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。     

樟脑胺氯乙酸铂对L_(1210)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L_(1210)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。     

亚硒酸钠对顺铂诱发染色体畸变作用的影响

在细胞中，顺铂(DDP)不仅与DNA结合，形成DNA链内和链间交联，从而阻滞其复制与表达，并导致细胞凋亡，而且引起DNA和染色体断裂，继而诱发各种染色体畸变。硒是一种具有重要生物学功能的元素，低剂量时具有抗诱变和抗癌作用。以往的研究表明，添加0．75～1．50mL／L剂量的亚硒酸钠显著     

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。     

顺铂对人体淋巴细胞的细胞毒性和遗传毒性特征

为了解顺铂对人体外周血淋巴细胞的细胞毒性和遗传毒性特征,在人体外周血淋巴细胞培养物中分别加入０．１ 和０．５ ｍ ｇ·Ｌ－ １顺铂,７２ ｈ 后观察淋巴细胞转化率,增殖指数,姐妹染色单体交换（ＳＣＥ）频率及染色体畸变（ＣＡ）率等． 结果表明,两顺铂组的淋巴细胞转化率均显著降低,ＳＣＥ频率和ＣＡ 率显著增高． 顺铂对人体淋巴细胞的细胞毒性主要特征是抑制其转化,较高剂量时使部分非转化小淋巴细胞发生聚集融合;遗传毒性特征表现为诱发高频ＳＣＥ和以裂隙及断裂为主的多种类型的染色体结构畸变,较高剂量时引起复杂交联．     

新铂类药物双环铂与顺铂、卡铂体内毒性的比较研究

目的:比较新铂类药物双环铂与顺铂、卡铂的体内毒性.方法:大鼠重复静脉注射双环铂、顺铂与卡铂,分别于给药结束以及恢复期末收集标本,进行血液学、血尿生化指标及病理切片的检测.结果:与溶剂对照组比较,重复静脉注射后,双环铂的高剂量组(13.89 mg·kg-1)全血网织红细胞以及红细胞明显降低(P＜0.01),骨髓切片示有核细胞显著减少;恢复期末网织红细胞和骨髓切片基本恢复至正常,而红细胞仍维持较低水平(P＜0.05).而双环铂各组尿酶、血尿素氮和肌苷以及肾脏病理切片在给药结束和恢复期均未见明显改变.结论:双环铂对SD大鼠的肾毒性明显低于顺铂,其骨髓抑制作用与卡铂相近,暗示肾毒性可能不会成为限制双环铂临床应用的主要毒副反应,临床应用需密切观察其对造血组织的损伤.     

顺铂及顺铂载体的研究进展

本文探讨抗肿瘤药顺铂的临床特点及其研究进展,为临床应用提供参考.通过查阅国内外相关文献,系统地了解抗肿瘤药顺铂的临床作用,剂量限制性毒性及耐药性,并检索未获批准及正在进行临床研究的顺铂载体,以分析其临床发展趋势.在过去的10年间,药物研发转向注重药物运输靶向介质,这些新型载体在保留传统顺铂的活性的同时,在很大程度上减少...     

顺铂和卡铂对胃癌细胞系的毒性作用比较

目的：体外比较顺铂和卡铂对胃癌细胞系的毒性作用,为临床化疗提供参考。方法：采用二甲基噻唑基四氮唑试验（MTT）在不同的培养时间,用不同浓度的药物,通过其细胞抑制率和半数抑制率（IC50）比较两种药物的细胞毒性。结果：不同培养时间的肿瘤细胞抑制率顺铂明显高于卡铂（P＜0．05）,顺铂的IC50也远小于卡铂。结论：顺铂对胃癌细胞系的体外细胞毒性作用大于卡铂。     

连接蛋白32及细胞缝隙连接对卵巢癌细胞顺铂耐药性的影响

目的研究连接蛋白32及细胞缝隙连接对卵巢癌细胞顺铂耐药性的影响。方法以A2780为亲代细胞,采用药物浓度递增法构建对顺铂耐药的卵巢癌细胞系(A2780-CDDP),CCK8法测定顺铂对肿瘤细胞的IC50,计算耐药指数(resistance index,RI)。"细胞接种荧光示踪法"检测卵巢癌细胞耐药行程过程中细胞的缝隙连接功能及Cx32的表达情况;调节A2780-CDDP细胞Cx32的表达,观察耐药性的变化;提细胞膜及胞浆蛋白,用Western印迹分别检测Cx32在A2780和A2780-CDDP的表达分布情况。结果本研究建立了顺铂耐药人卵巢癌细胞株A2780-CDDP,亲代细胞IC50为4.7 mg·L~(-1),A2780-CDDP的IC50为33.8 mg·L~(-1),耐药指数为7.2。同时,随着耐药性的增强,Cx32表达量逐渐增加,增强A2780-CDDP细胞中的GJ功能可提高顺铂的细胞毒性。此外,尽管Cx32在A2780-CDDP细胞中表达增加,但它更多地定位于细胞质而不是细胞膜,并且在A2780-CDDP细胞中下调Cx32的表达可以使其对顺铂治疗敏感。结论 Cx32参与顺铂耐药,Cx32在胞质中的定位对卵巢癌顺铂耐药有重要意义。     

铂类抗癌药物的发展历程

铂类抗癌药物是当今肿瘤化疗的基石。本文简要介绍已经上市的几个铂类抗癌药物的研发历史。     

Interaction of platinum agents,cisplatin, carboplatin and oxaliplatin against albumin in vivo rats and in vitro study using inductively coupled plasma‐mass spectrometory

The protein binding rates (PBR) of platinum‐containing agents cisplatin (CDDP), carboplatin (CBDCA) and oxaliplatin (L‐OHP) have been reported as 98%, 25–50% and 98%, respectively. To investigate the protein‐binding properties of albumin with cisplatin, carboplatin and oxaliplatin, inductively coupled plasma mass spectrometry (ICP‐MS) was used to measure their plasma concentration in rats over time. The study also examined the effects of cisplatin, carboplatin and oxaliplatin‐binding on albumin in vitro, using CD spectrometry and native‐polyacrylamide gel electrophoresis (native PAGE). The ratios of PBR to irreversible PBR, of cisplatin and oxaliplatin were 98%:98% and 90%:87%, respectively, indicating a higher affinity for irreversible binding with albumin. That of carboplatin was 25%:10%, indicating 60–70% reversible binding with albumin. The plasma protein binding rate concentrations of cisplatin, carboplatin and oxaliplatin after in vivo administration were 96%, 15% and 80%, respectively. The CD spectrometry of albumin was unaffected by cisplatin, carboplatin and oxaliplatin binding. Though similar protein binding rates were observed with oxaliplatin and cisplatin, oxaliplatin had a higher mobility rate during PAGE. It was confirmed that the binding of cisplatin and oxaliplatin with albumin affected its electric charge but not the structure. In conclusion, cisplatin and oxaliplatin bind irreversibly with albumin in plasma and may irreversibly interact with tissue protein and/or DNA. The difficulties involved with predicting the tissue concentrations of cisplatin and oxaliplatin from their plasma concentration inhibits their therapeutic drug monitoring. On the contrary, carboplatin, like some generic drugs, reversibly binds to plasma proteins. It is, therefore, possible to conduct therapeutic drug monitoring for carboplatin.     

Comparative cytotoxicity between cisplatin and second generation platinum analogs

The cytotoxic activity of cis-DDP and four second generation platinum coordination complexes (TNO-6; JM-82; JM-8; and JM-9) was compared on six established human colon carcinoma cell lines with different degrees of differentiation. Cytotoxicity was evaluated by the inhibition of colony formation technique. Cis-DDP was uniformity active against all lines. JM-8 and JM-9 were virtually ineffective for all cell lines, even at concentrations as high as 50 g/ml. JM-82 was slightly more active although (with the exception of LoVo cells) still about 10-fold less efficacious than cis-DDP. TNO-6 was the only derivative with appreciable cytotoxic activity although about 2 to 5-fold less than cis-DDP for lines SW48, 620, 480, and 1116. For LoVo and SW403, TNO-6 was slightly more active than cis-DDP. In both such instances, increased efficacy resulted from abrogation of the shoulder region of the survival curve while the slope remained essentially intact. Thus any enhancement in therapeutic efficacy with these second generation analogues can only be expected from possible decreases in toxic effects but not from superior tumor cell kill activity.     

Discrepancy between cytotoxicity and DNA interstrand crosslinking of carboplatin and cisplatin in vivo

We used the method of alkaline elution to compare quantitatively the DNA lesions produced by cisplatin and carboplatin in the AKR leukemia in vivo. These data were compared with cytotoxicity of each drug in the same animal model and in a solid tumor murine model (colon 26).DNA-protein and DNA-DNA interstrand crosslinks were formed in similar proportions by both drugs when peak values of crosslinking were compared. No clear difference in the rate of formation of both types of crosslinks could be observed between these drugs.On a molar basis a 3- to 4-fold more carboplatin had to be given to obtain equivalent frequencies of both types of crosslinks. In contrast, to obtain equitoxicity in the same animal tumor model, 13 fold higher doses of carboplatin had to be given. This difference in cytotoxicity between both drugs is comparable to the difference measured in colon 26 in vivo (16 fold). Both values are in the range of literature data (10–25 fold) dealing with the relative potency of cisplatin and carboplatin in murine tumor models.Abbreviations DIC DNA-DNA Interstrand Crosslinks - DPC Protein-DNA Crosslinks - EDTA Ethylene-Diammine-Tetra-Acetic Acid - PK Proteinase K - PSA Puck's Saline A - SSB Single Strand Breaks - ILS Increase in Life Span - Carboplatin-Cis-(diammino)(1,1-cyclobutane-dicarboxylato)-Platinum (II), Cisplatin Cis-Diamminedichloroplatinum (II) Supported by an award from the Belgian Work against Cancer.American Cancer Society Cancer Development Award Recipient.     

国产卡铂和顺铂在兔体内的药物动力学

本文以石墨炉原子吸收分光光度法为测定方法,对国产卡铂和顺铂在家兔体内的药物动力学进行了初步的研究和比较。本法中卡铂和顺铂在0～20μg/ml范围内药物血浆浓度同吸收峰高呈线性关系,相关系数r>0.99(P相似文献   

Toxicities of the platinum antineoplastic agents

The platinum agents (cisplatin, carboplatin and oxaliplatin) are among the most useful anticancer agents available to oncologists. The drugs have the potential to produce both mild and more serious side effects. However, in general, the platinum agents can be delivered with acceptable toxicity, even when used in combination chemotherapy regimens. Furthermore, with appropriate dose modifications, the large majority of patients who may benefit from this class of cytotoxic pharmaceutical drugs will be able to complete a planned therapeutic programme.     

Randomized cross-over clinical trial to study potential pharmacokinetic interactions between cisplatin or carboplatin and etoposide

AIMS: Cisplatin and carboplatin are often used in combination with etoposide. In a randomized cross-over study, the potential interaction between the two platinum drugs and the metabolism of etoposide was explored. In vitro investigations using human liver microsomes were also performed. METHODS: Etoposide was administered to 15 patients over 3 days, with the platinum drug administered on day 2. The alternate platinum drug was administered on the second course. The pharmacokinetics of etoposide were determined on all 3 days of each cycle. The effect of platinum drugs on etoposide metabolism by human liver enzymes was explored in vitro. RESULTS: Neither cisplatin nor carboplatin coadministration affected the pharmacokinetics of etoposide during cycle 1. When carboplatin was administered on course 2, etoposide AUC was 8% higher on day 2 compared with day 1 or day 3 (for day 2 vs day 3, 95% CI: -0.72, -0.08 mg ml(-1) min). In contrast, cisplatin on course 2 increased the AUC of etoposide (28%) on day 3 (day 3 vs day 1, 95% CI: 0.67, 2.09 mg ml(-1) min), with no effect on day 2. In vitro carboplatin and cisplatin (10-100 microm) inhibited the metabolism of etoposide, if rat liver microsomes were preincubated (30 min) with NADPH and the platinum complexes. With human liver microsomes a small effect on etoposide metabolism, but not on catechol formation, was observed. CONCLUSIONS: The interaction between etoposide and platinum drugs is small and, given the pharmacokinetic variability seen with etoposide, the clinical impact is unlikely to be significant.     

铂类抗肿瘤药物的研发进展及市场情况

近年来,铂类抗肿瘤药物的临床研究进展较快,其抗肿瘤谱广,抗肿瘤活性增强,不良反应降低,已成为目前有关抗肿瘤药物研发的重要领域。新的铂类抗肿瘤药物将从那些在临床研究中显示出低毒性、抗肿瘤谱广、与现有药物无交叉耐药性的化合物中产生。本文就其作用机制、国内外上市开发现状、国内外销售情况及国内研究开发进展等进行综述。