MMP-9抑制剂巴马司他对体外循环犬肺组织中iNOS表达的影响

目的研究外源性基质金属蛋白酶9（MMP-9）抑制剂巴马司他对体外循环犬肺组织中诱生型一氧化氮合酶（iNOS）的影响。方法将16只幼犬随机分成两组,建立犬的体外循环模型;在体外循环术中,实验组肺动脉内灌注含巴马司他（30 mg/kg）的肺保护液,对照组灌注不含巴马司他的肺保护液。术后3 h处死犬,在光镜和电镜下观察两组犬的肺组织病理变化,并检测肺组织中的iNOS。结果实验组较对照组肺组织再灌注病理损伤明显减轻,肺组织中iNOS表达明显减少（P〈0.05）。结论外源性MMP-9抑制剂巴马司他能减少犬肺组织中iNOS的表达,从而减轻肺组织损伤。     

POTENTIATION OF DOCETAXEL ANTITUMOR ACTIVITY BY BATIMASTAT AGAINST MOUSE FORESTOMACH CARCINOMA

INTRODUCTIONDocetaxel（Taxotere）isanewanticancerdrugre－latedtopaclitaxelobtainedbysemisynthesisfromanon－cytotoxicprecursorisolatedfromarenewablere－source—theneedlesofTaxusbaccataL（１）．Itsmecha－nismofactionappearedtoinducetubulinpolymerizationandformstablenon－functionalmicrotubuli．PhaseⅡandphaseⅢclinicaltrailsindicateditsactivityinovarian,breastandlungcancer（２）．Docetaxelhasadvantagesoverpaclitaxelinnaturalsupply,solubilityandeveneffi－cacy（３）．Thedrugtherapyofmaligna…     

The matrix metalloproteinase inhibitor batimastat inhibits angiogenesis in liver metastases of B16F1 melanoma cells

Matrix metalloproteinases (MMPs) have been shown to contribute functionally to tumor metastasis. MMP inhibitors are thus being assessed for clinical utility as anti-metastatic therapeutics. Batimastat (BB-94) is a synthetic MMP inhibitor that has been shown to inhibit tumor growth and metastasis in mice. Here we assessed the ability of batimastat to inhibit liver metastases of murine B16F1 cells, after injection of cells in mice via mesenteric vein to target the liver. We then determined which of the sequential steps in metastasis were affected by batimastat, in order to identify its mechanism of action in vivo. Intravital videomicroscopy was used to assess the effect on extravasation, and a cell accounting procedure was used to determine the effect on initial survival of cells. Stereological quantification of functional blood vessels was used to determine the effect on tumor vascularity, thereby avoiding problems associated with immunohistochemical detection of liver sinusoidal endothelial cells. We found that batimastat (50 mg/kg i.p. 5 h prior to and after cell injection, daily thereafter) resulted in a 23% reduction in mean diameter of liver metastases (equivalent to a 54% reduction in tumor volume), while not reducing the number of metastases. Extravasation of cells from the liver circulation was not affected: at 8, 24 and 48 h after injection of cells, the same proportion of cells had extravasated from treated vs. control mice. Batimastat also did not inhibit early survival of cells. However, batimastat-treated mice had a significantly reduced percentage vascular volume within liver metastases, indicating inhibition of angiogenesis. This study demonstrates in vivo that the mechanism by which batimastat limits growth of B16F1 metastases in liver is not by affecting extravasation, but by inhibiting angiogenesis within metastases. This finding suggests that MMP inhibitors may be appropriate for use in patients with metastatic cells that have already extravasated in secondary sites.     

内皮抑制素与巴马司他合用提高抗血管新生和抗肿瘤功效(英文)

目的　研究内皮抑制素与巴马司他合用的抗血管新生和抗肿瘤效果。方法　血管样管腔形成实验用来测定体外血管新生程度。通过测定血红蛋白含量检测体内血管新生程度。小鼠接种Lewis肺癌细胞 ,治疗 1 2d后测量肿瘤重量。结果　内皮抑制素在体外抑制了管腔形成数 (抑制率 33.5 % ) ,在体内减少了血红蛋白含量 (抑制率 38.8% ) ;然而在这两个实验中 ,内皮抑制素与巴马司他合用与单用内皮抑制素相比均显著提高了抑制率 (P <0 .0 5)。接受内皮抑制素的小鼠肿瘤重量减少了 46 .3% ;而接受共同治疗的小鼠肿瘤重量减少了 65 .7%。结论内皮抑制素与巴马司他合用提高了抗血管新生和抗肿瘤功效。     

多西紫杉醇单独或与巴马司他联合应用抗小鼠前胃癌转移的作用(英文)

研究细胞毒新药多西紫杉醇和第一个进入临床试验的金属蛋白酶抑制剂巴马司他 (BB- 94)单独或联合应用对小鼠前胃癌 (MFC)的抗转移作用 ,并与多柔比星做比较 .体外侵袭实验表明 :多西紫杉醇和 BB- 94均能抑制 MFC细胞侵袭并穿过重组基底膜的能力 ,而且 BB- 94可增强多西紫杉醇的这种作用 .多西紫杉醇还可抑制 MFC细胞在层粘连蛋白上的粘附作用 .体内实验表明 ,给予最大耐受剂量多西紫杉醇 (2 0 mg· kg-1)或多柔比星 (6mg·kg-1iv,每 4d1次 ,共计 3次 )和 BB- 94(30 mg·kg-1,ip,每日 1次 ,连续 2 0 d)均具有明显的抗肿瘤转移作用 .多西紫杉醇联用 BB- 94对肺转移灶的抑制率大于多柔比星联用 BB- 94,多西紫杉醇 ,多柔比星和 BB- 94,而且 BB- 94可明显增强多西紫杉醇的抗肿瘤转移作用 .     

肺动脉灌注含巴马司他肺保护液对体外循环犬肺的保护作用及机制探讨

目的探讨肺动脉持续灌注含巴马司他的肺保护液对体外循环中犬肺的保护作用,并探讨其机制。方法16只杂种犬,随机分为A、B组,各8只。常规建立体外循环,A组用不含巴马司他的肺保护液,B组用含巴马司他30mg／kg的肺保护液,流量30ml／（kg·min）灌注肺动脉。记录两组犬手术前后血气分析结果,计算肺泡—动脉氧分压差（A-aDO2）和呼吸指数（RI）。分别于转流前、停体外循环即刻、转流后1h、转流后2h采集静脉血,比色法测定血浆髓过氧化物酶（MPO）活性。体外循环结束后,取左上肺标本,光镜和电镜下观察肺组织形态学改变;取小块左肺组织称重烘烤计算肺组织湿重系数（W／D）。支气管肺泡灌洗液离心取上清液（BALF）,EIASA法测MMP-9浓度,考马斯亮蓝G-250法测总蛋白。结果转流后B组A-aDO2和RI明显低于对照组（P〈0．05）。两组血浆MPO活性相比,B组明显低于A组（P〈0．05）,B组肺湿干比重（W／D）、BALF总蛋白含量和MMP-9含量均低于A组（P均〈0．05）。肺组织病理显示肺灌注组损伤明显减轻。结论肺动脉持续灌注含巴马司他的肺保护液通过降低血MMP-9浓度和减少中性粒细胞集聚来降减轻体外循环中的肺损伤。     

Effects of an inhibitor of α-secretase, which metabolizes the amyloid peptide precursor, on memory formation in rats

Intracortical administration of 10⁻⁴ M batimastat, a specific inhibitor of α-secretase (a metalloproteinase which cleaves the amyloid peptide precursor), decreased the number of correct runs in a single-level eight-arm maze to 92.78 ± 1.03% compared with baseline (p < 0.01) within 60 min. However, injection of batimastat into the cerebral cortex of animals during the early postnatal period (days 5 and 7 of life) led to impaired orientation in the simple single-level maze when these adults reached adulthood (90.92 ± 2.21% correct runs, p < 0.001) as compared with controls. The data obtained here provide evidence for the important role of α-secretase in memory processes. The possible role of α-secretase in memory processes and the pathogenesis of Alzheimer’s disease is discussed. __________ Translated from Zhurnal Vysshei Nervnoi Deyatel’nosti imeni I. P. Pavlova, Vol. 55, No. 6, pp. 725–728, November–December, 2005.     

Bladder carcinoma: understanding advanced and metastatic disease with potential molecular therapeutic targets

This article is an expert review of bladder cancer genetics focusing on genetic changes and their significance in the pathogenesis and progression of bladder transitional cell carcinoma, in particular, muscle-invasive disease. Alongside the relevant genetic markers and their products, new therapeutic targets and agents that are being developed are presented.     

多西紫杉醇单独或与巴马司他联合应用抗小鼠前胃癌转移的作用

研究细胞毒新药多西紫杉醇和第一个进入临床试验的金属蛋白酶抑制剂巴马司他(BB-94)单独或联合应用对小鼠前胃癌(MFC)的抗转移作用,并与多柔比星做比较. 体外侵袭实验表明：多西紫杉醇和BB-94均能抑制MFC细胞侵袭并穿过重组基底膜的能力,而且BB 94可增强多西紫杉醇的这种作用. 多西紫杉醇还可抑制MFC细胞在层粘连蛋白上的粘附作用. 体内实验表明,给予最大耐受剂量多西紫杉醇(20 mg·kg^-1)或多柔比星（6 mg·kg^-1 iv, 每4 d 1次,共计3次)和BB- 94 (30 mg·kg^-1, ip, 每日1次,连续20 d)均具有明显的抗肿瘤转移作用. 多西紫杉醇联用BB-94对肺转移灶的抑制率大于多柔比星联用BB-94,多西紫杉醇, 多柔比星和BB-94,而且BB- 94可明显增强多西紫杉醇的抗肿瘤转移作用.