樟脑胺氯乙酸铂对L1210白血病细胞生物大分子的影响

樟脑胺氯乙酸铂(camphoramine chloroacetic platinum,CCP)是一新的抗癌铂类化合物。本文报道其对小鼠L₁₂₁₀白血病细胞DNA,RNA和蛋白质含量及合成代谢的影响,结果表明、CCP可使细胞内DNA,RNA及蛋白质含量有不同程度的下降,并可明显抑制DNA的合成。采用同位素、荧光探针技术初步分析讨论了CCP对DNA的作用方式。结果提示CCP可能是DNA模板损伤型药物,与DNA发生共价及非共价结合。     

樟脑胺氯乙酸铂对DNA模板的影响

本文报道樟脑胺氯乙酸铂(camphoramine chloroacetic platinum,CCP)对DNA模扳的影响。采用同位素、紫外光谱,粘度测定等技术,分析和讨论了CCP与DNA结合方式和对DNA二级结构的影响。结果表明,CCP可能以顺式双配位基形式与DNA发生共价结合,产生链内及链间交联,从而损伤了DNA模板,使DNA对碱及温度的敏感性增加,分子变短,粘度下降,最终抑制了DNA复制。     

铜(Ⅱ)配合物抗癌活性研究进展

金属配合物抗癌药物的研究已经成为抗肿瘤药物研究的热点之一。越来越多的研究表明铜(Ⅱ)配合物具有较好的抗癌活性。本文在参阅大量文献的基础上,对铜(Ⅱ)配合物的结构特征﹑和铂(Ⅱ)配合物的活性对比、与DNA的作用﹑与氨基酸的共价作用及对癌细胞的诱导凋亡作用等方面作了介绍。     

乙型肝炎病毒cccDNA临床研究进展

乙型肝炎病毒（HBV）特殊的复制中间体共价闭合环状DNA（cccDNA）是前基因组RNA的转录模板,在病毒持续感染、抗病毒治疗后病毒再度活跃及药物耐受方面起关键作用。有两种免疫机制介导cccDNA的清除,深入研究细胞内cccDNA含量的动态变化,与HBVDNA载量、外周血HBsAg、HBeAg及生化指标的关系,以及免疫学、病毒学的影响因素,在预测肝炎再发、评价抗病毒治疗的效果、预测持续应答率及判断停药时机等方面具有重要作用。     

氚标记( )与(-)棉酚在大鼠主要脏器的亚细胞分布及共价结合

给大鼠腹腔及睾内注射氚标记的( )与(-)棉酚后第7、18天,对主要脏器中各亚细胞组分的总放射活性及共价结合的放射活性进行了动态观察。结果表明,(-)棉酚在心肌线粒体共价结合放射活性较明显高于( )棉酚;( )及(-)棉酚在睾丸细胞膜、微粒体共价结合的放射活性随时间增高,且(-)棉酚较为明显。     

慢性乙型肝炎的治疗现状

对慢性乙型肝炎病毒(HBV)的分子生物学及致病机理的深入研究表明,共价闭合环状DNA(cccDNA)在慢性HBV感染的持续过程中起关键作用,而慢性感染是病毒、肝细胞和机体免疫系统之间处于相互作用的动态过程。     

顺铂、樟脑胺氯乙酸铂及碳铂对染色体损伤的比较

以CHL细胞为材料,比较了顺铂(DDP)、碳铂(JM 8)和樟脑胺氯乙酸铂(CCP)的细胞毒作用和对CHL细胞的染色体损伤。实验表明,这三种铂络合物都有较强的细胞毒作用,其中顺铂最强而CCP最弱。DDP,JM-8和CCP的IC~(90)(±SD)分别为0.68±0.21,4.4±0.6,10.8±1.5μmol/L。在微核及染色体畸变实验中,观察到在药物浓度小于或等于IC_(90)时,这三种化合物诱发的微核及染色体损伤相当,但药物浓度增加时,CCP所诱发的微核及染色体畸变均大于DDP而JM-8最轻。     

用5—FU治疗实验性急性胰腺炎

急性胰腺炎已被认为是临床一大问题,死亡率极高。其基本病机是由于蛋白分解酶引起的自我消化。所以一个合乎逻辑的设想,是找到一个方法暂时抑制胰腺分泌的合成和分解。细胞内蛋白质的合成是由去氧核糖核酸(DNA)和核糖核酸(RNA)所控制,蛋白质的合成直接关系到细胞内RNA的含量。胰腺腺泡的RNA是丰富的,并可产生丰富蛋白质的胰腺液。经证实,5—FU能引起正常胰腺细胞质含量的暂时性减少,同时     

氚标记(+)与(-)棉酚在大鼠主要脏器的亚细胞分布及共价结合

给大鼠腹腔及睾内注射氚标记的(+)与(-)棉酚后第7、18天,对主要脏器中各亚细胞组分的总放射活性及共价结合的放射活性进行了动态观察。结果表明,(-)棉酚在心肌线粒体共价结合放射活性较明显高于(+)棉酚;(+)及(-)棉酚在睾丸细胞膜、微粒体共价结合的放射活性随时间增高,且(-)棉酚较为明显。     

中国红参与朝鲜红参总甙对肝、肾组织DNA、RNA及蛋白质合成作用的比较

本文采用核酸及蛋白质前体标记物掺入法比较研究了中国红参根总甙(GCS)和朝鲜红参根总甙(GKS)对小鼠肝、肾组织 DNA、RNA 及蛋白质合成的影响。结果证明,GCS 和GKS 25mg/kg/日,连续灌胃给药7日,对肝、肾 RNA 和蛋白质合成均有促进作用。但对肝、肾的 DNA 合成则无明显影响。说明 GCS 与 GKS 的作用基本相同。     

乙双吗啉(AT-1727)对L_(1210)细胞动力学的影响

以显微分光光度法结合放射自显影两种方法,研究了乙双吗啉对L_(1210)细胞动力学的影响。两种方法获得基本相似的结果。ip乙双吗啉50 mg/kg后,4 N细胞由未给药时的6.6%增加到23%,分裂细胞则明显减少,提示乙双吗啉可诱导G_2期细胞堆积。显微镜观察可见,堆积的G_2期细胞出现核肿胀,大量空泡,核破裂等现象,提示G_2期的阻断可能和G_2期细胞损伤有关。     

Effect of the dialdehyde derivative of 5'-deoxyinosine on pyrimidine deoxyribonucleoside metabolism in L1210 cells

The effects of the dialdehyde derivatives of inosine (Inox) and 5'-deoxyinosine (5'-dInox) on L1210 cells were compared. The growth of L1210 cells was inhibited to a greater extent by 5'-dInox than by Inox. The increased inhibition of L1210 cell growth by 5'-dInox was also reflected by the increased inhibition of the incorporation of precursors into RNA, DNA and proteins. Even though 5'-dInox was a more potent inhibitor, Inox accumulated in the L1210 cells to levels 4- to 5-fold greater than 5'-dInox. The metabolism of [5-3H]deoxycytidine and [5-3H]deoxyuridine by L1210 cells in culture, in the presence of Inox or 5'-dInox, indicated that dCMP deaminase was an intracellular site of action for 5'-dInox. The dCMP deaminase activity in cell-free extracts prepared from 5'-dInox-treated cells was reduced markedly. This decrease in activity was not reversed by increased substrate concentrations nor was the activity subject to allosteric activation by dCTP. Deoxyuridine and deoxycytidine were able to reverse the effects of 5'-dInox on the inhibition of L1210 cell growth.     

A conformational and structure-activity relationship study of cytotoxic 3,5-bis(arylidene)-4-piperidones and related N-acryloyl analogues

A series of 3,5-bis(arylidene)-4-piperidones 1 and related N-acryloyl analogues 2 were prepared as candidate cytotoxic agents with a view to discerning those structural features which contributed to bioactivity. A number of the compounds were markedly cytotoxic toward murine P388 and L1210 leukemic cells and also to human Molt 4/C8 and CEM neoplasms. Approximately 40% of the IC50 values generated were lower than the figures obtained for melphalan. In virtually all cases, the N-acyl compounds were significantly more bioactive than the analogues 1. In general, structure-activity relationships revealed that the cytotoxicity of series 1 was correlated positively with the size of the aryl substituents, while in series 2, a -sigma relationship was established. In particular, various angles and interatomic distances were obtained by molecular modeling, and the presence of an acryloyl group on the piperidyl nitrogen atom in series 2 affected the relative locations of the two aryl rings. This observation, along with some differences in distances between various atoms in series 1 and 2, may have contributed to the disparity in cytotoxicity between 1 and 2. The results obtained by X-ray crystallography of representative compounds were mainly in accordance with the observations noted by molecular modeling. Selected compounds interfered with the biosynthesis of DNA, RNA, and protein in murine L1210 cells, while others were shown to cause apoptosis in the human Jurkat leukemic cell line. This study has revealed the potential of these molecules for development as cytotoxic and anticancer agents.     

Cellular activation of diaziquone [2,5-diaziridinyl-3,6-bis (carboethoxyamino)-1,4-benzoquinone] to its free radical species

Human leukemic cell lines K562 and HL60, and the murine leukemic cell line L1210, reduce Diaziquone (AZQ) (NCS182986) to its free radical anion. With all cell lines, the free radical was observed immediately in both aerobic and anaerobic cell suspensions. The steady-state concentration of AZQ free radicals was approximately 1% of the total AZQ concentration. L1210 cells treated with azide reduced AZQ, but cells treated with diamide and N-ethylmaleimide did not. NADPH and L-cysteine reduced AZQ. The latter did so under anaerobic conditions; the former did so under both anaerobic and aerobic conditions.     

海南哥纳香醇甲GHM-10对L1210细胞DNA分子结构及拓扑异构酶II活性的影响

目的： 研究海南哥纳香醇甲（GHM-10）抑癌细胞DNA合成的作用机制。 方法： 用单细胞凝胶电泳法检测GHM-10对L1210细胞DNA分子的损伤,碱洗脱法测定GHM-10对L1210细胞DNA单链长度的影响,用GHM-10对超螺旋pUC18 DNA的解旋能力测定它对DNA拓扑异构酶II活性的影响。 结果： L1210细胞用GHM-10 (4～10) μg.ml^-1处理4.5 h后,DNA分子受损,表现为电泳后在荧光显微镜下可见彗星状拖尾。GHM-10 (4～25) μg.ml^-1处理L1210细胞5 h, 可引起DNA单链断裂。 L1210细胞或从L1210细胞分离的蛋白质在用GHM-10处理后,DNA拓扑异构酶II的活性均被抑制。结论： GHM-10可引起L1210细胞DNA分子损伤; 无论在细胞内还是细胞外,GHM-10可抑制拓扑异构酶II的活性。     

The Cytotoxicity of 2-Formyl and 2-Acetyl-(6-picolyl)-4N-Substituted Thiosemicarbazones and Their Copper(II) Complexes

2-Acetyl-(6-picolyl)-⁴N-substituted thiosemicarbazones and their copper(II) complexes were shown to be potent antineoplastic and cytotoxic agents against murine and human cultured cells. Numerous derivatives were as active against solid tumor growth as clinically useful agents. The agents inhibited L₁₂₁₀ DNA and RNA syntheses with inhibition of key regulatory enzyme activities of the purine pathway as well as nucleoside kinase activities. d[NTP] pools were reduced and DNA strand scission occurred. These agents were DNA topoisomerase II inhibitors with lower IC₅₀ values than that of VP-16. However, they did not cause L₁₂₁₀ DNA protein linked breaks and actually protected against those breaks afforded by VP-16. The agents were not synergistic with VP-16 in reducing cell growth or DNA synthesis although they did reduce growth of L₁₂₁₀ cells in agar suspended media.     

Opposing effects of the polycation hexadimethrine (polybrene) on normal and leukemic lymphocytes

The polycationic compound hexadimethrine has opposing effects on normal and leukemic murine lymphocytes. This polycation significantly stimulated the DNA-synthetic response of murine spleen cells to alloantigens, whereas, at the same concentration, proliferation of the leukemic cell line, L1210, was inhibited. Other polycations tested did not show this effect. The hexadimethrine had no significant effect on the rejection rate of histoincompatible skin grafts in mice. Low concentrations did inhibit the growth of the L1210 leukemia cells in DBA/2J mice.     

Synthesis and biological activity of several amino nucleoside-platinum(II) complexes

Several platinum(II) complexes of 3',5'-diamino-3',5'-dideoxythymidine (compound 1), 5'-amino-5'-deoxythymidine (compound 2), and 3'-amino-3'-deoxythymidine (compound 3) and the respective 2'-deoxyuridine amino nucleoside complexes, 4-6, have been synthesized. Whereas compounds 1, 2, and 4-6 had no inhibitory effect on the replication of murine L1210 cells in cell culture, compound 3 [(3'-AdThd)2PtCl2] inhibited these cells with an ED50 of 0.8 microM. Incubation of L1210 cells with 10-20 microM compound 3 for 2 h produced less than 18% inhibition of RNA, DNA, or protein synthesis, which is of questionable significance. However a 16-h incubation resulted in an increased uptake of labeled thymidine into DNA (77%), labeled uridine into RNA (17%), and labeled amino acids into protein (100%). These unexpected results indicate that inhibition of macromolecules may not be involved in the inhibition of the replication of L1210 cells. The increased incorporation of labeled metabolites into macromolecules may be related to the increase in cell volume after a 2-h incubation of L1210 cells with compound 3 plus a marked increase after 2 h in the proportion of cells in their S phase. Compound 3 appears to delay the progression of cells through their cell cycle. A marked inhibitory effect on the transport of methionine or aminoisobutyric acid into L1210 cells was found with compound 3, which was slightly greater than that produced with cisplatin. Compound 3 had a dose-dependent effect on the survival of mice bearing the L1210 ascites neoplasm, with a T/C X 100 of 175 at a dose of 320 mg/kg. Investigation of the kinetics of decomposition in aqueous systems demonstrated that the primary UV-absorbing decomposition product is 3'-amino-3'-deoxythymidine and that only a limited amount of the compound is formed (less than 8%). Although 3'-amino-3'-deoxythymidine could account for a part of the inhibition of the replication of L1210 cells in culture, it cannot account for the inhibition of amino acid transport by compound 3, the platinum complex of 3'-amino-3'-deoxythymidine. Compound 3 has been shown to limit part of the amino acid uptake into L1210 cells in a similar manner to cisplatin.