Influence of carbonate on the binding of carboplatin to DNA

The reaction of aged carboplatin (reaction of carboplatin in 24 mM NaHCO(3) for 45 h, 37 degrees, pH 8.6) with pBR322 DNA at 0 < r < 2.8, where r = [drug]/[DNA-bp], in 24 mM HEPES buffer, pH 7.4, for 24 h, followed by agarose gel electrophoresis showed DNA mobility changes consistent with unwinding closed circular DNA. However, identical experiments conducted in a two-buffer system, 24 mM HEPES plus 24 mM carbonate, showed no DNA mobility changes, indicating that carbonate blocks formation of the 1,2 intrastrand cross-link on DNA. Studies with aged carboplatin and with cisplatin carried out with ca. 4.0 < r < 10.0 in the two-buffer system show that some DNA binding and unwinding occurs for both drugs. Since carbonate inhibits the binding of aged carboplatin and cisplatin to DNA, carbonate present in the body likely modulates the reactivity of these drugs with a variety of biological targets including DNA.     

多西紫杉醇联合卡铂治疗老年子宫内膜癌的疗效及安全性

目的:探讨多西紫杉醇与卡铂联合化疗在老年子宫内膜癌患者中的疗效及安全性。方法:选择2010年1月至2016年1月我院收治的子宫内膜癌患者78例作为研究对象,其中年龄60岁的患者42例纳入非老年组,年龄≥60岁的患者36例纳入老年组,均给予多西紫杉醇与卡铂联合化疗。对两组患者一般情况、化疗实施情况、临床疗效以及毒副反应进行观察与比较。结果:两组患者组织学分型有明显差异(P0.05),其他一般资料无显著差别(P0.05)。老年组患者采用低剂量完成化疗的比例明显高于非老年组,差异有统计学意义(P0.05),化疗周期及中断率无显著差异(P0.05)。两组患者临床疗效、血液系统毒副反应及消化系统毒副反应发生率均差异不显著(P0.05)。结论:多西紫杉醇与卡铂联合化疗在老年子宫内膜癌患者中治疗效果与非老年患者类似,安全性尚可,值得临床推广应用。     

Pravastatin attenuates carboplatin-induced cardiotoxicity via inhibition of oxidative stress associated apoptosis

The objective of this study was to evaluate the cardiac toxicity induced by carboplatin, a second generation platinum-containing anti-cancer drug, and to test whether pravastatin can reduce this cardio-toxicity. In the present study, infusion of carboplatin (100 mg/kg) to mice resulted in decreased survival rates and abnormal cardiac histology, concomitant with increased cardiac apoptosis. In addition, treatment of cultured rat cardiomyocytes with carboplatin (100 μM for 48 h) caused marked apoptosis and increased caspase-3, -9, and cytochrome C, but decreased BCL-XL protein expression, and this was inhibited by reactive oxygen species (ROS) scavenger n-acetylcysteine. Furthermore, pretreatment of cardiomyocytes with pravastatin (20 μM) before carboplatin exposure significantly attenuated apoptosis and decreased caspase-3, -9, cytochrome C activity. Lastly, mice pre-treated with pravastatin before carboplatin treatment showed improved survival rate and cardiac function, with reduced cardiomyocyte apoptosis via activating Akt and restoring normal mitochondrial HAX-1 in heart tissue. In summary, our results show that carboplatin can induce cardiotoxicity in vivo and in cultured cells via a mitochondrial pathway related to ROS production, whereas pravastatin administration can reduce such oxidative stress thus prevented cardiac apoptosis. Therefore, pravastatin can be used as a cytoprotective agent prior to carboplatin chemotherapy. Ching-Feng Cheng and Shu-Hui Juan contributed equally to the work.     

Carboplatin-induced alteration of the thiol homeostasis in the isolated perfused rat kidney

Carboplatin elicits minor side effects with respect to its first generation analogue cisplatin. Nevertheless, a dose-dependent nephrotoxicity of the drug has been reported to occur both in patients and in rats and a possible pathogenic role have been attributed to oxidative stress. We have studied the effect of carboplatin administration on the thiol/disulfide balance, on other biomarkers of oxidative stress and on antioxidant enzymes in the isolated perfused rat kidney. A 5-500 μM carboplatin dose range did not alter renal function but significantly decreased levels of cysteine, glutathione and exposed protein sulfhydryl groups. Only a minimal increment in disulfides was observed, whereas malonyldialdehyde and protein carbonyls did not increase significantly. Among the antioxidant enzymes studied, only thioltransferase was inhibited by the treatment. Our data suggest that a minimal oxidative stress is present under our experimental conditions, thus indicating that platinum-based drugs do not produce significant amount of reactive oxygen species.     

紫杉醇联合卡铂治疗卵巢癌的临床疗效及对患者血清CA125、CA199、CEA水平的影响

目的:分析紫杉醇联合卡铂治疗卵巢癌的临床疗效及对患者血清糖类抗原125(CA125)、糖类抗原199(CA199)、癌胚抗原(CEA)水平的影响。方法:选择我院2014年1月～2016年12月收治的41例卵巢癌患者,按随机数字表法分为对照组(n=20)和研究组(n=21)。对照组给予紫杉醇联合顺铂治疗,研究组给予紫杉醇联合卡铂治疗。比较两组临床疗效,治疗前后血清CA125、CA199、CEA水平、卡氏评分的变化,不良反应的发生情况和生存情况。结果:治疗后,研究组总有效率显著高于对照组(P0.05);两组血清CA125、CA199及CEA水平均较治疗前明显下降,且研究组低于对照组(P0.05);研究组卡氏评分改善率高于对照组(P0.05),胃肠道反应、神经毒性损伤、骨髓抑制及血液系统毒性率反应发生率低于对照组(P0.05);两组1年生存率及中位生存期比较差异无统计学意义(P0.05)。结论:紫杉醇联合卡铂治疗卵巢癌的疗效明显优于紫杉醇联合顺铂治疗,其能够降低患者血清CA125、CA199及CEA水平,改善患者生活质量。     

Simple and rapid determination of carboplatin in plasma by high-performance liquid chromatography. Error pattern and application to clinical pharmacokinetic studies

Carboplatin is an antitumor agent widely employed in cancer chemotherapy. A specific and selective method for the determination of carboplatin in human plasma and its applications to pharmacokinetic investigations is described. One ultrafiltration step, through a Centrifree micropartition system (Amicon) at 2000 g for 10 min, is the only requirement as sample treatment. The resulting solution is injected into an Inertsil ODS-2 (5 μm, 25 cm×4.6 mm I.D.) analytical column. The mobile phase consisted of 0.1 M potassium dihydrogenphosphate with 1 mM dipotassium edetate adjusted to a pH between 3 and 3.5. The limit of quantitation was 1 mg/l. The method showed good recovery (100.68±5.49%) and precision: the within-day relative standard deviation (RSD) for carboplatin (3–350 mg/l) was 2.07% and the between-day RSD for carboplatin, in the previously described range, was 1.31%. We determined the assay error pattern for proper weighting of serum level data in pharmacokinetic models. The selectivity (discrimination between the parent drug and platinum-containing species such as carboplatin metabolites), simplicity and speed of this assay for free carboplatin quantitation should facilitate pharmacokinetic investigations and therapeutic drug monitoring.     

Adsorption of the PtII Anticancer Drug Carboplatin by Mesoporous Silica

MCM‐41, a mesoporous silica nanomaterial with a high surface area for adsorption of small molecules, is a potential new type of delivery vehicle for therapeutic and diagnostic agents. In this report, we show that MCM‐41 adsorbs the front‐line anticancer drug carboplatin, [Pt(CBDCA‐O,O′)(NH₃)₂] (CBDCA=cyclobutane‐1,1‐dicarboxylate; 1 ), which is used to treat ovarian, lung, and other types of cancer. UV/Visible difference absorption spectroscopy shows that MCM‐41 adsorbs 1.8±0.2% of its own weight of carboplatin after a 24 h exposure to 26.9 mM drug in H₂O. The pseudo‐first‐order rate constant for adsorption of carboplatin by MCM‐41, measured using [¹H,¹⁵N] heteronuclear single quantum coherence (HSQC) NMR, and ¹⁵N‐labeled carboplatin is k₁=2.92±2.17×10^?6 s^?1 at ca. 25°.     

多西他赛联合卡铂治疗复发性卵巢癌的疗效观察

目的:分析多西他赛联合卡铂用于治疗复发性卵巢癌的临床疗效及用药安全性。方法:对28例复发性卵巢癌患者采用多西他赛联合卡铂方案治疗。结果:全组2例CR(7.14%),11例PR(39.28%),6例SD(21.42%),9例PD(32.14%),RR为46.42%。不良反应主要为血液系统毒性、胃肠道反应和神经系统毒性,但均未影响继续治疗,总体疗效满意。结论:多西他赛联合卡铂治疗复发性卵巢癌疗效较好,且使用过程简单,耐受性好。     

A phase II study of combined administration of dacarbazine and carboplatin with home therapy of recombinant interleukin-2 and interferon-α2a in patients with advanced malignant melanoma

Chemotherapy and interleukin-2 (IL-2) and/or interferon (IFN) produce objective responses in a proportion of patients with advanced malignant melanoma. The duration of response to chemotherapy is usually less than 4 months, and immunotherapy has resulted in longlasting remissions in a small number of patients with metastatic melanoma. The current study was conducted to improve the antitumor efficacy and the interactions between recombinant (r) IL-2, rIFN2a and chemotherapy. A total of 16 evaluable patients with metastatic malignant melanoma were entered into a phase-II study designed to assess the response rate and therapeutic efficacy of dacarbazine and carboplatin followed by rIL-2 and rIFN2a. Patients received 750 mg/m² dacarbazine with 400 mg/m² carboplatin each by intravenous bolus on days 1 and 22. Recombinant IL-2 and IFN2a were administered on an outpatient basis (home therapy) subcutaneously for 6 consecutive weeks: 4.8×10⁶ IU/m² rIL-2 daily, 5 days a week; 6.0×10⁶ IU/m² rIFN2a thrice weekly. There were responses in 6 of the 16 enrolled patients with an overall response rate of 37.5% (95% confidence interval: 14%–61%). All responding patients had partial responses. The median survival time of the responding patients was significantly better than that of patients with progressive and stable disease (P=0.03). The median duration of response was 11 months (range 2–24 months). Responses in lung, liver, soft tissue and lymph-node sites were noted.     

紫杉醇+卡铂化疗方案联合放疗对高危子宫内膜癌患者血清肿瘤标志物、Th1/Th2型细胞因子及癌基因表达的影响

摘要 目的：探讨紫杉醇+卡铂化疗方案联合放疗对高危子宫内膜癌（EC）患者血清肿瘤标志物、辅助性T细胞（Th）1/Th2型细胞因子及癌基因表达的影响。方法：选取我院2018年4月~2019年2月期间收治的80例高危EC患者作为研究对象,按照随机数字表法分为对照组（n=40）和研究组（n=40）,在常规治疗的基础上,对照组接受紫杉醇+卡铂化疗方案,研究组在对照组的基础上结合放疗。观察两组治疗后的客观缓解率和疾病控制率,对比两组血清肿瘤标志物、Th1/Th2型细胞因子水平及癌基因表达的变化情况,记录两组不良反应发生率、3年肿瘤复发率及淋巴结转移率。结果：研究组的客观缓解率、疾病控制率高于对照组（P<0.05）。治疗后,两组甲壳质酶蛋白40（YKL-40）、人附睾蛋白4（HE4）、细胞角蛋白-19片段（CYFRA21-1）、癌胚抗原（CEA）均下降,且研究组的下降程度大于对照组（P<0.05）。治疗后,两组白介素-4（IL-4）下降,γ-干扰素（IFN-γ）、IFN-γ/IL-4升高,且研究组的改善程度大于对照组（P<0.05）。治疗后,两组c-erbB2、c-myc下降,P53、P16升高,且研究组的改善程度大于对照组（P<0.05）。两组不良反应发生率对比无差异（P>0.05）。研究组的3年肿瘤复发率、淋巴结转移率低于对照组（P<0.05）。结论：紫杉醇+卡铂化疗方案联合放疗用于高危EC患者,可调节免疫平衡、癌基因表达,降低血清肿瘤标志物水平,从而提高临床疗效。