马菌素醇(TNP-470)对鸡胚尿囊膜(CAM)血管生成的抑制作用。方法100只鸡胚(7日龄)随机分为四组As2O3联合TNP-470组、As2O3组、TNP-470组、生理盐水(NS)对照组,以甲基纤维素作为载体,加药孵育后观察药物对血管生成的影响。结果与NS对照组比较,As2O3和TNP-470均有显著抑制CAM血管生成作用(P<0·001),且联合组的抑制作用强于单药组(P<0·05)。结论As2O3和TNP-470对CAM血管生成均有明显的抑制作用,两药联合应用有协同增效作用。     

TNP-470联合重组人内皮抑素抑制小鼠肺腺癌生长的研究

目的:观察TNP470和重组人内皮抑素（recombinant human endostatin,rhES）联合治疗对小鼠肺腺癌LA795肿瘤生长的抑制作用。方法: 用甲醇诱导能高效分泌表达重组人内皮抑素（rhES）的毕赤酵母菌株分泌表达rhES，将皮下接种LA795肺腺癌细胞的T739雄性近交系小鼠随机分成3组，每组各10只，分别给予PBS，rhES及TNP470+rhES皮下注射，每日1次，连续14 d；观察各组小鼠肿瘤生长情况，游标卡尺测量肿瘤体积大小。断颈处死小鼠，原位肿瘤免疫组化观察肿瘤内部微血管密度（microvessel density, MVD）。结果: 经甲醇诱导，毕赤酵母重组菌分泌表达rhES，并应用肝素亲和层析将其纯化；动物试验显示与PBS对照组比较，rhES治疗组及rhES＋TNP470治疗组均明显抑制小鼠肿瘤的生长（P<0.01），TNP470+rhES组与rhES组比较亦有显著性差异（P<0.01）。原位肿瘤免疫组化显示联合治疗组抑制血管生成更显著（P<0.01）。结论: TNP470联合rhES治疗对小鼠肺腺癌LA795生长的抑制效果比单独使用rhES的治疗效果更佳，具有良好的协同治疗作用     

5—FU和生物制剂联合诱导结肠癌细胞凋亡的研究

免疫治疗是抗肿瘤治疗的一个重要方面,药物治疗和免疫治疗相结合是抗肿瘤治疗的一个重要研究方向。Fas系统在结肠癌的肿瘤免疫中具有重要作用,针对Fas系统的免疫治疗可能有一定效果。本实验旨在观察治疗结肠癌的首选药物5-氟尿嘧啶(5-FU)和抗Fas单抗对结肠癌细胞株SW480的联合作用及其作用机制。     

血管生成抑制剂TNP—470抑制Lewis肺癌生长和转移的实验研究

目的采用Ｌｅｗｉｓ肺癌来验证血管生成抑制剂ＴＮＰ－４７０对肿瘤生长和转移的抑制作用。方法将Ｌｅｗｉｓ肺癌细胞接种于Ｃ５７ＢＬ小鼠皮下（２．４×１０６／鼠）。将２０只小鼠随机分成对照组和治疗组,自第２天起分别给予溶剂（３％酒精）０．２ｍｌ和ＴＮＰ－４７０（４０ｍｇ／ｋｇ）,隔天给药１次,共８次。第２２天时,测定对照组和治疗组的皮下瘤重及肺转移率,分别进行ｔ检验和χ２检验。结果两组皮下瘤重分别为３．７７±１．０５ｇ和１．９８±０．９６ｇ（Ｐ＝０．０００９）;两组肺转移率分别为８０％和３０％（Ｐ＝０．０３）。结论血管生成抑制剂ＴＮＰ－４７０能明显抑制Ｌｅｗｉｓ肺癌的生长和转移。     

术前5-FU持续静脉输注联合CF治疗Ⅱ期乳腺癌的近期疗效分析

目的：探讨长时间静脉输注５－ＦＵ加口服甲酰四氢叶酸钙（ｃａｌｃｉｕｍ ｆｏｌｉｎａｔｅ,ＣＦ）片剂,在Ⅱ期乳腺癌术前新辅助化疗中的应用,并与ＣＭＦ方案进行疗效及毒副反应比较。方法：以随机对照研究,对两组共７０例乳腺癌患者术前化疗疗效及毒副反应进行观察、比较与分析。结果：５－ＦＵ静滴加口服ＣＦ组有效率达７１．９％,ＣＭＦ组３１．６％。结论：５－ＦＵ静滴加口服ＣＦ方案作乳腺癌术前新辅助化疗疗效明显,毒副反应可耐受,值得在临床进一步探索。     

抗促胃液素疫苗mG17-CRM197单用及联合5-FU抑制小鼠结肠癌的生长

目的：观察抗促胃液素(gastrin,又称胃泌素）疫苗mG17-CRM197（mG17）单用及联合氟尿嘧啶（fluorouracil,5-FU）对小鼠结肠癌C38移植瘤的抑制作用。方法：采用Western blotting法检测结肠癌细胞促胃液素受体（CCKBR）的表达情况,磺酰罗丹明B（SRB）法检测mG17-NH2对C38细胞增殖的影响。C57BL/6小鼠随机分为PBS组、CRM197组、mG17组、5-FU组和mG17/5-FU组,ELISA法检测小鼠血清中抗G17抗体水平;免疫后的小鼠皮下进行肿瘤移植,5-FU组和mG17/5-FU组给予5-FU（20 mg/kg,q2d×5）,其他组给予生理盐水,通过肿瘤生长曲线和瘤质量评价不同治疗方案对C38移植瘤生长的影响。结果：小鼠结肠癌C38细胞表达CCKBR,mG17-NH2浓度依赖性上调CCKBR的表达,且能促进 C38细胞增殖（细胞增殖率为115.7%~133.5%）。mG17疫苗免疫3次后,小鼠血清抗mG17抗体水平依次升高。mG17组、5-FU组和mG17/5-FU组对C38移植瘤有显著抑制作用,抑瘤率分别为58.0%、60.5%和80.7%;按金氏法计算,mG17与5-FU联用的Q值为0.97,两药联用出现相加作用。结论：mG17-CRM197疫苗对小鼠结肠癌C38移植瘤治疗有效,与5-FU联用增强对小鼠结肠癌的抑制。     

Inhibition of hepatic metastasis in mice treated with cell-binding domain of human fibronectin and angiogenesis inhibitor TNP-470

Background. To prevent tumor metastasis, we administered the cell-binding domain of fibronectin, in combination with the angiogenesis inhibitor TNP-470, to mice with hepatic metastasis. We then assessed the prevention of tumor metastasis resulting from the inhibition of adhesive interactions and the inhibition of angiogenesis. Methods. A hepatic metastasis model was created by injecting 1 × 10³ colon 26/TC-1 cells into the anterior mesenteric vein of CDF1 mice. The cell-binding domain obtained from fibronectin included the Arg-Gly-Asp (RGD) sequence. A fibronectin-binding domain (FND)-treated group, an FND plus TNP-470 group, and a control group were established. The animals were killed 4 weeks after the injections of the treatment agents had been completed and the number of metastatic liver nodules was counted. In a simultaneous experiment with the same design, the mice were not killed at 4 weeks, and their survival was observed. Results. The mean number of nodules in the FND plus TNP-470 group was significantly lower than that in the control group (P = 0.019337). The inhibition rate was 51% in the FND group, 60% in the FND 10 μg plus TNP-470 10 mg/kg group, and 64% in the FND 10 μg plus TNP-470 100 mg/kg group compared with the control group. Mice from the FND group that were not killed died after 6–8 weeks, but mice from the FND plus TNP-470 group died after 8–12 weeks. Conclusion. The cell-binding domain of fibronectin may, potentially, be an effective form of antiadhesive therapy that competes with native adhesion molecules and blocks adhesion during the metastatic process. When the cell-binding domain of fibronectin is combined with TNP-470 to inhibit angiogenesis, more effective inhibition of metastatic tumor growth and prolongation of survival can be achieved than after treatment with the cell-binding domain alone. Received: December 19, 2000 / Accepted: August 10, 2001     

Clinical and pharmacokinetic study of TNP-470, an angiogenesis inhibitor, in combination with paclitaxel and carboplatin in patients with solid tumors

Purpose Preclinical studies have demonstrated a synergistic effect with the angiogenesis inhibitor TNP-470 and several cytotoxic agents. A recent clinical trial with the combination of paclitaxel and TNP-470 has shown promising effects. The present study was designed to determine the toxicity and pharmacokinetics of carboplatin in combination with TNP-470 in comparison with the doublet regimen of paclitaxel and carboplatin in patients with solid tumors.Experimental design Enrolled in the study were 17 patients with lung (11), head/neck (3), sarcoma (2) and thymoma (1). The patients received intravenous paclitaxel and carboplatin on day 1 followed by TNP-470 (60 mg/m² i.v. over 1 h administered thrice weekly on Monday, Wednesday, and Friday). Each cycle of therapy consisted of 3 weeks. The initial cohort of three patients received carboplatin at AUC 5 mg/ml×min. No dose-limiting toxic effects occurred, thus the subsequent cohort received carboplatin at AUC 6 mg/ml×min. In addition to toxicity, the pharmacokinetics of carboplatin were evaluated, and tumor response and patient survival rates were assessed.Results The administered regimen of paclitaxel (225 mg/m² i.v. over 3 h) and carboplatin (AUC 6 mg/ml×min i.v. over 1 h) on day 1 followed by TNP-470 (60 mg/m² i.v. over 1 h administered thrice weekly on Monday, Wednesday, and Friday) was defined as both the maximum tolerated and optimal dose. Hematological toxic effects were similar to those expected with the chemotherapy doublet. All neurocognitive impairments were graded as mild to moderate and reversed after discontinuation of TNP-470 administration. No alterations in the pharmacokinetic disposition of carboplatin were noted. Overall, the median survival duration was 297 days. Four patients (24%) had a partial response, and eight (47%) had stable disease.Conclusions The combination of TNP-470, paclitaxel, and carboplatin is a reasonably well tolerated regimen. Further randomized studies of TNP-470 with this doublet regimen are now warranted for non-small-cell lung carcinoma and other solid tumors.     

Experimental study of the effect of angiogenesis inhibitor TNP-470 on the growth and metastasis of gastric cancer in vivo

Objective: To study the effect of angiogenesis inhibitor TNP-470 on the growth and metastasis of gastric cancer in vivo. Methods: Metastatic model simulating human gastric cancer was established by orthotopic implantation of histologically intact tumor tissue into gastric wall of nude mice. TNP-470 was administrated S.C. at doses of 0 mg/kg, 15 mg/kg, 30 mg/kg, 60 mg/kg every other day for eight weeks. Ten weeks after implantation, the mice were sacrificed and the tumor size measured and the presence of metastasis recorded. The microvascular density was examined by immunohistochemical staining with anti-human factor VIII antibody. Results: Compared to the untreated controls, growth of the orthotopically implanted tumor was significantly reduced in size in the mice treated with TNP-470 with an inhibition rate of 59.9%, 77.0% and 84.9% at the dosage of 15 mg/kg, 30 mg/kg and 60 mg/kg, respectively. Tumor metastasis to the liver and peritoneum was also significantly inhibited in a dose-dependent manner. The microvascular density was also decreased significantly in the treated mice. Conclusion: Angiogenesis inhibitor TNP-470 has strong inhibitory effect both on tumor growth and metastasis of human gastric cancer in nude mice.     

Polyamine catabolism in colorectal cancer cells following treatment with oxaliplatin, 5-fluorouracil and N 1 , N 11 diethylnorspermine

PURPOSE: Our previous studies showed that combined treatment of oxaliplatin and N(1), N(11) diethyl-norspermine (DENSPM) results in massive induction of spermidine/spermine N(1)-acetyltransferase (SSAT) mRNA and activity. Since oxaliplatin and 5-fluorouracil (5FU) are used clinically in treatment of colorectal cancers, this study examines the effect of adding DENSPM to oxaliplatin/5FU combination on SSAT and spermine oxidase (SMO) in HCT-116 cells. METHODS: HCT-116 cells were treated with clinically relevant concentrations of drugs for 20 h followed by 24 h in drug free medium. SSAT and SMO mRNA and protein were assayed by QRT-PCR and Westerns respectively; polyamine pools were measured by HPLC. SSAT and SMO mRNA in tumor biopsies from patients with rectal cancer receiving oxaliplatin, capecitabine and radiation were measured by QRT-PCR. RESULTS: Oxaliplatin + 5FU + DENSPM produced significantly higher levels of SSAT and SMO mRNA, protein and activity than those seen with oxaliplatin+5FU with a significant depletion of cellular spermine and spermidine pools. Oxaliplatin/DENSPM was superior to 5FU/DENSPM in SSAT induction but similar for SMO. Oxaliplatin + DENSPM revealed synergistic growth inhibition at >IC(50) concentrations and antagonism at 相似文献   

Angiogenesis inhibitorO-(chloroacetyl-carbamoyl) fumagillol (TNP-470) inhibits tumor angiogenesis,growth and spontaneous metastasis of MKL- 4 human breast cancer cells in female athymic nude mice

Accumulated knowledge regarding the important roles played by angiogenesis in solid tumor growth and metastasis has prompted the development of angiogenesis inhibitors for clinical use in cancer therapy. Among these inhibitors,O-(chloroacetyl-carbamoyl)fumagillol (TNP-470) has been reported to have both antitumor and antimetastatic activities in rodent and human tumor models. We recently established a new metastasis model of MKL-4 human breast cancer cells in female nude mice. This cell line is a co-transfectant of the MCF-7 cell line with genes of a potent angiogenic factor, fibroblast growth factor 4, and a genetic marker, bacteriallacZ. In this paper, we describe the inhibitory effects of TNP-470 on tumor angiogenesis, growth and metastasis in this MKL-4 metastasis model. Subcutaneous injection of 10 or 50 mg/kg of TNP-470 every other day for two weeks obviously inhibited the tumor growth and metastasis of MKL-4 cells in female nude mice. The treatment of TNP-470 at both doses significantly reduced the tumor volumes, respectively, to 28% and 14% of that in the control group (P<0.05 in each comparison). The positive rate of metastasis into the axillary lymph nodes was 100% in the control group, whereas it was only 3396 in both of the treatment groups. Distant metastasis into the inguinal lymph nodes, lungs, kidneys and liver also tended to decrease in both of the treatment groups. Immunohisto-chemical analysis using anti-factor VIII antibody revealed that the number of microvessels in both of the treatment groups was significantly less than that in the control group (P<0.01 in each comparison). To the best of our knowledge, this is the first report describing simultaneous demonstration of the antiangiogenic, antitumor and antimetastatic effects of TNP-470 on human breast cancer cells in nude mice. This work was supported in part by a grant from the Ministry of Education, Science and Culture of Japan and by a Research Project Grant (No. 5-3O4) from Kawasaki Medical School     

血管生成抑制剂TNP-470对胃癌生长及转移抑制作用的实验研究

目的研究血管生成抑制剂ＴＮＰ－４７０对胃癌生长及转移的抑制作用。方法完整组织块裸鼠胃壁原位种植,建立类似于临床的胃癌转移模型。移植后第１周开始皮下注射ＴＮＰ－４７０,隔天１次,剂量为０ｍｇ／ｋｇ、１５ｍｇ／ｋｇ、３０ｍｇ／ｋｇ、６０ｍｇ／ｋｇ,共用８周。移植后第１０周处死动物,测量肿瘤大小,观察转移情况,以兔抗人Ⅷ因子抗体免疫组化染色检测肿瘤微血管密度。结果ＴＮＰ－４７０对体内胃癌的生长及转移均有抑制作用,ＴＮＰ－４７０剂量为１５ｍｇ／ｋｇ、３０ｍｇ／ｋｇ、６０ｍｇ／ｋｇ的抑瘤率分别为５９．９％、７７．０％和８４．９％,肝转移抑制率分别为５１．３％、８７．８％和８７．８％,腹膜转移抑制率分别为３２．８％、６６．４％和７７．６％。用ＴＮＰ－４７０治疗后,肿瘤的微血管密度明显减少。结论ＴＮＰ－４７０对体内胃癌的生长及转移均有抑制作用。