Side effects after docetaxel treatment in Taiwanese breast cancer patients with CYP3A4, CYP3A5, and ABCB1 gene polymorphisms

Background

Breast cancer patients initiating TEC (including docetaxel, epirubicin, and cyclophosphamide) treatment were genotyped for CYP3A4, CYP3A5, and ABCB1 to identify variability factors of side effects for docetaxel.

Methods

The planned dose of docetaxel per course was formulated according to each patient's height and weight. Each participant had received TEC treatment for 6 consecutive cycles. The single nucleotide polymorphisms (SNPs) of CYP3A4?4 (352A > G), CYP3A4?5 (653C > G), and CYP3A4?18A (20070T > C) for the CYP3A4 gene, CYP3A5?3A (6986A > G) for the CYP3A5 gene, and − 41A > G, − 145C > G, 1236C > T, 2677G > T(A), and 3435C > T SNPs for the ABCB1 gene were determined by using the restriction fragment length polymorphism of polymerase chain reaction products and the restriction enzymes.

Results

Fifty-nine Taiwanese women (mean age, 46 y; range, 30-64 y) treated for breast cancer with TEC were recruited. We found that patients carrying the CYP3A5?1/?3 genotype demonstrated more side effects of fever, pleural effusion, and febrile neutropenia than those with the CYP3A5?3/?3 genotype (p = 0.075, 0.077, and 0.030, respectively); moreover, patients with the ABCB1 2677G/G genotype also showed more side effects of fever and febrile neutropenia than those with other genotypes (p = 0.024 and 0.027), In regard to ABCB1 3435C > T, patients with ABCB1 3435C/C tended to suffer leucopenia (p = 0.057).

Conclusions

There could be correlations between certain side effects of docetaxel treatment and polymorphisms of these metabolic enzymes. Unfortunately, there is not so much evidence due to the small sample size of this study which restricts the statistical power.     

腹腔热灌注联合多西他赛、奥沙利铂静脉化疗治疗晚期卵巢癌疗效观察

目的:探讨肿瘤细胞减灭术(CRS)后腹腔热灌注联合多西他赛、奥沙利铂静脉化疗治疗晚期卵巢癌的临床疗效。方法:取2011年1月至2014年12月在河北医科大学第二医院就诊的晚期卵巢癌患者42例,其中观察组21例(CRS后+腹腔热灌注+多西他赛、奥沙利铂静脉化疗)、紫杉醇+卡铂组21例(CRS后+紫杉醇、卡铂静脉化疗)。比较两组的疗效、肿瘤控制、腹水控制、生活质量、治疗过程中的不良反应及并发症、无进展生存期(PFS)等。结果:观察组与对照组肿瘤控制差异无统计学意义(P0.05);腹水控制、生活质量、PFS均优于对照组,差异有统计学意义(P0.05)。不良反应及并发症无明显差异(P0.05)。结论:在临床上对于晚期卵巢癌患者采取CRS术后腹腔热灌注联合多西他赛、奥沙利铂静脉化疗,对于患者的疗效、肿瘤控制、腹水控制、生活质量、PFS有提高,且不明显增加不良反应及并发症。     

聚己内酯-吐温80共聚物纳米粒在神经胶质瘤化疗中的应用

目的 研究新型载多西紫杉醇聚己内酯-吐温80共聚物(PCL-Tween 80)纳米粒在神经胶质瘤化疗中的应用.方法 以PCL-Tween 80和聚己内酯为材料,利用改良的溶剂萃取/挥发方法制备载多西紫杉醇纳米粒并进行性质表征.利用激光共聚焦显微镜观察纳米粒的细胞摄取情况,并利用噻唑蓝(MTT)法测定纳米粒对C6细胞的细胞毒作用.结果 载药纳米粒呈球形,粒径约为200 nm.PCL-Tween 80纳米粒的载药量为10%,28 d内可以释放包裹药物的34.90%.与同浓度的泰素帝(Taxotere(R))比较,载多西紫杉醇PCL-Tween 80纳米粒对C6细胞的细胞毒性作用更强.结论 载多西紫杉醇PCL-Tween 80纳米粒用于神经胶质瘤的化疗极具应用前景.     

Nanoparticle drug loading as a design parameter to improve docetaxel pharmacokinetics and efficacy

Nanoparticle (NP) drug loading is one of the key defining characteristics of an NP formulation. However, the effect of NP drug loading on therapeutic efficacy and pharmacokinetics has not been thoroughly evaluated. Herein, we characterized the efficacy, toxicity and pharmacokinetic properties of NP docetaxel formulations that have differential drug loading but are otherwise identical. Particle Replication in Non-wetting Templates (PRINT^®), a soft-lithography fabrication technique, was used to formulate NPs with identical size, shape and surface chemistry, but with variable docetaxel loading. The lower weight loading (9%-NP) of docetaxel was found to have a superior pharmacokinetic profile and enhanced efficacy in a murine cancer model when compared to that of a higher docetaxel loading (20%-NP). The 9%-NP docetaxel increased plasma and tumor docetaxel exposure and reduced liver, spleen and lung exposure when compared to that of 20%-NP docetaxel.     

载多西紫杉醇的新型超声微泡的制备及性能观察

目的制备携载多西紫杉醇的新型超声微泡,并观察其药物携载能力。方法以PLGA为膜材料,以多西紫杉醇为携载药物,采用复乳化法和冷冻干燥技术,制备载药超声微泡;选择高效液相色谱法测定制剂中药物含量及超声环境下的释放量。结果载药超声微泡样品呈白色粉末状,表面光泽且粒径较均一,载药率和包封率分别可达2.36%和61.40%,且稳定可控;模拟超声环境下药物释放量明显增加。结论所制微泡对多西紫杉醇的携载能力有明显提高,并可在超声环境下稳定释放药物。     

载多西紫杉醇脂质微泡联合超声靶向微泡破裂对兔VX2肝癌微血管的作用

目的探讨载多西紫杉醇脂质微泡（DLLM）联合超声靶向微泡破裂（UTMD）对兔VX2肝癌微血管的抑制作用。方法建立60只兔VX2肝癌动物模型,将其随机分为6组（n=10）：单纯药物组（Doc组）、单纯载药微泡组（DLLM组）、药物＋超声组（Doc＋US组）、单纯微泡＋超声组（PLM＋US组）、载药微泡＋超声组（DLLM＋US组）及对照组,比较各组动物肿瘤组织的血管密度（MVD）、CD34及VEGF的表达。结果处理后DLLM＋US组的CD34表达水平低于其他各组,MVD明显降低,与其他各组相比差异有统计学意义（P〈0.01）;DLLM＋US组的VEGF表达水平明显低于其他各组（P〈0.01）。结论 DLLM联合UTMD能抑制兔VX2肝癌的微血管生成,从而抑制兔VX2肝癌的生长。     

Serum testosterone level as possible predictive marker in androgen receptor axis-targeting agents and taxane chemotherapies for castration-resistant prostate cancer

Purpose

Currently, several therapeutic options for castration-resistant prostate cancer (CRPC) are available, for which predictive biomarkers have not been established. Therefore, we aimed to reveal the association between pretreatment serum testosterone level and antitumor outcomes when treated with androgen receptor axis-targeting agents and taxane chemotherapies for CRPC.

DP方案治疗晚期胃癌的临床疗效观察

目的：研究多西他赛（DTX）与顺铂（DDP）联合治疗晚期胃癌临床疗效以及毒副反应。方法：入选病例均为ⅢB/Ⅳ期胃癌,共36例,所有病人均接受两次以上的化疗周期。结果：CR3例、PR15例、SD10例、PD4例、未能评估两例、临床有效率（PR＋CR）为50%,主要副作用为胃肠道反应、白细胞减少、贫血、脱发、无治疗死亡相关病例。结论：多西他赛加顺铂方案治疗晚期胃癌疗效较好,病人耐受性良好。     

多西他赛诱导肺腺癌A549/DTX细胞株的建立及耐药机制分析

目的 建立人肺腺癌细胞A549多西他赛（DTX）耐药细胞株,并对其耐药机制进行初步分析。方法 采用逐步增加多西他赛浓度、间歇诱导的方法,建立人肺癌A549/DTX体外耐药细胞模型;MTT法检测A549/DTX的耐药特性;流式细胞仪比较多西他赛对耐药细胞株A549/DTX及亲本细胞株A549凋亡的影响;Western blot分析多西他赛作用后两种细胞凋亡调节因子Bc1-2、Bax表达差异。结果 MTT显示A549/DTX的多西他赛耐药指数为18.5;流式细胞分析显示经12.5、25、50 μg/L多西他赛作用24 h后,A549/DTX的细胞凋亡率为(6.2±4.1)％、(13.6±2.7)％、(20.5±5.1)％,A549细胞凋亡率为(15.7±3.5)％、(28.5±2.9)％和(33.1±4.8)％,两者比较差异有统计学意义（P＜0.01）;Western blot显示,与A549相比,A549/DTX细胞Bcl-2蛋白表达明显升高,Bax蛋白明显降低(P＜0.01)。结论 逐步增加浓度、间歇诱导的方法建立了稳定、耐药性较高的A549/DTX细胞株,并认为凋亡受抑是A549/DTX的耐药机制之一,与Bcl-2表达上调、Bax表达下调相关。     

吉非替尼与多西他赛对不同肿瘤细胞株相互作用的实验研究

目的 探讨吉非替尼与多西他赛以不同顺序同步或序贯给药对于不同细胞株的细胞增殖能力及细胞周期和凋亡的影响.方法 用四甲基偶氮唑盐法检测同步、不同序贯疗法(多西他赛序贯吉非替尼或吉非替尼序贯多西他赛)对于A431、A549、SPC-A1及NCI-H292细胞株的细胞存活率的影响,并通过流式细胞仪检测不同的给药顺序下A549及A431细胞周期及凋亡的变化.结果 两药联合采用不同的给药方式、在不同细胞株中表现出的作用不同:多西他赛序贯吉非替尼组对比单药组对细胞生长抑制作用在4种细胞株中均有增强;同步组及吉非替尼序贯多西他赛组对比单药组对细胞生长抑制作用在A549、SPC-A1、NCI-H292细胞株中均有减弱,表现出拮抗作用.而在A431细胞株中有所增强,表现为协同作用;设置一定的给药间期可削弱这种拮抗或协同作用.流式细胞仪检测发现,两药联合时细胞凋亡情况在A549细胞与A431细胞中存在明显差别.结论 吉非替尼与多西他赛联合的相互作用随细胞株不同而有差异,且与序贯给药的顺序有关,其机制值得进一步研究.