Phase I and pharmacologie study of liposomal daunorubicin (DaunoXome)

Summary We have completed a phase I and pharmacology study of liposomally-encapsulated daunorubicin (DaunoXome). Of 32 patients entered, 30 were evaluable. No toxicity was encountered at the initial doseescalation steps from 10 to 60 mg/m². At 80 mg/m², two patients manifested grade 2 neutropenia. At least grade 3 neutropenia occurred in all patients receiving 120 mg/m². Alopecia and subjective intolerance were mild. Cardiotoxicity was not observed except for an episode of arrhythmia in a patient with lung cancer and prior radiation. Only one minor objective response was observed in this population of refractory solid tumors. Pharmacokinetics differed from those of the free drug with no detection of daunorubicinol. We recommend future phase II studies with a dose of 100 mg/m² in previously treated and 120 mg/m² of DaunoXome in previously untreated patients with solid tumors.EDW is supported in part by ACS award 92-14-1     

TAD方案治疗急性非淋巴细胞白血病疗效的评价

采用 TAD 方案治疗急性非淋巴细胞性白血病(ANLL)12例,年龄17～47岁。总有效率为66.7%,完全缓解率(CR)为41.7%。5例获 CR 的时间是26～66天,平均53天,较国内其它方案为快。CR 时间为2～9月,平均6.2月,较其它方案又较短。TAD 方案对心脏的毒性作用轻微。TAD 方案对5例获 CR 者,于诱导治疗第一疗程后,除1例外,骨髓中白血病细胞百分比下降均不明显;但于第二疗程后,白血病细胞全部减少到骨髓有核细胞总数的20%/以下,这种现象似可作为本方案预后的观察指标。     

Anthracycline-induced cardiotoxicity: Overview of studies examining the roles of oxidative stress and free cellular iron

The risk of cardiotoxicity is the most serious drawback to the clinical usefulness of anthracycline antineoplastic antibiotics, which include doxorubicin (adriamycin), daunorubicin or epirubicin. Nevertheless, these compounds remain among the most widely used anticancer drugs. The molecular pathogenesis of anthracycline cardiotoxicity remains highly controversial, although the oxidative stress-based hypothesis involving intramyocardial production of reactive oxygen species (ROS) has gained the widest acceptance. Anthracyclines may promote the formation of ROS through redox cycling of their aglycones as well as their anthracycline-iron complexes. This proposed mechanism has become particularly popular in light of the high cardioprotective efficacy of dexrazoxane (ICRF-187). The mechanism of action of this drug has been attributed to its hydrolytic transformation into the iron-chelating metabolite ADR-925, which may act by displacing iron from anthracycline-iron complexes or by chelating free or loosely bound cellular iron, thus preventing site-specific iron-catalyzed ROS damage. However, during the last decade, calls for the critical reassessment of this “ROS and iron” hypothesis have emerged. Numerous antioxidants, although efficient in cellular or acute animal experiments, have failed to alleviate anthracycline cardiotoxicity in clinically relevant chronic animal models or clinical trials. In addition, studies with chelators that are stronger and more selective for iron than ADR-925 have also yielded negative or, at best, mixed outcomes. Hence, several lines of evidence suggest that mechanisms other than the traditionally emphasized “ROS and iron” hypothesis are involved in anthracycline-induced cardiotoxicity and that these alternative mechanisms may be better bases for designing approaches to achieve efficient and safe cardioprotection.     

道诺霉素抑制视网膜色素上皮细胞炎前因子的表达

目的　观察道诺霉素对视网膜色素上皮细胞细胞(RPE)炎前因子表达的影响 .方法　培养的人 RPE经 IL- 1β(10μg· L- 1 )刺激以及不同浓度的道诺霉素作用后 ,用EL ISA、免疫组化和原位杂交等方法 ,检测培养的人 RPE炎前因子 m RNA和蛋白质的表达 .结果　 EL ISA显示对照组培养 RPE在 IL- 1β刺激 8h后 ,上清中 IL- 6与 IL- 8分别为2 0 0 0 pg· m L- 1· 10 - 6 cells和 5 0 0 0 pg· m L- 1· 10 - 6 cells.使用 10 0 μg·L- 1 道诺霉素作用于培养的 RPE后 IL- 6与 IL-8分别为 180 pg· m L- 1 · 10 - 6 cells (P <0 .0 1)和 32 0pg· m L- 1· 10 - 6 cells(P<0 .0 1) .免疫组化和原位杂交亦显示不同浓度道诺霉素可以不同程度地抑制 RPE内炎前因子蛋白质与 m RNA的表达 .结论　道诺霉素能有效地抑制 IL -1β诱导的培养的 RPE IL - 6和 IL - 8的表达     

4种细胞因子对K562/S及其耐药细胞株K562/A02积蓄柔红霉素的影响

目的通过检测４种常用细胞因子对白血病细胞株Ｋ５６２／Ｓ及其多药耐药细胞株Ｋ５６２／Ａ０２积蓄柔红霉素（ＤＮＲ）能力的影响,评价细胞因子在抗白血病细胞多药耐药性方面的应用前景。方法用流式细胞仪及荧光法检测重组人α－干扰素（ＩＦＮ－α）、白细胞介素２（ＩＬ－２）、肿瘤坏死因子（ＴＮＦ）、重组人粒－单集落刺激因子（ＧＭ－ＣＳＦ）对Ｋ５６２／Ｓ及Ｋ５６２／Ａ０２积蓄柔红霉素能力的影响。结果ＩＬ－２、ＴＮＦ、ＧＭ－ＣＳＦ作用后Ｋ５６２／Ｓ及Ｋ５６２／Ａ０２细胞株对柔红霉素的积蓄无改变,而ＩＦＮ－α可显著提高耐药细胞系Ｋ５６２／Ａ０２细胞内ＤＮＲ浓度,在１５０ｍｉｎ时升高了４.０１倍（Ｐ＜０.０５）。结论小剂量（５００Ｕ／ｍｌ） α－干扰素作用后,多药耐药细胞株 Ｋ５６２／Ａ０２对抗肿瘤药物ＤＮＲ的积蓄作用大大提高,提示ＩＦＮ－α具有提高耐药细胞株细胞内药物浓度、恢复其药物敏感性、逆转多药耐药性的作用。     

联合应用化疗药物对三氧化二砷耐药白血病细胞的毒性实验研究

目的:探讨化疗药物联合应用对三氧化二砷(As2O3)耐药白血病细胞(K562/AS2)的毒性作用。方法:细胞毒实验采用MTT法,二药合用时细胞毒性作用采用ChouTalalay联合指数法分析,细胞表面P糖蛋白(Pgp)和细胞内柔红霉素(DNR)浓度测定采用流式细胞术测定。结果:K562/AS2细胞对三氧化二砷、柔红霉素、鬼臼乙叉苷(VP16)、三尖杉酯碱(H)、米托蒽醌(NVT)和阿糖胞苷(AraC)的耐药倍数分别为7.4、2.9、3.8、3.6、2.8和1.1。K562细胞和K562/AS2细胞的细胞表面Pgp或细胞内任意荧光强度无显著的统计学意义(P>0.05)。As2O3与DNR、VP16、H或NVT联合应用时,对K562、K562/AS2和Pgp表达的白血病细胞(K562/A02)细胞的联合指数均大于1。异搏定与DNR联合应用时,对K562和K562/AS2细胞的联合指数均大于1,但是对K562/A02细胞的联合指数均小于1。结论:K562/AS2细胞对As2O3、DNR、VP16和NVT耐药,其机制与Pgp表达无关。异搏定联合应用DNR可以逆转K562/A02对DNR的耐药性,不能逆转DNR对As2O3耐药细胞的耐药性。As2O3与DN、VP16、H和NVT联合应用时,对K562、K562/AS2和K562/A02细胞的毒性均为拮抗作用。     

High-dose versus standard-dose daunorubicin in induction therapy for young patients with de novo acute myeloid leukaemia: a meta-analysis of randomised trials

Purpose: To compare the efficacy and safety of high-dose versus standard-dose daunorubicin for young patients with de novo acute myeloid leukaemia (AML) using meta-analysis.

Methods: Two trials were taken from 2,481 full-text articles. Heterogeneity was assessed using the I² index. Quality assessment was performed with the Cochrane Collaboration’s risk-of-bias tool.

Results: The analysis showed that high-dose daunorubicin induction therapy was associated with higher complete remission (CR) rate (n?=?965; RR?=?1.80; 95% CI?=?1.36–2.38; p?I^2?=?0%) and improved overall survival (n?=?1040; HR?=?0.74; 95% CI?=?0.63–0.87; p?=?0.0003; I^2?=?0%) compared with standard-dose daunorubicin. However, there was no significant interaction between treatment efficacy and prognostic category based on cytogenetics (favourable, intermediate and unfavourable) (p?=?0.44, I^2?=?0%).

Conclusion: High-dose daunorubicin therapy could increase CR rate and improve long-term outcome for young patients with de novo AML. However, further study is needed to identify those who can benefit from high-dose daunorubicin.     

姜黄素下调CyclinD1和Bcl-2的表达增强急性髓系LSCs对柔红霉素的敏感性

目的 探讨姜黄素(CUR)增强急性髓系白血病干细胞(LSCs)CD34+ CD38-KG1a细胞对柔红霉素(DNR)敏感性的机制.方法 流式细胞术分析KG1a细胞的CD34、CD38表面分子的表达情况.四甲基偶氮唑蓝(MTT)法获取CUR作用CD34+CD38-KG1a细胞的IC50 .M T T 法、甲基纤维素克隆形成实验和流式细胞术分别检测DNR对两种细胞(CD34+ CD38-KG1a和CUR/CD34+CD38-KG1a)的增殖抑制作用、克隆形成能力和凋亡影响.逆转录PCR(RT-PCR)检测细胞Bcl-2、Bax和XIAP的mRNA表达.Western blot分析细胞周期蛋白D1(CyclinD1)、Bcl-2、Bax 和 XIAP蛋白表达.结果 KG1a细胞系的CD34+CD38-KG1a细胞比例为(98 .2 ± 3 .2)% .CUR作用CD34+CD38-KG1a细胞24 h的IC50 =100 μmol/L.中、高浓度(0 . 8、2 .0 μg/mL)DNR对CUR/CD34+CD38-KG1a细胞的增殖抑制作用比CD34+CD38-KG1a细胞强(P＜0 .05).DNR对CUR/CD34+CD38-KG1a细胞克隆形成能力的抑制作用较CD34+ CD38-KG1a细胞强(P＜0 .05).各DNR浓度组中 ,CUR/CD34+CD38-KG1a细胞凋亡率均比CD34+CD38-KG1a细胞高(P＜0 .05).Bcl-2的mRNA及CyclinD1和Bcl-2蛋白表达下降.Bax、XIAP的mRNA和蛋白表达变化不明显.结论 CUR能增强CD34+ CD38-KG1a细胞对DNR的敏感性 ,与CUR下调CD34+CD38-KG1a细胞CyclinD1和Bcl-2的表达相关.     

Codelivery of Adriamycin and P-gp Inhibitor Quercetin Using PEGylated Liposomes to Overcome Cancer Drug Resistance

Transmembrane protein P-gp's overexpression at the drug-resistant cell membrane is the most important characteristic of multidrug resistance (MDR). Quercetin (QUE) can effectively suppress the function of P-gp to reverse MDR. This study uses QUE as the P-gp inhibitor andfilm-ultrasound technique with ammonium sulfate transmembrane gradient method to prepare long-circulating liposomes simultaneously encapsulating QUE and Adriamycin (doxorubicin) (AMD/DOX). The optimal conditions for the preparation of AMD_QUE_long-circulating liposomes (SLs) are as follows: hydrogenated soybean phospholipids (HSPC):cholesterol:DSPE-PEG 2000 = 73.07:24.36:2.57 mol/mol, QUE:HSPC = 1:20 mol/mol, AMD:HSPC = 1:7.9 w/w (NH₄₎₂SO₄ 0.15 mol/L, drug loaded (AMD) at 55°C for 25 min). The average encapsulation efficiency of AMD and QUE was 97.49% and 95.50%, respectively. The average particle size is 85 nm (n = 3), and the average zeta potential is ?14.9 mV. First, the pharmacokinetic study proved that codelivery liposomes enveloping QUE and AMD (AMD_QUE_SL) can obviously increase the blood concentration of AMD (C_max: 140.50 ± 32.37 μg/mL) and extend the half-life period of AMD in plasma (t_1/2:14.02 ± 1.54 h). Second, AMD_QUE_SL can obviously enhance the cell toxicity to AMD-resistant cell strains (HL-6/ADR and MCF-7/ADR), and the reverse effects on the resistance of HL-6/ADR and MCF-7/ADR is increased to 4.81-fold and 3.21-fold, respectively. Third, according to the in vivo pharmacodynamic study, the relative tumor volume and relative tumor growth of the AMD_QUE_SL group were the lowest. The inhibition rate of tumor growth of this group was the highest. It can be concluded that AMD_QUE_SL can effectively reverse MDR, lower cardiac toxicity of AMD in clinical treatment, and improve the clinical treatment effect of AMD.