反应停对人癌裸鼠肿瘤及新血管形成的影响

目的:观察反应停对人卵巢癌细胞(OVCAR-3)及人结肠癌细胞(HCT-8)生长及肿瘤组织内新血管形成的影响。方法:建立人癌裸鼠异种移植的模型,将接种肿瘤后的裸鼠分别灌胃给予不同剂量的反应停,并与正常对照组进行比较,观察肿瘤生长的情况;采用免疫组化检验方法检测肿瘤组织中微血管密度(MVD)。结果:对人癌裸鼠OVCAR-3肿瘤,反应停中、高剂量组均可显著抑制肿瘤生长(P<0.05、P<0.01),对HCT-8的生长却无明显影响,但反应停均呈剂量依赖性降低上述肿瘤组织MVD。结论:反应停的抗肿瘤作用可能与抗新血管形成作用无关。     

反应停的抗新生血管形成及抗肿瘤作用研究

目的　研究反应停的抗新生血管形成及抗肿瘤作用。方法　在HUVECs中MTT法检测细胞活性,电镜观察细胞死亡类型,流式细胞仪定量细胞凋亡率;用鸡胚尿囊膜模型观察新生血管形成;肉瘤S180小鼠体内模型观察反应停的抗肿瘤作用,并通过免疫组化观察反应停对肿瘤组织微血管数的影响。结果　反应停对HUVECs有直接抑制作用,IC50为(22 .91±1. 74) μmol·L-1;经反应停作用48h后的HU VECs,随剂量增加,电镜下可见核不规则,染色体浓集,空泡状内质网及凋亡小体等不同时期细胞凋亡现象;流式细胞检测显示反应停可依剂量诱导HUVECs凋亡或坏死;鸡胚尿囊膜新生血管形成模型中,反应停抑制新生血管形成的阳性率随剂量而增加;小鼠S180肿瘤移植模型中,反应停单独使用,虽可明显减少肿瘤血管密度, 无抑制肿瘤生长作用;与环磷酰胺联合使用,可减少环磷酰胺用量,与环磷酰胺有协同抗肿瘤作用。结论　反应停有抗新生血管形成作用,单独应用对小鼠S180肿瘤无抑制作用,但与环磷酰胺有协同作用。     

从赤组织中分离到的福安肽的抗肿瘤活性的初步研究

目的研究从赤组织中分离到的福安肽(Fuantai,FAT)的抗肿瘤活性及对促血管生成因子表达的影响。方法MTT法检测FAT对体外培养的人癌细胞生长的影响;小鼠移植性肝癌(H22)模型用于检查FAT对肿瘤生长的影响;免疫组化法检查福安肽对癌组织促血管生成因子表达的影响。结果FAT对体外培养的人早幼粒白血病细胞(HL-60)、人子宫颈癌细胞(HeLa)和人低分化鼻咽癌细胞(CNE-2Z)的生长无明显影响;FAT无论腹腔注射还是灌胃都显著抑制小鼠移植性肝癌的生长,且对小鼠体重增长无明显影响。当FAT的用量为50.0 mg/(kg.d)(ip或ig)共21 d对H22的抑制率分别为67.5%和84.0%。免疫组化检测结果显示,FAT明显下调小鼠肝癌组织血管内皮细胞生长因子,碱性成纤维细胞因子和血小板衍生生长因子的表达。结论FAT的抗肿瘤活性可能与其抑制肿瘤血管生成有关。     

牛蒡子苷元诱导人白血病细胞凋亡的作用及机制

牛蒡子来源于菊科两年生草本植物牛蒡子属牛蒡(Aictium lappa L.)的干燥成熟果实,为常用中药.有疏风散热、解毒透疹、利咽消肿等功效,现代药理学研究表明牛蒡子有抗病毒[1,5]、抗炎[2]、抗癌[3,4]、抑制热休克反应[6]等广泛的药理活性.其主要活性成分是牛蒡子苷元(arctigenin,ARG)[1].     

Paclitaxel is more effective than thalidomide in inhibiting LNCaP tumor growth in a prostate cancer model

LNCaP tumors were treated by either administration of paclitaxel, thalidomide or by orchiectomy in order to determine their relationship with markers pertaining to the process of tumor growth, apoptosis or angiogenesis. Forty rats bearing LNCaP tumors were divided into 4 groups of 10 and treated by either paclitaxel (20 mg/kg x 5 days); thalidomide (200 mg/kg x 5 days/week x 5 weeks); or orchiectomy. After 6 weeks serum samples were removed for PSA determination and the animals sacrificed for evaluation of: A) tumor volume; B) tissue bcl-2, cyclin D, PSA and factor VIII immunohistochemically graded (0-5 scale) for marker expression; and C) serum PSA. Comparisons were made to untreated LNCaP tumors. Statistically significant differences were determined using the nonparametric Mann-Whitney test. Paclitaxel produced significant differences in volume (p < 0.001), expression of bcl-2 (p < 0.043), cyclin D (p < 0.023), tissue PSA (p < 0.001) and serum PSA (p < 0.019) levels. Thalidomide altered expression of bcl-2 (p < 0.011) and tissue PSA (p < 0.002). Orchiectomy altered volume (p < 0.002) and bcl-2 expression (p < 0.001). All three therapies have been suggested for prostate cancer and each produced alterations in accepted markers for treatment response (either reduced volume or serum PSA). Paclitaxel significantly influenced the most markers. Of interest was that all treatments, especially thalidomide, a known antiangiogenesis agent, reduced factor VIII, although not significantly. Evidently each treatment evokes different pathways of activity.     

沙利度胺对人慢性粒细胞白血病细胞株K562细胞凋亡的影响研究

目的:研究沙利度胺对人慢性粒细胞白血病细胞株K562细胞凋亡的影响。方法:将K562细胞分为对照(未加药)组和沙利度胺低、中、高剂量(0·5、1·0、2·0mmol·L-1)组,加入相应药物分别作用24、48、72、96h后,MTT法检测各组细胞生长抑制率,Wright-Giemsa染色观察各组细胞形态变化,AnnexinⅤ-FITC/PI双染法流式细胞仪检测各组细胞凋亡率。结果:K562细胞的生长抑制率和凋亡率与沙利度胺浓度和作用时间均呈正相关;与对照组比较,沙利度胺3个剂量组作用72、96h后细胞的生长抑制率明显升高(P<0·05),4个时间点的细胞凋亡率均明显升高(P<0·01)。沙利度胺3个剂量组作用72h后,K562细胞出现细胞体积缩小等凋亡形态。结论:沙利度胺能够抑制K562细胞的增殖,呈一定的浓度和时间依赖性,并能够诱导K562细胞的凋亡。     

槐果碱和氧化槐果碱抗肿瘤药理作用的研究进展

经体外实验发现,槐果碱能浓度相关地抑制肝癌细胞(HepG2、9711、SMMC-7721、HCC-LM3、MHCC-97H)、大肠癌(SW480、LS174t、SW620、HCT-116)以及食管癌EC109、胃癌BGC823、白血病(K562、HL-60)、淋巴瘤U937、肺癌A549、神经胶质瘤C6、卵巢癌(SKOV3、PM-2)等细胞的增殖。氧化槐果碱可抑制HepG2、SW480、LS174t、BGC823、C6、乳腺癌MCF-7等细胞的增殖。整体实验结果发现,槐果碱能抑制HCC-LM3、肉瘤W256、S37、S180、EAC、Lio 1、白血病615(L615)、宫颈癌14(U14)等细胞移植瘤在小鼠或大鼠体内的生长。临床上槐果碱还可用于治疗恶性葡萄胎。文中综述槐果碱和氧化槐果碱抗肿瘤细胞作用的文献,并对其研究进展做了分析。     

沙利度胺对A549细胞体外增殖的影响及其作用机制

目的探讨沙利度胺对人非小细胞肺癌细胞株A549体外增殖和其对A549细胞中血管内皮生长因子(VEGF)和血管内皮生长因子C(VEGF-C)表达的影响。方法体外培养A549细胞株,分为对照组和沙利度胺组,后者分别加入不同质量浓度(5,10,20,40,60 mg/L)的沙利度胺体外培养24 h。采用MTT法检测对A549细胞增殖的抑制率,采用RT-PCR和Western-blot方法分别检测各组VEGF和VEGF-C mRNA和蛋白水平的表达。结果沙利度胺体外能抑制A549细胞增殖,呈浓度依赖性(P<0.05)。不同浓度沙利度胺作用于A549细胞后,VEGF和VEGF-C mRNA和蛋白水平的表达均降低(P<0.05)。结论沙利度胺体外能抑制A549细胞的增殖,呈浓度依赖性,其作用机制可能与沙利度胺下调VEGF及VEGF-C的表达有关。     

沙利度胺对胶原诱导型关节炎大鼠关节炎症的抑制作用及其机制探讨

目的研究沙利度胺对胶原诱导型关节炎大鼠的关节炎症及血浆血管内皮生长因子(VEGF)表达的影响。方法采用胶原诱导型关节炎(CIA)大鼠为动物模型,经给予沙利度胺治疗,测定不同时间点大鼠的足爪厚度、血浆VEGF浓度,进行踝关节病理评分和放射学检查,并与正常对照组、单纯造模组、甲氨蝶呤治疗组相比较。结果沙利度胺可以有效减轻CIA大鼠足爪肿胀程度,降低血浆VEGF浓度,疗效与甲氨蝶呤相似。结论沙利度胺可以通过影响VEGF的表达,抑制滑膜炎症及周围组织破坏,有效减轻CIA大鼠关节的炎症程度。     

Enhancement of all-trans retinoic acid-induced HL-60 cell differentiation by thalidomide and its metabolites

Thalidomide (Thal: 1) and its two metabolites, 5-hydroxythalidomide (5-HT: 2) and N-hydroxythalidomide (N-HT: 3), showed an enhancing effect on all-trans retinoic acid (ATRA)-induced HL-60 cell differentiation. 5-HT and N-HT showed tubulin polymerization-inhibiting activity, but thalidomide did not.     

沙立度胺抗肿瘤作用机制与临床应用研究进展

沙立度胺最初作为一种镇静止吐剂用于治疗妊娠呕吐,但由于其严重的致畸作用被禁用。近年来研究发现沙立度胺具有抑制新生血管形成及免疫调节等活性被广泛用于多种恶性肿瘤治疗的研究,并在多发性骨髓瘤(MM)及多种实体肿瘤的治疗中显示了良好的疗效。该文就沙立度胺抗肿瘤的作用机制及抗肿瘤临床应用研究进展做一综述。     

Slit2/Robo1信号在胃肠道血管畸形发病机制中的作用以及沙利度胺对其表达的影响

目的：探讨Slit2/Robo1信号在胃肠道血管畸形发病机制中的作用以及沙利度胺对其表达的影响。方法：收集7例胃肠道血管畸形患者血管病变组织与正常黏膜组织,分别检测Slit2,Robo1,VEGF基因和蛋白水平的表达。体外培养原代人脐静脉内皮细胞至对数生长期,同步化后用不同浓度的沙利度胺（50、100、200mg/L）作用24-48小时后,实时定量PCR法测定处理组与溶剂对照组的Slit2,Robo1,VEGF mRNA表达水平,免疫印迹方法测定Slit2,Robo1,VEGF蛋白表达水平。结果：显示胃肠道血管畸形患者血管病变组织中Slit2,Robo1,VEGF基因及蛋白表达水平显著高于正常黏膜组织。沙利度胺能够明显抑制Slit2,Robo1,VEGF基因与蛋白的表达。结论：Slit2,Robo1可能与胃肠道血管畸形的发病相关,而沙利度胺可抑制其表达,这一作用可能是沙利度胺抑制血管生成,从而治疗GIVM的机制之一。     

沙利度胺联合孕三烯酮对大鼠子宫内膜异位症血管生成的影响

目的探讨沙利度胺、孕三烯酮及两者联合用药对大鼠子宫内膜异位组织中血管生成的影响。方法24只子宫内膜异位症模型SD大鼠,随机分为模型对照、沙利度胺(20mg·kg-1·d-1)、孕三烯酮(0.5mg·kg-1·d-1)及联合用药(沙利度胺20mg·kg-1·d-1和孕三烯酮0.5mg·kg-1·d-1)4组,每组6只。药物溶于生理盐水中腹腔注射给药,模型对照组每日腹腔注射生理盐水2mL。给药4wk后处死,免疫组织化学SP法测定血管内皮生长因子(VEGF)和肿瘤坏死因子α(TNF-α)在异位内膜的表达,并通过Ⅷ因子标记异位子宫内膜血管,检测异位内膜组织中微血管密度(MVD)。结果沙利度胺组、孕三烯酮组及联合用药组异位内膜MVD、VEGF和TNF-α的表达均显著低于模型对照组(P<0.01),其中联合用药组MVD和VEGF比沙利度胺组和孕三烯酮组降低得更为显著(P<0.05),联合用药组TNF-α与孕三烯酮组无显著差异(P>0.05)。结论沙利度胺和孕三烯酮可抑制大鼠异位内膜的MVD、VEGF和TNF-α的表达,从而抑制子宫内膜异位症血管生成,当两者联合用药时,作用更强。     

槐定碱的抗肿瘤药理作用研究进展

体外实验发现槐定碱能浓度相关地抑制大肠癌LS174t细胞、SW620细胞、SW480细胞、HCT-116细胞,胃癌BGC823细胞、MGC-803细胞、SGC7901细胞、MKN45细胞、MKN28细胞,胰腺癌capan-1细胞,肝癌97H细胞、Bel细胞、HepG2细胞,食管癌EC109细胞,食管胃交界腺癌OE-19细胞、SK-GT2细胞,白血病K562细胞、HL60细胞,淋巴瘤U937细胞,骨髓瘤NS-1细胞,乳腺癌MCF-7细胞,卵巢癌PM-2细胞、SKVO3细胞,宫颈癌HeLa细胞,肺癌A549细胞、NCI细胞,DMS153细胞,黑素瘤A375细胞,舌鳞癌TCA8113细胞,神经胶质瘤U87细胞、U87MG细胞,前列腺癌PC3细胞增殖。整体实验发现槐定碱抑制SW480细胞、HCT-116细胞,白血病L1210细胞,肺癌Lewis细胞,肉瘤S180细胞、S37细胞、W256细胞、EAC细胞移植瘤在小鼠或大鼠体内生长。临床上槐定碱已被试用于治疗恶性滋养细胞肿瘤、消化道肿瘤、恶性淋巴瘤,有开发成抗肿瘤新药的潜力。     

Biological evaluation of a new family of aminosteroids that display a selective toxicity for various malignant cell lines

This study investigated the antineoplasic potential of a new family of aminosteroids. The antiproliferative activity of seven 5α-androstane-3α,17β-diol derivatives selected from a screening study was measured on nine cancerous cell lines (HL-60, K-562, LNCaP, PC-3, Shionogi, MCF-7, MDA-MB-231, BT-20, and OVCAR-3) and two normal cell lines (peripheral blood lymphocytes and WI-38). The aminosteroids efficiently inhibited the cell growth of seven cancer cell lines [inhibitory concentration (IC(50)) values=0.2-6.4 μmol/l] and showed weak toxicity on normal cell lines. Two representative aminosteroids were tested and found to induce apoptosis and a G0/G1 cell cycle block in HL-60-treated cells, but not terminal myeloid differentiation. By a nuclear morphology analysis with fluorescence microscopy, typical apoptotic morphological changes were exhibited by treated cells. One aminosteroid tested in vivo (xenograft model) reduced the breast cancer (MCF-7 cells) tumor growth induced in nude mice. Furthermore, the information gathered suggests that this family of aminosteroids induced growth inhibition cells by arresting the cell cycle and triggering apoptosis.     

二氢青蒿素联合环氧化酶2抑制剂抗S180肉瘤作用机制研究

目的探讨二氢青蒿素联合环氧化酶2抑制剂对S180肉瘤的生长抑制作用及其可能的机制。方法采用ICR小鼠皮下移植瘤模型,观察二氢青蒿素联合环氧化酶2抑制剂对小鼠S180肉瘤生长抑制作用,以及对肿瘤COX-2、VEGF、CD31蛋白表达与白细胞数目的影响。结果二氢青蒿素分别以50、100、150mg·kg-1剂量与环氧化酶2抑制剂美洛昔康10mg·kg-1剂量合用能明显抑制S180肉瘤的生长,抑瘤率最高达55.38%,优于两药单用的效果;免疫组织化学检测表明,3个剂量的二氢青蒿素合用环氧化酶2抑制剂的肿瘤组织COX-2、VEGF及CD31蛋白的表达量均下降;Westernblot方法检测得在高剂量二氢青蒿素(150mg.kg-1.d-1)联合应用美洛昔康(10mg.kg-1.d-1)组VEGF和COX-2蛋白的表达量均有下降,与模型对照组差异有显著性(P<0.05);RT-PCR检测得各合用药物组的肿瘤组织VEGFmRNA表达量均减少(P<0.05)。结论二氢青蒿素联合环氧化酶2抑制剂能明显抑制S180肉瘤的生长,其机制可能与下调肿瘤组织中COX-2和VEGF的表达有关。     

Differential alteration by thalidomide of the glutathione content of rat vs. rabbit conceptuses in vitro

Thalidomide has been shown to cause limb reduction defects in rabbits with much greater potency than in rats, possibly due to inherent biochemical differences between the two species. Whole embryo culture was used to make direct comparisons between thalidomide-sensitive New Zealand White rabbits and thalidomide-resistant Sprague-Dawley rats, focusing on the possible roles of glutathione (GSH) and cysteine in mechanisms of thalidomide teratogenicity. Conceptuses were treated by adding thalidomide (0, 5, 15, and 30 μM) directly to the culture media containing conceptuses of similar gestational stages. Embryos and visceral yolk sacs (VYS) were measured for changes in GSH and cysteine content using HPLC after 24 h of exposure in vitro. Thalidomide-induced (15 and 30 μM) depletion of VYS GSH occurred only in the rabbit, where GSH concentrations (pmol/μg protein) fell significantly to about 50% of control. Rat VYS did not show a significant GSH depletion at any thalidomide concentration tested. Comparison between species showed that the control rabbit VYS contained 35% less GSH than the control rat VYS. Control rat embryos and control rabbit embryos contained similar concentrations of GSH, but thalidomide treatment preferentially depleted GSH in the rabbit at lower thalidomide concentrations (5 μM). Cysteine concentrations were not significantly altered from control in the embryo or VYS of either species when treated with thalidomide. However, although control cysteine concentrations did not differ significantly between rat and rabbit VYS, control cysteine levels in rabbit embryos were 65% lower than those in control rat embryos. Rabbit conceptuses displayed lower species-specific GSH and cysteine levels and a greater propensity for thalidomide-induced GSH depletion than in rat conceptuses, consistent with the greater sensitivity of the rabbit to thalidomide teratogenicity. These thalidomide-induced and inherent species differences implicate a possible role for GSH and redox status in the mechanisms of thalidomide teratogenicity.     

沙利度胺联合用药抗肿瘤研究进展

20世纪60年代沙利度胺因其具有致畸性而退出历史舞台,后来研究发现其致畸现象的背后是抗血管生成的作用。而抗血管生成作用这时已被学术界认为是对抗肿瘤生成的一个重要因素。后来,研究人员又发现了沙利度胺的其他抗肿瘤机制,这样沙利度胺便被作为一种极具潜力的抗肿瘤药物而被广泛研究。本文重点综述了沙利度胺的抗肿瘤作用机制以及它与其他药物联合用药用于治疗实体瘤的研究进展。