硼替佐米联合自体造血干细胞移植治疗多发性骨髓瘤的临床分析

目的探讨硼替佐米联合自体造血干细胞移植治疗多发性骨髓瘤的疗效和安全性。方法对1例轻链型多发性骨髓瘤患者,采用VTD方案（硼替佐米1.3 mg/m2,d 1、4、8、11;沙利度胺200 mg,d 1～14;地塞米松10 mg,d 1～4、d 9～12）化疗3个周期获得完全缓解后再行自体造血干细胞移植,监测M蛋白、肝肾功能、骨髓像、血象等指标,移植后再行白介素-2的免疫治疗。结果自体造血干细胞移植后患者造血重建顺利,相关并发症控制较好,随访至今一直无病生存。结论硼替佐米联合自体造血干细胞移植治疗多发性骨髓瘤是安全有效的。     

硼替佐米联合CHOP方案治疗血管免疫母细胞性T细胞淋巴瘤14例

目的 探讨硼替佐米联合CHOP方案治疗血管免疫母细胞性T细胞淋巴瘤(AITL)的有效性及安全性.方法 14例AITL患者应用硼替佐米(2mg/m2第1天)联合CHOP方案治疗,每21 d为1个疗程,对疗效、安全性及生存情况进行分析.结果 14例患者中初治12例,难治2例.12例患者治疗有效,其中完全缓解6例,部分缓解6例.14例患者3年预计生存率为55％,中位无进展生存时间9.4个月,3年预计无进展生存率为38％.Ⅲ～Ⅳ级中性粒细胞减少(6例)为最常见的血液学毒性;非血液学毒性均为Ⅰ～Ⅱ级,主要包括周围神经毒性(8例),恶心、呕吐(6例),腹泻(4例),感染(4例).结论 硼替佐米联合CHOP方案治疗AITL可在不增加治疗相关不良反应的同时,提高治疗缓解率,改善预后,可用于AITL的诱导及挽救治疗.     

硼替佐米对佐剂性关节炎模型大鼠的免疫调节作用及其机制研究

目的:研究硼替佐米对佐剂性关节炎模型大鼠的免疫调节作用及其机制。方法:取大鼠随机分成正常对照组、模型组、阳性对照组(甲氨蝶呤0·5mg·kg-1,3d1次)和硼替佐米低、高剂量组(0·2、1·0mg·kg-1,每日1次),每组10只,后4组用完全弗氏佐剂建立佐剂性关节炎模型,建模给药后第16天开始尾静脉注射相应药物,给药15d。评价建模给药后各组小鼠关节炎指数(3d1次),检测建模给药30d后各组大鼠外周血CD3+T、CD4+T、CD8+T细胞含量和CD4+T/CD8+T细胞比例,以及血清中γ干扰素(IFN-γ)、白细胞介素(IL)-4、IL-17水平。结果:与正常对照组比较,模型组大鼠关节炎指数评分更高,外周血CD4+T、CD4+T/CD8+T细胞比例及血清中IFN-γ、IL-4表达均明显增强(P<0·05)。与模型组比较,硼替佐米高剂量组和阳性对照组大鼠关节炎指数评分更低,外周血CD4+T、CD4+T/CD8+T细胞比例及血清中IFN-γ、IL-17表达均明显降低(P<0·05),仅硼替佐米高剂量组IL-4表达明显增加(P<0·05);硼替佐米低剂量组上述指标均无明显差异。结论:硼替佐米可能通过调节T细胞功能及其释放的细胞因子水平减缓佐剂性关节炎模型大鼠的关节肿胀程度。     

硼替佐米为主的联合化疗方案加或不加造血干细胞移植治疗多发性骨髓瘤疗效分析

目的 观察以硼替佐米为主的联合化疗方案加或不加造血干细胞移植(SCT)治疗多发性骨髓瘤(multiple myeloma,MM)患者的疗效及不良反应.方法 31例初治或复发(难治)MM患者接受硼替佐米为主治疗.之后有6例患者接受SCT治疗.按照EBMT标准评价疗效,WHO标准判断不良反应.结果 ①有5例患者由于急性肾功能衰竭、肿瘤溶解综合征等原因终止治疗,其中3例死亡.可以统计疗效的26例患者共完成了99个疗程的治疗,总有效率(ORR)为80.8%.15例初治患者的ORR为100.0%.11例复发(难治)患者的ORR为54.6%.②15例初治患者中有7例完成了8个疗程的治疗,动态观察发现随着疗程的延长疗效不断提高.③6例初治患者化疗达完全缓解(CR)或接近CR(mCR)后行SCT治疗,其中1例复发,5例随访至移植后6～11个月仍持续CR.未采取SCT巩固的9例初治患者中除1例持续CR外有6例在停药后1～3个月复发或进展,2例失访.④多数治疗相关不良反应为l～2级,有3例患者因为末梢神经炎、窦性心动过缓等原因降低硼替佐米的用量,5例因严重不良反应终止治疗.结论 硼替佐米治疗初治及复发(难治)MM疗效肯定,但可能需要进行巩固治疗(如SCT)以维持疗效.硼替佐米不良反应多数轻微且可以耐受,但也应注意少见的严重不良反应.     

基于FAERS数据库的硼替佐米不良事件信号挖掘研究

目的 基于美国FDA不良事件报告系统（FAERS）对硼替佐米相关不良事件进行数据挖掘,为临床安全使用硼替佐米提供参考。方法 采用比例报告比值比法（PPR）和报告比值比法（ROR）对FAERS中2004年第一季度至2019年第四季度共64个季度的硼替佐米相关不良事件报告进行信号检测。结果 共提取到以硼替佐米为首要怀疑药品的不良事件报告18 389例,男女比例为1.29∶1,中位年龄65岁,医师报告占48.3%(8881/18 389),来自美国的报告占48.3%(8890/18 389),主要给药途径为静脉注射和皮下注射,占41.9%,另有近25%的病例死亡。在报告数居前50位并检测出信号的相关不良事件中,浆细胞骨髓瘤、血红蛋白降低、骨髓功能衰竭、血肌酐升高、肌无力、低钾血症未被药品说明书收载。结论 硼替佐米相关不良事件报告中,体重>75 kg的男性患者远多于女性患者,提示体重与硼替佐米不良事件有关;患者年龄集中在65岁以上,提示老年人更易发生不良反应;可进一步研究硼替佐米与尚未收载于药品说明书中的不良事件的因果关系,同时警惕这些不良反应对原发疾病的影响。     

Dissociation of E-cadherin/β-catenin complex by MG132 and bortezomib enhances CDDP induced cell death in oral cancer SCC-25 cells

E-cadherin/β-catenin complex plays an important role in maintaining the homeostasis of tissues and regulating cell proliferation, survival and apoptosis. To address the relationships between the change of E-cadherin/β-catenin complex and cell apoptosis, human oral squamous carcinoma SCC-25 cells were used to investigate whether the dissociation of the E-cadherin/β-catenin complex was the main reason of MG132- or bortezomib-induced apoptosis. We found that MG132 or bortezomib alone induced remarkable loss of cell integrity and contact, inhibited cell growth, survival, migration and caused cell cycle arrest, intracellular ROS production. Further experiments showed that colony formations were significantly decreased by MG132 and bortezomib alone or plus cis-diaminedichloroplatinum (CDDP). Immunofluorescence staining showed that SCC-25 cells exhibited remarkable accumulations of β-catenin in cytoplasm and few E-cadherin in cell membranes after MG132 or bortezomib treatment. Western blot results showed that MG132 or bortezomib induced high accumulation of ubiquitinated proteins and activation of apoptosis related protein caspase-3. Meanwhile, the combinational use of MG132 or bortezomib with CDDP led to synergistic effects on SCC-25 cells. However, knockdown of β-catenin could decrease MG132 or bortezomib induced cell death. Taken together, our data suggest that the regulation of E-cadherin/β-catenin complex could be a promising therapeutic target to overcome the multidrug resistance of oral cancer.     

Antiproliferative activity of bortezomib alone and in combination with cisplatin or docetaxel in head and neck squamous cell carcinoma cell lines

Purpose

Proteasome inhibition has been shown to be effective in multiple myeloma and solid tumor models. In this in vitro study, we investigated the antitumor effect of bortezomib (Velcade^®) in squamous cell carcinoma of the head and neck (SCCHN) cell lines and examined the interaction of the drug with docetaxel (TAX) and cisplatin (CDDP).

Methods

Dose escalation studies were performed with eight squamous cell carcinoma cell lines using bortezomib alone or in combination with TAX or CDDP. Growth inhibitory and proapoptotic effects were measured quantitatively using cytohistology and western blot analysis.

Results

Bortezomib alone showed a significant antiproliferative activity in all SCCHN cell lines (P = 0.012), and the activity was further enhanced by the addition of TAX or CDDP (P ≤ 0.036). When the combination of bortezomib and CDDP was used, the dose of the latter could be reduced to yield the same antiproliferative effect as the cytotoxic drug alone (P < 0.012).

Conclusions

Our results indicate that bortezomib increases the cytotoxic activity of TAX and CDDP in SCCHN cell lines. In vivo and in the clinical setting, the addition of bortezomib may allow to reduce the doses of TAX or CDDP to decrease the systemic toxicity of these drugs.

     

High immunoproteasome concentration in the plasma of patients with newly diagnosed multiple myeloma treated with bortezomib is predictive of longer OS

PurposeProteasome inhibitors (PI) bortezomib or carfilzomib among them, play a crucial role in the modern standard therapy for multiple myeloma (MM). In this study, we intended to evaluate whether immunoproteasome (IMP) concentration could act as an effective biomarker which determines the probability of response to treatment with bortezomib, in order to detect groups of patients who are more likely to respond to treatment with PI.Materials and methodsIn our study, we evaluated IMP concentration in the plasma of 40 patients with monoclonal gammopathy of undetermined significance (MGUS) and 116 patients with newly diagnosed MM during treatment with or without PI.ResultsThe values of all the studied parameters after the applied chemotherapy in the responders’ group of patients declined considerably during the consecutive cycles of chemotherapy compared to their initial levels. On the contrary, in the group of non-responders, we observed no change in the measured IMP parameters during the consecutive cycles of therapy. We also showed that higher baseline IMP concentration might indicate longer overall survival (OS) in all patients.ConclusionsOur results indicate that assessing plasma IMP concentration can be applied as a strong biomarker for predicting clinical response to treatment and OS in patients with newly diagnosed MM.