人附睾蛋白4在卵巢癌早期诊断中的临床价值研究

目的：探讨人附睾蛋白4(HE4)在卵巢癌早期诊断中的临床价值。方法132例盆腔肿物患者为研究对象,根据病理检测结果分成良性肿瘤组(A组, n=72)和恶性肿瘤组(B组, n=60),同时将100例健康血样标本归入对照组(C组),对比三组受试者血清中HE4水平及糖类抗原125(CA125)水平,记录其对卵巢癌的诊断指标差异。结果①B组HE4及CA125平均水平分别为(298.20±158.32)pmol/L和(449.23±201.92)pmol/L,明显高于良性肿瘤所在A组及C组检出水平(P<0.05);B组HE4及CA125阳性检出率分别为100.00%及81.67%,明显高于A、C两组,差异均具有统计学意义(P<0.05),且HE4检出率优于CA125(P<0.05);②对卵巢癌患者给予HE4联合CA125检测,灵敏度可达89.92%,高于单项检测灵敏度(P<0.05)。结论对疑似卵巢癌患者给予HE4和CA125水平检测,可有效提升该疾病早期诊断准确率,值得临床推广。     

Combretastatin A4磷酸酯二钠抑制血管生成作用的研究

目的 探讨Combretastatin A4磷酸酯二钠(CA4P)对血管生成的影响.方法 建立鸡胚绒毛尿囊膜(CAM)模型及兔角膜新生血管(CNV)模型,评价CA4P对两种模型中血管生成的影响.结果 与对照组相比,CA4P高、中剂量具有明显的抑制CAM血管生成的作用(P<0.01或P<0.05);CA4P各剂量对CNV也显示了不同程度的抑制作用(P<0.01或P<0.05).结论 CA4P具有抑制血管生成的作用.     

抗肿瘤新药——Combretastatin A4磷酸酯

CA4磷酸酯(Combretastatin A4phosphate,CA4P)系从非洲植物中提取出的血管损伤剂(Vascular Disrupting Ag_ents,VDA)类抗肿瘤药前体,合成后的CA4P与CA4相比水溶性增强,有关CA4P制剂已进行了一系列离体及临床研究。CA4P不同于传统微管蛋白抑制剂,在小于1/10最大耐受剂量(MTD)时即可发挥抗肿瘤作用,导致肿瘤血管关闭、坏死[1]。临床前试验表明,CA4P对靶细胞选择性高,只破坏肿瘤血管细胞而不损坏正常组织细胞[2]。近年来的研究发现,CA4P与细胞毒化疗法如放射、放射免疫疗法及抗血管生成剂(Antiangiogenic agents)等有协同作用。…     

NF-κB基因多态性与中国汉族2型糖尿病及其血管并发症的关系研究

目的探讨NF-κB的(CA)基因多态性与2型糖尿病(T2DM)及其血管并发症的相关性。方法分析了140例T2DM组和100例健康对照组(CON)NF-κB的(CA)重复序列的多态性。结果 1、A4、A5、A7、A8、A9、A10为中国汉族人常见等位基因;A9可能为参与T2DM发病的基因,而A5可能为避免发生T2DM的基因。2、发现40种基因型,正常人群以基因型A4/A5及A5/A5为主;T2DM患者以A4/A9基因型为主。结论 NF-κB基因在T2DM的易感性上起了非常重要的作用:A9(132bp)可能为其致病基因,A(5124bp)可能为其保护基因。     

血清胸苷激酶1与CEA、CA125、CA72-4、CYFRA211、NSE联合检测在肺癌诊断中的价值

目的探讨血清胸苷激酶1(TK1)与癌胚抗原(CEA)、糖类抗原125(CA125)、糖类抗原72-4(CA72-4)、细胞角蛋白片段21-1(CYFRA21-1)、神经元烯醇化酶(NSE)等肿瘤标志物联合检测对肺癌诊断的价值。方法采用免疫印迹增强化学发光法检测49例肺癌患者(A组)、32例肺部良性疾病患者和29例健康体检者(B组)血清TK1、CEA、CA 125、CA72-4、CYFRA21-1、NSE的水平。结果 TK1对肺癌诊断的敏感度为77.55%,特异度为93.44%。以上6项指标联合检测的敏感度和准确度分别为88.24%和90.91%。结论联合检测血清TK1、CEA、CA 125、CA72-4、CYFRA21-1、NSE的水平在提高敏感度的同时,也提高了肺癌诊断的准确度。     

Value of combined measurements of serum thymidine kinase 1,CEA, CA125, CA72-4,CYFRA21-1 and NSE in diagnosis of lung cancer

目的 探讨血清胸苷激酶1(TK1)与癌胚抗原(CEA)、糖类抗原125(CA125)、糖类抗原72-4(CA72-4)、细胞角蛋白片段21-1(CYFRA21-1)、神经元烯醇化酶(NSE)等肿瘤标志物联合检测对肺癌诊断的价值.方法 采用免疫印迹增强化学发光法检测49例肺癌患者(A组)、32例肺部良性疾病患者和29例健康体检者(B组)血清TK1、CEA、CA125、CA72-4、CYFRA21-1、NSE的水平.结果 TK1对肺癌诊断的敏感度为77.55％,特异度为93.44％.以上6项指标联合检测的敏感度和准确度分别为88.24％和90.91％.结论 联合检测血清TK1、CEA、CA 125、CA72-4、CYFRA21-1、NSE的水平在提高敏感度的同时,也提高了肺癌诊断的准确度.     

CEA、CA19-9、CA72-4及CA242在胃癌诊断中的应用价值

目的观察探讨CEA、CA19-9、CA72-4及CA242在胃癌诊断的应用价值。方法选取我院2011年1月至2012年12月经内镜活检加病理证实为胃癌的患者80例,设为观察组A,经内镜活检加病理证实为良性胃病的患者84例,设为观察组B,再选取我院同期体检健康的人群90例,作为对照组,观察对比两组患者血清中CEA、CA19-9、CA72-4及CA242的检测结果。结果观察组A血清中CEA、CA19-9、CA72-4及CA242水平皆明显高于观察组B和对照组(P<0.05),观察组B血清中CEA、CA19-9、CA72-4及CA242与对照组相比差异不明显(P>0.05)。结论通过检测血清中CEA、CA19-9、CA72-4及CA242可协助临床早期诊断及鉴别诊断胃癌,及早为临床治疗提供可靠的参考依据。     

柯萨奇病毒A组16型感染性滴度检测用国家参考品的制备及标定

目的 制备柯萨奇病毒A组16型(coxsackievirus A16,CA16)感染性滴度检测用国家参考品,为CA16疫苗生产过程中的病毒滴度控制和CA16疫苗的免疫效果评价提供国家参考品.方法 将验证合格的CA16(C1亚型)培养液分装(0.5 ml/支)制成候选参考品.3个独立实验室分别对候选参考品进行协作标定,用细胞培养法检测CA16感染性滴度,用Behrens-K(a)rber法计算半数细胞感染量(50％ cell culture infective does,CCID50).同时,将CA16参考品分别置于-20、4、22～25(室温)和37℃条件下或反复冻融,进行热稳定性、长期稳定性和冻存稳定性研究.结果 制备的CA16参考品的病毒滴度为(6.80±0.95) lgCCID50/ml.CA16参考品于-60℃保存12个月、-20℃保存6个月和4℃保存28 d后的病毒滴度无显著下降,表明稳定性较好;在22～25℃(室温)和37℃条件下,CA16参考品每天的病毒滴度损失率分别为3.4％和4.4％,而且分别保存27和21 d后病毒滴度无明显下降;对CA16参考品反复冻融的病毒滴度损失率为4.8％/次.结论 成功制备了CA16感染性滴度检测用候选国家参考品,将CA16参考品赋值确定为(6.80±0.95) lgCCID50/ml.     

血清D-二聚体与CEA、CA72-4联合检测在胃癌诊断中的价值

目的:探讨血清D-二聚体与肿瘤标志物癌胚抗原(CEA)、糖类抗原72-4(CA72-4)联合检测在胃癌诊断中的价值。方法:将100例胃癌患者为(A组)、50例胃良性疾病患者为(B组)、50例健康体检者为(C组),通过免疫比浊法及放射免疫分析法检测三组的血清D-二聚体、CEA、CA72-4水平。结果:A组患者上述3项指标均高于B组和C组(P0.05)。Ⅱ期胃癌患者的血清CA72-4和Ⅲ、Ⅳ期胃癌患者的上述3项指标均高于C组(P0.05)。CEA+CA72-4+D-二聚体联合检测的胃癌诊断灵敏度最高(91.00%)。结论:胃癌患者血清D-二聚体、CA72-4、CEA水平随肿瘤临床分期的进展而明显升高。其中,D-二聚体阳性检出率最高,与肿瘤标志物联合检测可进一步提高胃癌诊断灵敏度。     

Combretastatin A4磷酸酯二钠在大鼠体内的药物动力学

目的研究前药Combretastatin A4磷酸酯二钠(CA4P)在大鼠体内生成Combretastatin A4(CA4)的药物动力学。方法采用HPLC法测定iv10、20mg·kg-1CA4P后,大鼠体内不同时间点的原药CA4的血药浓度。药-时数据经DAS统计软件拟合处理。结果两个剂量组的CA4在大鼠体内的过程均符合二室模型,t1/2β分别为34.427±2.849、30.076±3.107min;Vd分别为1.402±0.178、1.568±0.131L·kg-1;Cl分别为0.061±0.003、0.058±0.003L·min-·1kg-1;AUC0-t分别为132.393±3.144、291.872±15.555mg·L-·1min。结论静注CA4P后,CA4在大鼠体内以二室模型的规律快速代谢和消除。     

一系列新型虫草素衍生物的设计、合成及其抗肿瘤活性研究

本研究合成了一系列6位嘌呤环取代苯磺酰胺基团的虫草素衍生物,并对其进行了抗肿瘤活性研究.我们对虫草素衍生物具有抗肿瘤活性的药效结构部分做了初步探讨.在MDA-MB-231和A549细胞的抗增殖活性实验中,苯环上有4-甲基和4-硝基取代基的化合物活性优于先导化合物.然而,在HeLa细胞的抗增殖活性实验中,4-甲氧基苯、2...     

Potential antitumor agents. 56. "Minimal" DNA-intercalating ligands as antitumor drugs: phenylquinoline-8-carboxamides

A series of isomeric phenylquinoline-8-carboxamides have been synthesized and evaluated as antitumor agents. This configuration is close to the minimum chromophore required for intercalative binding, since the binding mode of the compounds is dependent on the presence and position of the phenyl ring. If the ring is appended at the 4- or 5-position, it cannot lie within the DNA-intercalation site, and the compounds do not intercalate as shown by both unwinding and helix extension assays. In contrast, the 2-, 3-, and 6-phenyl isomers (where the phenyl ring lies coplanar with the quinoline and in the intercalation site) bind by intercalation. Only those isomers that intercalate show in vivo antitumor activity, with the 2-phenyl derivative in particular possessing broad-spectrum activity in both leukemia and solid-tumor assays.     

Synthesis and structure-activity relationship studies of 2,3-dihydroimidazo[2,1-a]isoquinoline analogs as antitumor agents

5-Aryl-2,3-dihydroimidazo[2,1-a]isoquinolines were reported to have strong antitumor activity and one of the derivatives such as 5-[4′-(piperidinomethyl)phenyl]-2,3-dihydroimidazo[2,1-a] isoquinoline (1, SDZ 62–434) was found to be more effective than the clinical cytostatic agent edelfosine (2) inin vitro andin vivo assays. Currently SDZ 62–434 is in clinical trials in Europe. The structure-activity relationship studies of SDZ 62–434 showed that compounds with substitution on ring A were less active than the lead compound. Ring B in SDZ 62–434 was essential for the activity because compounds without B ring had no antitumor activity. Among the 3-arylisoquinolin-1-one derivatives, 3-[4′-(piperidonomethyl)phenyl] substituted analog had no antitumor activity but simple phenyl substituted compound, such as4, showed the most potent antitumor activity in various human tumor cell lines.     

Synthesis and structure-activity relationships of potential anticancer agents: alkylcarbamates of 3-(9-acridinylamino)-5-hydroxymethylaniline

A series of potential 9-anilinoacridine antitumor agents, 3-(9-acridinylamino)-5-hydroxymethylaniline (AHMA) derivatives with monosubstituent at C4' and disubstituents at C4' and C5' of the acridine ring and their alkylcarbamates, were synthesized for evaluation of their antitumor activity. A structure-activity relationship (SAR) study showed that the AHMA-alkylcarbamates were more potent than their corresponding parent AHMA compounds. In addition, the cytotoxicity of the AHMA-alkylcarbamate decreased with increasing length and size of the alkyl function. Among these compounds, AHMA-ethylcarbamate (18) and 4'-methyl-5'-dimethylaminoethylcarboxamido-AHMA-ethylcarb amate (34) possess potent cytotoxicity on the inhibition of human leukemic HL-60 cell growth in culture. Further in vivo studies of these compounds displayed significant anticancer therapeutic effects in mice bearing sarcoma 180, Lewis lung carcinoma, and P388 leukemia.     

抗癌新药石蒜内铵(AT-1840)构效关系研究

自翁尊尧等合成并发现石蒜内铵(lycobetain,AT-1840,Ⅰ)的抗癌活性和不抑制骨髓造血功能的作用机理以来,已对其构效关系进行了一些研究,主要得出以下结论:石蒜内铵Ⅰ分子中的亚甲二氧基和由酚羟基与季铵基组成的内铵盐部分对其抗癌活性是必需的,五元氮杂环部分对石蒜内铵的抗癌活性则没有明显的影响。     

Synthesis of water-soluble (aminoalkyl)camptothecin analogues: inhibition of topoisomerase I and antitumor activity.

Water-soluble analogues of the antitumor alkaloid camptothecin (1) were prepared in which aminoalkyl groups were introduced into ring A or B. Most of the analogues were prepared by oxidation of camptothecin to 10-hydroxycamptothecin (2) followed by a Mannich reaction to give N-substituted 9-(aminomethyl)-10-hydroxycamptothecins (4-12) or by subsequent modification of Mannich product 4 (13, 15, 17, 19, 21). Others were obtained by modification of the hydroxyl group of 2 (25,26) or by total synthesis (35,42,43). These analogues, as well as some of their synthetic precursors, were evaluated for inhibition of topoisomerase I, cytotoxicity, and antitumor activity. Although there was not a quantitative correlation between these assays, compounds that inhibited topoisomerase I were also cytotoxic and demonstrated antitumor activity in vivo. Further evaluation of the most active water-soluble analogue led to the selection of 9-[(dimethylamino)methyl]-10-hydroxycamptothecin (4, SK&F 104864) for development as an antitumor agent. In addition to its water solubility, ease of synthesis from natural camptothecin, and high potency, 4 demonstrated broad-spectrum activity in preclinical tumor models and is currently undergoing Phase I clinical trials in cancer patients.     

Antitumor agents. 78. Inhibition of human DNA topoisomerase II by podophyllotoxin and alpha-peltatin analogues

It has been reported that the action of etoposide (VP-16) (14) as an antitumor agent is mediated through its interaction with DNA topoisomerase II which results in DNA breakage inside the cell. In order to understand the mechanism of action as well as structure-activity relationships of 14, several novel, synthetic and some naturally occurring analogues related to podophyllotoxin were examined for inhibition of the DNA topoisomerase II activity. Compound 2 exhibited enhanced activity and compound 5 slightly diminished activity relative to 14. A 4 beta-substituted ether at the C ring and O-demethylation at the E ring appear to enhance activity.     

Structural studies on bioactive compounds. 8. Synthesis, crystal structure, and biological properties of a new series of 2,4-diamino-5-aryl-6-ethylpyrimidine dihydrofolate reductase inhibitors with in vivo activity against a methotrexate-resistant tumor cell line

A series of 2,4-diamino-5-aryl-6-ethylpyrimidines embracing basic substituents in the 5-aryl ring was synthesized and evaluated for inhibitory activity against rat liver dihydrofolate reductase (DHFR). Maximal enzyme inhibition was observed for compounds bearing a benzylamino (19) or N-alkylbenzylamino substituent (29 and 30) in the 4-position of the phenyl ring and a nitro group in the 3-position, the corresponding 3-amino, 3-azido, or unsubstituted analogues proving only weakly active or inactive as DHFR inhibitors. Selected compounds were also screened in vivo against a methotrexate-resistant tumor, the M5076 murine reticulosarcoma, and antitumor activity in general paralleled activity against DHFR, the (3,4-dichlorobenzyl)amino analogue 26 proving the least toxic compound to exhibit significant antitumor activity. The X-ray crystal structure of the ethanesulfonic acid salt of the N-methylbenzylamino compound 29 has been determined to facilitate future molecular modeling studies in this new series of DHFR inhibitors.     

Synthesis of antineoplaston A10 analogs as potential antitumor agents

Several aniline mustard analogues were obtained by introducingN,N-bis(2-chloroethyl)amino moiety to phenyl ring of A10 analogues in order to increase reactivity of A10 analogs and selectivity into DNA. Thein vitro antitumor activity of synthesized compounds was evaluated using five different solid tumor cell lines by SRB method. Aniline mustard analogues exhibited more potent antitumor activity than A10 analogs. Especially,m-aniline mustard of benzoyl analogue displayed remarkable antitumor activity.     

Synthesis and antitumor activity evaluation of novel oleanolic acid derivatives

Ten novel oleanolic acid (OA) derivatives were synthesized through modifications at positions of A ring and C-28. Inhibitory activities of the oleanolic acid derivatives against SGC7901 and A549 cell lines were evaluated and confirmed by the tetrazolium bromidesalt (MTT) assay. The lab results revealed that all these compounds displayed some antitumor activity against SGC-7901 and A-549 cell lines. Among them, II₄ and II₅ exhibited excellent antitumor activities against SGC7901 cells and A549 cells, compared with gefitinib. Molecular docking studies have shown that compounds II₄ and II₅ produce potent antitumor activities by interacting with C-kit receptor through hydrogen bonds and hydrophobic bonds.