• 【硼替佐米,环磷酰胺和倍他米松的联合治疗方案比VAD / CyBet治疗方案具有更快,更好和更持久的应答:瑞典一项回顾性分析的结果。】 复制标题 收藏 收藏
    DOI:10.1159/000345422 复制DOI
    作者列表:Uttervall K,Admasie J,Alici E,Lund J,Liwing J,Aschan J,Barendse M,Deneberg S,Mellqvist UH,Carlson K,Nahi H
    BACKGROUND & AIMS: BACKGROUND:Induction therapy for multiple myeloma (MM) and remission status before high-dose treatment (HDT) have been shown to be prognostic factors for survival outcome, although the optimal induction therapy is yet to be defined. METHODS:We conducted a retrospective analysis of the impact of induction therapy on survival outcome before and after HDT in MM patients. The study included 236 consecutive patients who underwent HDT. RESULTS:One hundred and forty-two patients (62%) were treated with vincristine, doxorubicin and dexamethasone (VAD) or cyclophosphamide and betamethasone (CyBet) and 94 (38%) were treated with bortezomib, cyclophosphamide and betamethasone (VCB) as induction. Time to first and time to best response was faster in the VCB group than in the VAD/CyBet group, with 42 versus 75 (p < 0.001) and 54 versus 88 days (p < 0.001), respectively. After induction therapy, 49% of the patients in the VCB group and 38% in the VAD/CyBet group achieved a very good partial response or better. Multivariate analysis revealed younger age, lower International Staging System stage and induction treatment with VCB as variables associated with favourable time to progression. CONCLUSIONS:Outcome measured as response and time to progression before and after HDT in MM differs depending on type of induction treatment and suggests that VCB is a highly effective induction regimen that confers a post-HDT advantage.
    背景与目标: 摘要背景:对多发性骨髓瘤(MM)的诱导治疗和大剂量治疗(HDT)之前的缓解状态已被证明是生存结果的预后因素,尽管最佳诱导治疗尚待确定。
    方法:我们对诱导疗法对MM患者HDT前后生存结果的影响进行了回顾性分析。该研究包括236名接受HDT治疗的连续患者。
    结果:142例患者(62%)接受了长春新碱,阿霉素和地塞米松(VAD)或环磷酰胺和倍他米松(CyBet)的治疗,而94例(38%)接受了硼替佐米,环磷酰胺和倍他米松(VCB)的治疗。 VCB组的首次响应时间和最佳响应时间比VAD / CyBet组更快,分别为42天与75天(p <0.001)和54天与88天(p <0.001)。诱导治疗后,VCB组中49%的患者和VAD / CyBet组中38%的患者获得了很好的局部缓解或更好的缓解。多变量分析显示年龄较小,国际分期系统阶段较低和以VCB作为与进展良好时间相关的变量进行诱导治疗。
    结论:根据诱导治疗的类型不同,MM发生HDT前后反应和进展时间的结果也有所不同,这表明VCB是一种高度有效的诱导方案,具有HDT后的优势。
  • 【TNF通过减少蛋白酶体亚基的表达和展开蛋白应答的失调来增强硼替佐米(Velcade)的抗癌活性。】 复制标题 收藏 收藏
    DOI:10.1002/ijc.22695 复制DOI
    作者列表:Nowis D,McConnell EJ,Dierlam L,Palamarchuk A,Lass A,Wójcik C
    BACKGROUND & AIMS: :Bortezomib (Velcade) exploits proteasome inhibition as a unique mechanism of anticancer activity. The effectiveness of bortezomib is, however, limited, therefore, the search for therapeutic regimens combining bortezomib with other agents. In the present work we demonstrate enhanced anticancer activity of bortezomib by its combination with tumor necrosis factor (TNF) in the experimental model of C-26 colon carcinoma in mice. This interaction likely relies on the induction of a dysregulated response to ER stress, leading to apoptosis of cancer cells, evidenced by caspase-3 cleavage, p53 accumulation as well as increased SAPK/JNK phosphorylation. ER stress induced by the combination of TNF and bortezomib is corroborated by upregulation of BiP, PDI and calnexin as well as cleavage of caspase-12; however, in contrast to the classic pathway, it is also associated with decreased phosphorylation of eIF2 alpha and prevention of XBP-1 splicing. TNF prevented the upregulation of Hsp27 induced by bortezomib, which may contribute to enhanced ER stress. Moreover, TNF interfered with bortezomib-induced upregulation of distinct subunits of the 26S proteasome. Bortezomib concentration used in this study was not sufficient to prevent TNF from inducing nuclear translocation of p65/RelA; however, the combination of both agents reduced total p65/RelA levels. Combined treatment of tumor-bearing mice with bortezomib and TNF not only inhibited tumor growth but also significantly prolonged animal survival. Therefore, combination of bortezomib with TNF is an attractive option for further clinical studies.
    背景与目标: :硼替佐米(Velcade)利用蛋白酶体抑制作为抗癌活性的独特机制。然而,硼替佐米的有效性受到限制,因此,寻求将硼替佐米与其他药物联合使用的治疗方案。在目前的工作中,我们证明了硼替佐米与肿瘤坏死因子(TNF)的组合在小鼠C-26结肠癌的实验模型中增强了抗癌活性。这种相互作用可能依赖于对ER应激反应失调的诱导,从而导致癌细胞凋亡,这由caspase-3裂解,p53积累以及SAPK / JNK磷酸化增加证明。 TNF和硼替佐米的组合诱导的ER应激通过BiP,PDI和钙联接蛋白的上调以及caspase-12的裂解得到证实。但是,与经典途径相反,它还与eIF2α的磷酸化水平降低和XBP-1剪接的阻止有关。 TNF预防了由硼替佐米诱导的Hsp27的上调,这可能有助于增强ER应激。此外,TNF干扰了硼替佐米诱导的26S蛋白酶体不同亚基的上调。本研究中使用的硼替佐米浓度不足以阻止TNF诱导p65 / RelA的核易位。然而,两种药物的组合降低了总的p65 / RelA水平。硼替佐米和TNF联合治疗荷瘤小鼠,不仅抑制了肿瘤的生长,而且还显着延长了动物的生存期。因此,硼替佐米与TNF的组合是进一步临床研究的有吸引力的选择。
  • 【硼替佐米在复发/难治性多发性骨髓瘤中的成本效益:瑞典的观点。】 复制标题 收藏 收藏
    DOI:10.1111/j.1600-0609.2010.01526.x 复制DOI
    作者列表:Hornberger J,Rickert J,Dhawan R,Liwing J,Aschan J,Löthgren M
    BACKGROUND & AIMS: OBJECTIVES:To estimate the cost-effectiveness of bortezomib (BTZ) compared with dexamethasone (DEX) and lenalidomide plus dexamethasone (LEN/DEX) for the treatment of relapsed/refractory multiple myeloma in Sweden. METHODS:We used partitioned survival analysis to assess survival data decomposed into three states: (i) alive before disease progression; (ii) alive after progression; and (iii) dead. The effects of treatment on time to progression and overall survival (OS) were obtained from published reports of the APEX, MM-009, and MM-010 randomized clinical trials. Costs included drug and administration costs, adverse events, treatment of relapses, and end-of-life costs. Utility estimates were derived from the literature. RESULTS:BTZ mean OS was 57.4 months compared with 44.6 and 54.1 months for DEX and LEN/DEX, respectively. Mean lifetime direct medical costs per patient were approximately 2010 SEK 1,904,462, 1,278,854, and 2,450,588 for BTZ, DEX, and LEN/DEX, respectively. Mean incremental cost per quality-adjusted life-year of BTZ compared to DEX was 2010 SEK 902,874 (€95,073) (95% CI: 514,791, 962,416) and was dominant with respect to LEN/DEX. CONCLUSION:BTZ and LEN/DEX are projected to prolong survival relative to DEX. From a Swedish perspective, BTZ is cost-effective compared to DEX and LEN/DEX.
    背景与目标: 目的:评估硼替佐米(BTZ)与地塞米松(DEX)和来那度胺加地塞米松(LEN / DEX)在瑞典治疗复发/难治性多发性骨髓瘤的成本效益。
    方法:我们使用分区生存分析来评估分解成三个状态的生存数据:(i)在疾病进展之前还活着; (ii)进展后还活着; (iii)死亡。从APEX,MM-009和MM-010随机临床试验的已发表报告中可以获得治疗对进展时间和总生存期(OS)的影响。费用包括药品和管理费用,不良事件,复发治疗和生命周期终止费用。效用估计值是从文献中得出的。
    结果:BTZ平均OS为57.4个月,而DEX和LEN / DEX分别为44.6和54.1个月。对于BTZ,DEX和LEN / DEX,每位患者的平均终生直接医疗费用分别约为2010 SEK 1,904,462、1,278,854和2,450,588。与DEX相比,BTZ每质量调整生命年的平均增量成本为902,874瑞典克朗(95,073欧元)(95%CI:514,791,962,416),并且在LEN / DEX方面占主导地位。
    结论:相对于DEX,BTZ和LEN / DEX有望延长生存期。从瑞典的角度来看,与DEX和LEN / DEX相比,BTZ具有成本效益。
  • 【硼替佐米联合多西他赛治疗晚期雄激素非依赖性前列腺癌的I / II期研究。】 复制标题 收藏 收藏
    DOI:10.1158/1078-0432.CCR-06-2046 复制DOI
    作者列表:Dreicer R,Petrylak D,Agus D,Webb I,Roth B
    BACKGROUND & AIMS: PURPOSE:To determine the dose-limiting toxicities and maximum tolerated dose, and evaluate the antitumor activity of bortezomib/docetaxel combination therapy in androgen-independent prostate cancer. EXPERIMENTAL DESIGN:Two bortezomib doses (1.3 and 1.6 mg/m(2)/dose) in combination with four docetaxel doses (25-40 mg/m(2)/dose) were evaluated. Both drugs were administered weekly for 2 out of 3 weeks. Antitumor activity was evaluated using prostate-specific antigen (PSA) levels and Response Evaluation Criteria in Solid Tumors guidelines. RESULTS:Eighty-three patients received at least one dose of study drug. No dose-limiting toxicities were observed despite escalation to the highest dose level. PSA response (>or=50% decline in PSA levels from the baseline) occurred in 19 (28%) of 67 evaluable patients and was maintained for >or=4 weeks in 14 patients (21%). According to Response Evaluation Criteria in Solid Tumors guidelines, 11% achieved a partial response, and an additional 67% had stable disease. The degree of proteasome inhibition was similar to that reported with single-agent bortezomib. Treatment was well tolerated; fatigue was the most common drug-related adverse event, whereas diarrhea was the most common drug-related grade 3/4 adverse event. No clinically significant febrile neutropenia or neuropathy occurred. CONCLUSIONS:The maximum tolerated dose of this 21-day regimen has not been reached. The highest dose level (1.6 mg/m(2) bortezomib plus 40 mg/m(2) docetaxel) was feasible and tolerable; bortezomib plus docetaxel showed antitumor activity. Activity and tolerability results were consistent with previous studies of bortezomib alone or in combination with docetaxel. Further investigations are warranted to determine activity and optimize bortezomib/docetaxel therapy in androgen-independent prostate cancers.
    背景与目标: 目的:确定剂量限制的毒性和最大耐受剂量,并评估硼替佐米/多西他赛联合治疗对雄激素非依赖性前列腺癌的抗肿瘤活性。
    实验设计:评估了两种硼替佐米剂量(1.3和1.6 mg / m(2)/剂量)与四种多西他赛剂量(25-40 mg / m(2)/剂量)的组合。两种药物每周给药3周,共2周。使用前列腺特异性抗原(PSA)水平和《实体瘤指南》中的反应评估标准评估抗肿瘤活性。
    结果:八十三名患者至少接受了一剂研究药物。尽管升级到最高剂量水平,仍未观察到剂量限制性毒性。在67位可评估患者中,有19位(28%)发生了PSA反应(PSA水平较基线下降≥50%),并且在14位患者(21%)中维持了≥4周。根据《实体瘤反应评估标准》指南,有11%的患者获得了部分缓解,另有67%的患者患有稳定的疾病。蛋白酶体的抑制程度与单药硼替佐米报道的相似。治疗耐受性良好;疲劳是最常见的与药物相关的不良事件,而腹泻是最常见的与药物相关的3/4级不良事件。没有发生临床上明显的发热性中性粒细胞减少或神经病。
    结论:尚未达到该21天治疗方案的最大耐受剂量。最高剂量水平(1.6 mg / m(2)硼替佐米加40 mg / m(2)多西他赛)是可行且可耐受的;硼替佐米加多西他赛显示出抗肿瘤活性。活性和耐受性结果与硼替佐米单独或与多西他赛联合使用的先前研究一致。有必要进行进一步的研究以确定在雄激素非依赖性前列腺癌中的活性并优化硼替佐米/多西他赛疗法。
  • 【地拉罗司,硼替佐米,达沙替尼和环孢素滴眼液的综述:在皮肤医学中的可能用途和已知的副作用。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Scheinfeld N
    BACKGROUND & AIMS: :Recently, a number of medications approved for nondermatologic use have proved useful against dermatologic diseases. This article reviews the dermatologic uses and effects of deferasirox, bortezomib, dasatinib, and cyclosporine eye drops. Deferasirox--an oral iron chelator--could be an effective treatment against porphyria cutanea tarda, hemochromatosis, and pathogens such as mucor that thrive in iron rich environments. Bortezomib, a proteasome inhibitor and multiple myeloma treatment, may be effective against nodular amyloid and has been effectively used against squamous cell carcinoma; although trials demonstrate it is ineffective against metastatic melanoma. Bortezomib has many cutaneous side effects including erythematous plaques or nodules, a generalized morbilliform erythema with ulcerations and fever, purpuric eruptions, leukocytoclastic vasculitis, Sweet's syndrome, and folliculitis. Dasatinib is a multi-targeted tyrosine kinase inhibitor active in vitro against most cell lines containing BCR-ABL mutations that confer resistance to imatinib. Dasatinib is likely to be effective against dermatofibroma sarcoma protuberans and cutaneous acute lymphoblastic leukemia, and has caused panniculitis. Cyclosporine 0.05% ocular emulsion (eye drops) are approved to treat dry eyes including dry eyes caused by collagen vascular disease. Cyclosporine eye drops might also have utility in treating eye pathology of ocular rosacea, atopic keratoconjunctivitis, graft versus host disease, herpes keratitis, chronic sarcoidosis of the conjunctiva, conjunctival manifestations of actinic prurigo, keratitis of keratitis-ichthyosis deafness (KID) syndrome, and lichen planus-related kerato-conjunctivitis. This article speculates that cyclosporine eye drops would also be useful for any disease causing ectropion or eclabion of the eye as well as toxic epidermal necrolysis-related eye pathology (in particular corneal scarring).
    背景与目标: :最近,许多非皮肤科药物被证明可有效治疗皮肤病。本文回顾了地拉罗司,硼替佐米,达沙替尼和环孢霉素滴眼剂的皮肤病学用途及其作用。 Deferasirox-一种口服铁螯合剂-可能是一种有效的疗法,可用于治疗皮肤卟啉卟啉症,血色素沉着病以及在富含铁的环境中壮成长的病原体,例如粘液。硼替佐米是一种蛋白酶体抑制剂和多发性骨髓瘤治疗药物,可能对结节性淀粉样蛋白有效,并已有效用于鳞状细胞癌。尽管试验表明它对转移性黑色素瘤无效。硼替佐米具有许多皮肤副作用,包括红斑或结节,泛发性溃疡性和发热性丝状红斑,紫癜性爆发,白细胞碎裂性血管炎,Sweet's综合征和毛囊炎。达沙替尼是一种多靶点酪氨酸激酶抑制剂,在体外对大多数含有赋予伊马替尼耐药性的BCR-ABL突变的细胞系具有活性。达沙替尼可能有效对抗皮肤纤维瘤肉瘤和皮肤急性淋巴细胞性白血病,并已引起脂膜炎。批准使用环孢素0.05%眼用乳剂(眼药水)治疗干眼症,包括由胶原蛋白血管疾病引起的干眼症。环孢素滴眼液也可能用于治疗眼部酒渣鼻,特应性角结膜炎,移植物抗宿主病,疱疹性角膜炎,结膜慢性结节病,光化性瘙痒的结膜表现,角膜炎,角膜炎,鱼鳞病和角膜炎(KID)综合征,扁平苔藓相关的角膜结膜炎。本文推测,环孢菌素滴眼液也可用于任何引起眼部外翻或松弛的疾病,以及与毒性表皮坏死相关的眼部病理(尤其是角膜瘢痕形成)。
  • 【先前治疗的多发性骨髓瘤患者中的Daratumumab,硼替佐米和地塞米松与硼替佐米和地塞米松的比较:CASTOR三年随访。】 复制标题 收藏 收藏
    DOI:10.1016/j.clml.2019.09.623 复制DOI
    作者列表:Mateos MV,Sonneveld P,Hungria V,Nooka AK,Estell JA,Barreto W,Corradini P,Min CK,Medvedova E,Weisel K,Chiu C,Schecter JM,Amin H,Qin X,Ukropec J,Kobos R,Spencer A
    BACKGROUND & AIMS: BACKGROUND:In the phase III CASTOR study in relapsed or refractory multiple myeloma, daratumumab, bortezomib, and dexamethasone (D-Vd) demonstrated significant clinical benefit versus Vd alone. Outcomes after 40.0 months of median follow-up are discussed. PATIENTS AND METHODS:Eligible patients had received ≥ 1 line of treatment and were administered bortezomib (1.3 mg/m2) and dexamethasone (20 mg) for 8 cycles with or without daratumumab (16 mg/kg) until disease progression. RESULTS:Of 498 patients in the intent-to-treat (ITT) population (D-Vd, n = 251; Vd, n = 247), 47% had 1 prior line of treatment (1PL; D-Vd, n = 122; Vd, n = 113). Median progression-free survival (PFS) was significantly prolonged with D-Vd versus Vd in the ITT population (16.7 vs. 7.1 months; hazard ratio [HR], 0.31; 95% confidence interval [CI], 0.25-0.40; P < .0001) and the 1PL subgroup (27.0 vs. 7.9 months; HR, 0.22; 95% CI, 0.15-0.32; P < .0001). In lenalidomide-refractory patients, the median PFS was 7.8 versus 4.9 months (HR, 0.44; 95% CI, 0.28-0.68; P = .0002) for D-Vd (n = 60) versus Vd (n = 81). Minimal residual disease (MRD)-negativity rates (10-5) were greater with D-Vd versus Vd (ITT: 14% vs. 2%; 1PL: 20% vs. 3%; both P < .0001). PFS2 was significantly prolonged with D-Vd versus Vd (ITT: HR, 0.48; 95% CI, 0.38-0.61; 1PL: HR, 0.35; 95% CI, 0.24-0.51; P < .0001). No new safety concerns were observed. CONCLUSION:After 3 years, D-Vd maintained significant benefits in patients with relapsed or refractory multiple myeloma with a consistent safety profile. D-Vd provided the greatest benefit at first relapse and increased MRD-negativity rates.
    背景与目标: 背景:在一项针对复发或难治性多发性骨髓瘤的CASTOR III期研究中,达拉妥单抗,硼替佐米和地塞米松(D-Vd)与单纯Vd相比具有显着的临床益处。讨论了中位随访40.0个月后的结果。
    患者和方法:符合条件的患者接受了≥1线治疗,并在有或没有daratumumab(16 mg / kg)的情况下,给予硼替佐米(1.3 mg / m2)和地塞米松(20 mg)8个周期,直至疾病进展。
    结果:意向性治疗(ITT)人群中的498例患者(D-Vd,n = 251; Vd,n = 247),47%的患者曾接受过1种治疗(1PL; D-Vd,n = 122) ; Vd,n = 113)。在ITT人群中,D-Vd相对于Vd的中位无进展生存期(PFS)显着延长(16.7 vs. 7.1个月;危险比[HR]为0.31; 95%置信区间[CI]为0.25-0.40; P < .0001)和1PL子组(27.0 vs. 7.9个月; HR,0.22; 95%CI,0.15-0.32; P <.0001)。在来那度胺难治性患者中,D-Vd(n = 60)vs Vd(n = 81)的中位PFS为7.8 vs 4.9个月(HR,0.44; 95%CI,0.28-0.68; P = .0002)。 D-Vd相对于Vd的最小残留疾病(MRD)阴性率(10-5)更高(ITT:14%vs. 2%; 1PL:20%vs.3%;两者P <.0001)。 D-Vd相对于Vd显着延长了PFS2(ITT:HR,0.48; 95%CI,0.38-0.61; 1PL:HR,0.35; 95%CI,0.24-0.51; P <.0001)。没有发现新的安全隐患。
    结论:3年后,D-Vd在复发或难治性多发性骨髓瘤患者中保持了显着的获益,并具有一致的安全性。 D-Vd在首次复发时提供最大的益处,并增加了MRD阴性率。
  • 【硼替佐米和顺铂一线治疗恶性胸膜间皮瘤的II期研究和无进展生存率的前瞻性验证是间皮瘤临床试验的主要终点(欧洲研究与治疗组织)】 复制标题 收藏 收藏
    DOI:10.1016/j.ejca.2013.05.008 复制DOI
    作者列表:O'Brien ME,Gaafar RM,Popat S,Grossi F,Price A,Talbot DC,Cufer T,Ottensmeier C,Danson S,Pallis A,Hasan B,Van Meerbeeck JP,Baas P
    BACKGROUND & AIMS: BACKGROUND:This was a prospective phase II study of cisplatin and bortezomib (CB) in the first line treatment of malignant pleural mesothelioma (MPM) with validation of progression free survival rate at 18 weeks (PFSR-18)(1) as primary end-point. METHODS:Chemotherapy-naïve patients with histologically proven MPM and performance status (PS) 0/1, were treated with cisplatin 75 mg/m(2) on day 1 and bortezomib 1.3mg/m(2) on days 1, 4, 8, 11 every 3 weeks. The primary end-point validation utilised the landmark method. RESULTS:Between 2007 and 2010 82 patients were entered. PFSR-18 was 53% (80% confidence intervals, CIs, 42-64%). The overall survival (OS) was 13.5 months (95% CI 10.5-15) with 56% (95% CI 44-66%) alive at 1 year. The median PFS was 5.1months (95% CI 3.3-6.5) and the response rate was 28.4% (95% CI 18.9-39.5%). The most frequent grade 3-4 toxicities were hyponatremia (46%), hypokalaemia (17%), fatigue (12.2%), thrombocytopenia (11%), neutropenia (9.7%) and neurotoxicity (motor, sensory, other: 1.2%, 8.5%, 2.4%). There were two toxic deaths (32 and 74days) due to acute pneumonitis and cardiac arrest. End-point validation showed that patients with no progression/progression at 18 weeks had median OS of 16.9/11.9 months, respectively. Hazard ratio was 0.46 (CI 0.32-0.67), logrank test and C-index were 0.007 and 0.60. CONCLUSION:The 50% PFSR-18 for CB was contained within the 80% CI for (42-64%). Therefore the null hypothesis could not be rejected. Accordingly this combination does not warrant further investigation. PFSR-18 was confirmed as a strong predictor of survival.
    背景与目标: 背景:本研究为顺铂和硼替佐米(CB)在恶性胸膜间皮瘤(MPM)一线治疗中的前瞻性II期研究,以18周无进展生存率(PFSR-18)(1)为主要终点,观点。
    方法:未经化学疗法治疗且经组织学证实为MPM且表现状态(PS)为0/1的患者,在第1天接受顺铂75 mg / m(2),在第1,4,8天接受硼替佐米1.3mg / m(2)的治疗。 ,每3周11个。主要的终点验证利用了地标方法。
    结果:2007年至2010年间,共纳入82例患者。 PFSR-18为53%(80%置信区间,CI为42-64%)。总体生存期(OS)为13.5个月(95%CI 10.5-15),其中56%(95%CI 44-66%)在1年时还活着。 PFS中位数为5.1个月(95%CI为3.3-6.5),缓解率为28.4%(95%CI为18.9-39.5%)。 3-4级最常见的毒性反应是低钠血症(46%),低血钾症(17%),疲劳(12.2%),血小板减少症(11%),中性粒细胞减少症(9.7%)和神经毒性(运动,感觉,其他:1.2%, 8.5%,2.4%)。由于急性肺炎和心脏骤停,有两次中毒死亡(分别为32天和74天)。终点验证显示,在18周时无进展/进展的患者的OS中位数分别为16.9 / 11.9个月。危险比为0.46(CI 0.32-0.67),对数秩检验和C指数分别为0.007和0.60。
    结论:CB的50%PFSR-18包含在80%的CI中(42-64%)。因此,原假设不能被拒绝。因此,这种组合不值得进一步研究。 PFSR-18被证实是生存的有力预测指标。
  • 【硼替佐米对PC12衍生神经细胞中全局基因表达的影响。】 复制标题 收藏 收藏
    DOI:10.3390/ijms21030751 复制DOI
    作者列表:Łuczkowska K,Rogińska D,Ulańczyk Z,Machaliński B
    BACKGROUND & AIMS: :Peripheral neuropathy is one of the main side-effects of novel therapeutics used in oncohematological diseases, but the molecular basis underlying its development and progression as well as neurotoxicity mechanisms induced by the use of these therapeutics are still not fully elucidated. The aim of this study was to demonstrate the effect of bortezomib on global gene and miRNA expression on PC12-derived nerve cells. Microarray analysis showed that expression of 1383 genes was downregulated at least two fold and 671 genes were upregulated at least two fold in PC12-derived nerve cells treated with bortezomib compared to untreated/control cells. Analysis of functional annotations mainly identified downregulated processes (e.g., regulation of cell cycle, DNA replication and repair, regulation of cell migration, neuron projection morphogenesis and neurotransmitter secretion). The result of miRNA expression analysis demonstrated only 11 significantly downregulated miRNAs (at least two fold) in bortezomib-treated PC12-derived nerve cells vs. control cells. MiRNAs regulate gene expression, therefore we decided to conduct an analysis comparing the outcomes of miRNA microarray expression data to the obtained mRNA data. The most interesting miRNA-target gene correlation is downregulated expression of miR-130a-3p and miR-152-3p and as a result of this downregulation the expression of the Gadd45 increased. This gene is a member of a group of genes, the transcript expression of which is enhanced after stressful growth arrest conditions and treatment with DNA-damaging agents like drugs or mutagens.
    背景与目标: 周围神经病变是肿瘤血液学疾病中使用的新型疗法的主要副作用之一,但其发展和进程的分子基础以及使用这些疗法引起的神经毒性机制仍未完全阐明。这项研究的目的是证明硼替佐米对PC12来源的神经细胞的整体基因和miRNA表达的影响。微阵列分析显示,与未经处理/对照的细胞相比,在用硼替佐米处理过的PC12衍生的神经细胞中,1383个基因的表达被下调了至少两倍,而671个基因被上调了至少两倍。对功能注释的分析主要确定了下调的过程(例如,细胞周期调节,DNA复制和修复,细胞迁移调节,神经元投射形态发生和神经递质分泌调节)。 miRNA表达分析的结果表明,相比于对照细胞,在硼替佐米治疗的PC12衍生的神经细胞中只有11个显着下调的miRNA(至少两倍)。 MiRNA调节基因表达,因此我们决定进行分析,将miRNA微阵列表达数据的结果与获得的mRNA数据进行比较。最有趣的miRNA-靶基因相关性是miR-130a-3p和miR-152-3p的表达下调,并且由于这种下调,Gadd45的表达也增加了。该基因是一组基因的成员,在紧张的生长停滞条件下以及用诸如药物或诱变剂之类的DNA破坏剂处理后,其转录本表达得以增强。
  • 【具有伯基特淋巴瘤对硼替佐米有效的复杂基因特征的成纤维细胞血细胞淋巴瘤。】 复制标题 收藏 收藏
    DOI:10.1002/hon.2024 复制DOI
    作者列表:Dasanu CA,Bauer F,Codreanu I,Padmanabhan P,Rampurwala M
    BACKGROUND & AIMS: :Plasmablastic lymphoma shares many morphologic features with plasmablastic plasma cell myeloma. The activation of MYC oncogene in these lymphomas may be an important pathogenetic element associated with Epstein-Barr virus infection. We describe herein an elderly man with a plasmablastic lymphoid neoplasm displaying unique morphologic, cytogenetic and clinical features. This case might offer additional insights to the complex but fascinating topic of hybrid haemato-lymphoid neoplasms such as plasmablastic lymphoma-myeloma. In addition, the patient responded to the treatment with bortezomib. Newer antimyeloma agents such as bortezomib have shown promise in the treatment of these neoplasms and should further be explored for their therapy.
    背景与目标: :成浆细胞淋巴瘤与成浆细胞浆细胞骨髓瘤具有许多形态学特征。这些淋巴瘤中MYC癌基因的激活可能是与爱泼斯坦-巴尔病毒感染相关的重要致病因素。我们在这里描述了一位老人,患有浆母细胞淋巴样肿瘤,表现出独特的形态,细胞遗传学和临床特征。这种情况可能为杂种血细胞淋巴瘤(例如浆母细胞淋巴瘤-骨髓瘤)这一复杂但引人入胜的话题提供更多的见解。此外,患者对硼替佐米的治疗有反应。新型抗骨髓瘤药物如硼替佐米已在这些肿瘤的治疗中显示出希望,应进一步探索其治疗方法。
  • 【硼替佐米联合替莫唑胺和区域放射疗法在新诊断多形性胶质母细胞瘤患者中的前期治疗的2期研究:安全性和有效性评估。】 复制标题 收藏 收藏
    DOI:10.1016/j.ijrobp.2018.01.001 复制DOI
    作者列表:Kong XT,Nguyen NT,Choi YJ,Zhang G,Nguyen HN,Filka E,Green S,Yong WH,Liau LM,Green RM,Kaprealian T,Pope WB,Nghiemphu PL,Cloughesy T,Lassman A,Lai A
    BACKGROUND & AIMS: PURPOSE:To assess the safety and efficacy of upfront treatment using bortezomib combined with standard radiation therapy (RT) and temozolomide (TMZ), followed by adjuvant bortezomib and TMZ for ≤24 cycles, in patients with newly diagnosed glioblastoma multiforme (GBM). METHODS AND MATERIALS:Twenty-four patients with newly diagnosed GBM were enrolled. The patients received standard external beam regional RT with concurrent TMZ beginning 3 to 6 weeks after surgery, followed by adjuvant TMZ and bortezomib for ≤24 cycles or until tumor progression. During RT, bortezomib was given at 1.3 mg/m2 on days 1, 4, 8, 11, 29, 32, 36, and 39. After RT, bortezomib was given at 1.3 mg/m2 on days 1, 4, 8, and 11 every 4 weeks. RESULTS:No unexpected adverse events occurred from the addition of bortezomib. The efficacy analysis showed a median progression-free survival (PFS) of 6.2 months (95% confidence interval [CI] 3.7-8.8), with promising PFS rates at ≥18 months compared with historical norms (25.0% at 18 and 24 months; 16.7% at 30 months). In terms of overall survival (OS), the median OS was 19.1 months (95% CI 6.7-31.4), with improved OS rates at ≥12 months (87.5% at 12, 50.0% at 24, 34.1% at 36-60 months) compared with the historical norms. The median PFS was 24.7 months (95% CI 8.5-41.0) in 10 MGMT methylated and 5.1 months (95% CI 3.9-6.2) in 13 unmethylated patients. The estimated median OS was 61 months (95% CI upper bound not reached) in the methylated and 16.4 months (95% CI 11.8-21.0) in the unmethylated patients. CONCLUSIONS:The addition of bortezomib to current standard radiochemotherapy in newly diagnosed GBM patients was tolerable. The PFS and OS rates appeared promising, with more benefit to MGMT methylated patients. Further clinical investigation is warranted in a larger cohort of patients.
    背景与目标: 目的:评估硼替佐米联合标准放射治疗(RT)和替莫唑胺(TMZ)联合佐剂硼替佐米和TMZ≤24个周期的前期治疗在新诊断为多形胶质母细胞瘤(GBM)的患者的安全性和有效性。
    方法与材料:纳入24例新诊断为GBM的患者。患者在手术后3至6周开始接受标准的外部束区域RT并发TMZ,随后进行辅助TMZ和硼替佐米≤24个周期或直至肿瘤进展。在放疗期间,在第1、4、8、11、29、32、36和39天服用硼替佐米的剂量为1.3 mg / m2。在放疗之后,在1、4、8和8天服用硼替佐米的剂量为1.3mg / m2。每4周11个。
    结果:添加硼替佐米未发生意外不良事件。功效分析显示中位无进展生存期(PFS)为6.2个月(95%置信区间[CI] 3.7-8.8),与历史标准相比(18和24个月为25.0%),≥18个月的PFS率很有希望; 30个月时为16.7%)。就总生存期(OS)而言,中位OS​​为19.1个月(95%CI 6.7-31.4),≥12个月时OS率有所改善(12.时为87.5%,24时为50.0%,36-60个月时为34.1% )与历史规范进行比较。 10名MGMT甲基化患者的中位PFS为24.7个月(95%CI 8.5-41.0),而13名未甲基化患者的中位PFS为5.1个月(95%CI 3.9-6.2)。甲基化患者的估计中位OS为61个月(未达到95%CI上限),未甲基化患者的估计中位OS为16.4个月(95%CI 11.8-21.0)。
    结论:在新诊断的GBM患者中,将硼替佐米加到目前的标准放化疗中是可以忍受的。 PFS和OS率似乎很有希望,对MGMT甲基化患者有更多益处。有必要对更多的患者进行进一步的临床研究。
  • 【鞘脂代谢的失调导致硼替佐米引起的神经性疼痛。】 复制标题 收藏 收藏
    DOI:10.1084/jem.20170584 复制DOI
    作者列表:Stockstill K,Doyle TM,Yan X,Chen Z,Janes K,Little JW,Braden K,Lauro F,Giancotti LA,Harada CM,Yadav R,Xiao WH,Lionberger JM,Neumann WL,Bennett GJ,Weng HR,Spiegel S,Salvemini D
    BACKGROUND & AIMS: :The development of chemotherapy-induced painful peripheral neuropathy is a major dose-limiting side effect of many chemotherapeutics, including bortezomib, but the mechanisms remain poorly understood. We now report that bortezomib causes the dysregulation of de novo sphingolipid metabolism in the spinal cord dorsal horn to increase the levels of sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) ligands, S1P and dihydro-S1P. Accordingly, genetic and pharmacological disruption of S1PR1 with multiple S1PR1 antagonists, including FTY720, blocked and reversed neuropathic pain. Mice with astrocyte-specific alterations of S1pr1 did not develop neuropathic pain and lost their ability to respond to S1PR1 inhibition, strongly implicating astrocytes as a primary cellular substrate for S1PR1 activity. At the molecular level, S1PR1 engaged astrocyte-driven neuroinflammation and altered glutamatergic homeostasis, processes blocked by S1PR1 antagonism. Our findings establish S1PR1 as a target for therapeutic intervention and provide insight into cellular and molecular pathways. As FTY720 also shows promising anticancer potential and is FDA approved, rapid clinical translation of our findings is anticipated.
    背景与目标: :化学疗法诱发的疼痛性周围神经病的发展是许多化学疗法(包括硼替佐米)的主要剂量限制性副作用,但其机制仍知之甚少。我们现在报告硼替佐米引起脊髓背角新生鞘脂代谢的失调,从而增加了鞘氨醇-1-磷酸(S1P)受体1(S1PR1)配体,S1P和二氢-S1P的水平。因此,用多种S1PR1拮抗剂(包括FTY720)对S1PR1的遗传和药理破坏可阻断和逆转神经性疼痛。具有S1pr1星形胶质细胞特异性改变的小鼠没有发展成神经性疼痛,也没有丧失对S1PR1抑制的反应能力,强烈暗示星形胶质细胞是S1PR1活性的主要细胞底物。在分子水平上,S1PR1参与星形胶质细胞驱动的神经炎症并改变了谷氨酸能稳态,而S1PR1拮抗作用阻止了该过程。我们的发现将S1PR1确立为治疗干预的目标,并为细胞和分子途径提供了见识。由于FTY720还显示出有希望的抗癌潜力,并且已获得FDA批准,因此有望对我们的发现进行快速的临床翻译。
  • 【硼替佐米治疗联合化学疗法治疗非小细胞肺癌患者后发生的严重可逆性心力衰竭:病例报告。】 复制标题 收藏 收藏
    DOI:10.1186/1471-2407-6-129 复制DOI
    作者列表:Voortman J,Giaccone G
    BACKGROUND & AIMS: BACKGROUND:Bortezomib (Velcade), a dipeptide boronate proteasome inhibitor, is a novel anti-cancer agent registered for multiple myeloma (MM). It has also shown promising clinical activity in non-small cell lung cancer (NSCLC). Clinical experience with bortezomib so far indicates that overall incidence of cardiac failure associated with bortezomib therapy remains incidental. Nevertheless, acute development or exacerbation of congestive cardiac failure has been associated with bortezomib treatment. CASE PRESENTATION:We present here a case of severe, but reversible, congestive cardiac failure in a lung cancer patient who had no prior cardiac history, after receiving an experimental treatment of bortezomib combined with chemotherapy. Elevated levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), as retrospectively measured in archived serum samples, were suggestive of pre-existent (sub-clinical) left ventricular dysfunction. CONCLUSION:Based on literature, we hypothesize that baseline presence of sub clinical cardiomyopathy, characterized by a dysregulation of the ubiquitin-proteasome system, could have predisposed this patient for a cardiac side effect induced by systemic proteasome inhibition. Patients with heart disease or risk factors for it should be closely monitored when being submitted to treatment with proteasome inhibition therapy such as bortezomib. Caution is therefore warranted in lung cancer patients who often present with cardiac comorbidities.
    背景与目标: 背景:硼替佐米(Velcade)是一种二肽硼酸盐蛋白酶体抑制剂,是一种注册于多发性骨髓瘤(MM)的新型抗癌药。它还在非小细胞肺癌(NSCLC)中显示出令人鼓舞的临床活性。迄今为止,硼替佐米的临床经验表明,与硼替佐米治疗相关的心力衰竭总发生率仍然是偶然的。然而,硼替佐米治疗已引起充血性心力衰竭的急性发展或加重。
    病例介绍:在此我们接受了硼替佐米的实验治疗和化学疗法治疗后,没有既往心脏史的肺癌患者发生严重但可逆的充血性心力衰竭的病例。回顾性分析在存档的血清样本中,N端前B型利尿钠肽(NT-proBNP)的水平升高提示左心功能不全(先前存在)。
    结论:基于文献,我们假设以亚临床心肌病为基线存在,其特点是泛素-蛋白酶体系统功能失调,可能使该患者易受系统性蛋白酶体抑制所致的心脏副作用。当患有蛋白酶体抑制疗法(如硼替佐米)时,应密切监测患有心脏病或有此危险因素的患者。因此,对于经常表现出心脏合并症的肺癌患者,应格外小心。
  • 【硼替佐米用于先前未经治疗的多发性骨髓瘤患者:随机对照试验的系统评价和荟萃分析。】 复制标题 收藏 收藏
    DOI:10.1007/s00277-013-1711-7 复制DOI
    作者列表:Zeng Z,Lin J,Chen J
    BACKGROUND & AIMS: :Multiple myeloma (MM) is an incurable disease with a poor survival, which has not been affected even by high-dose chemotherapy. This systematic review was performed to assess the efficacy and safety of the novel agent bortezomib for patients with previously untreated MM. We systematically searched biomedical literature databases and identified randomized controlled trials (RCTs) comparing bortezomib with placebo, no bortezomib, or other active agents for patients with previously untreated MM. Overall survival (OS), reported as hazard ratio (HR) with 95% confidence interval (CI), was the primary outcome measure. The secondary outcomes included time to progression (TTP), progression-free survival (PFS), and response rates. Five RCTs involving 2,728 patients were included. Three trials compared bortezomib with no bortezomib, and two compared bortezomib with other active agents (vincristine ± adriamycin-based chemotherapy). All included RCTs had methodological shortcomings, including no or unclear allocation concealment and blinding. Compared with no bortezomib or vincristine-based chemotherapy, the bortezomib-based regimen significantly improved the OS of patients with previously untreated MM. HR was 0.71 (95% CI 0.55-0.93) and 0.77 (95% CI 0.60-0.99), respectively. However, when compared with the vincristine + adriamycin-based regimen, the OS was similar (HR = 0.87, 95% CI 0.57-1.33). TTP, PFS, and response rates were also improved in patients receiving bortezomib-based regimen. However, the risk of peripheral neuropathy was found to be significantly higher. In summary, bortezomib appears to improve survival and response rates of patients with previously untreated MM in spite of higher risk of peripheral neuropathy.
    背景与目标: :多发性骨髓瘤(MM)是一种无法治愈的疾病,其生存率很低,即使进行大剂量化疗也没有受到影响。进行了这项系统的评估,以评估新型药物硼替佐米对先前未经治疗的MM患者的疗效和安全性。我们系统地搜索了生物医学文献数据库,并确定了将硼替佐米与安慰剂,无硼替佐米或其他活性药物用于以前未经治疗的MM患者进行比较的随机对照试验(RCT)。总体生存期(OS)以危险比(HR)表示,置信区间(CI)为95%,是主要的结局指标。次要结果包括进展时间(TTP),无进展生存期(PFS)和缓解率。纳入了5项RCT,涉及2,728例患者。三项试验比较了硼替佐米与无硼替佐米,两项试验将硼替佐米与其他活性剂(以长春新碱±阿霉素为基础的化疗)进行比较。所有纳入的RCT都有方法上的缺陷,包括没有或不清楚的分配隐藏和盲目性。与不使用硼替佐米或长春新碱为基础的化疗相比,基于硼替佐米的方案显着改善了先前未经治疗的MM患者的OS。 HR分别为0.71(95%CI 0.55-0.93)和0.77(95%CI 0.60-0.99)。但是,与基于长春新碱阿霉素的方案相比,OS相似(HR = 0.87,95%CI 0.57-1.33)。接受基于硼替佐米的治疗方案的患者的TTP,PFS和反应率也得到改善。然而,发现周围神经病的风险明显更高。总之,尽管周围神经病变的风险较高,但硼替佐米似乎可以改善先前未经治疗的MM患者的存活率和反应率。
  • 【新型抗骨髓瘤药物perifosine,硼替佐米和来那度胺对不同细胞系的体外细胞毒性。】 复制标题 收藏 收藏
    DOI:10.1007/s10637-010-9576-2 复制DOI
    作者列表:Schmidt-Hieber M,Dabrowski R,Weimann A,Aicher B,Lohneis P,Busse A,Thiel E,Blau IW
    BACKGROUND & AIMS: :The novel AKT inhibitor perifosine, a synthetic alkylphospholipid, is currently being investigated in clinical trials for the treatment of different hematological and oncological malignancies. The in vitro cytotoxicity of perifosine, bortezomib and lenalidomide against 6 cell lines derived from hematological malignancies was investigated using trypan blue staining, flow cytometry-based detection of activated caspases, Annexin V assays, immunohistochemistry studies (KI-67 and caspase-3 staining) and the immature-myeloid-information (IMI) technique. Perifosine and bortezomib induced concentration- and time-dependent cytotoxicity in all cell lines tested. Perifosine together with bortezomib largely exerted additive or synergistic effects with combination indices ranging from 1.13 to 0.22 for combined efficacies of 25% to 75% after 24-hour incubation. Lenalidomide-triggered cytotoxicity was low in all cell lines tested with any assay (less than 10% compared to the negative control). Finally, perifosine, but not bortezomib or lenalidomide, significantly increased the number of cells detected in the IMI channel. Perifosine and bortezomib- but not lenalidomide- trigger substantial cytotoxicity by caspase activation and mainly act additively or synergistically. The IMI technique might be a useful tool for studying cytotoxicity of agents like perifosine that interact mainly with the cellular membrane.
    背景与目标: :新型AKT抑制剂periposine,一种合成的烷基磷脂,目前正在临床试验中用于治疗不同的血液和肿瘤恶性肿瘤。使用台盼蓝染色,基于流式细胞仪的活化半胱天冬酶检测,膜联蛋白V分析,免疫组织化学研究(KI-67和caspase-3染色),研究了哌磷磷,硼替佐米和来那度胺对6种衍生自血液系统恶性肿瘤的细胞系的体外细胞毒性。以及未成熟的骨髓信息(IMI)技术。 Perifosine和bortezomib在所有测试的细胞系中诱导浓度和时间依赖性的细胞毒性。 Perifosine与硼替佐米在24小时孵育后的组合指数从1.13至0.22发挥了很大的累加或协同作用,综合功效从25%到75%不等。在任何试验中测试的所有细胞系中来那度胺触发的细胞毒性均较低(与阴性对照相比不到10%)。最后,periposine(而不是硼替佐米或来那度胺)显着增加了在IMI通道中检测到的细胞数量。 Perifosine和硼替佐米(而非来那度胺)可通过caspase激活而触发实质性的细胞毒性,并且主要起累加或协同作用。 IMI技术可能是研究主要与细胞膜相互作用的药剂(如过磷酸氢钙)的细胞毒性的有用工具。
  • 【蛋白酶体抑制剂硼替佐米在人乳腺癌细胞中的差异性细胞和分子效应。】 复制标题 收藏 收藏
    DOI:10.1158/1535-7163.MCT-05-0147 复制DOI
    作者列表:Codony-Servat J,Tapia MA,Bosch M,Oliva C,Domingo-Domenech J,Mellado B,Rolfe M,Ross JS,Gascon P,Rovira A,Albanell J
    BACKGROUND & AIMS: :The cellular and molecular effects of the proteasome inhibitor bortezomib on breast cancer cells are as yet poorly characterized. Here, in a panel of six breast cancer cell lines, bortezomib reduced viability in a concentration-dependent, time-dependent, and cell line-dependent manner. Proteasome activity was relatively high in two of the three more resistant cell lines. No relationship was observed between bortezomib effects on cell viability and expression/phosphorylation of HER-2, epidermal growth factor receptor (EGFR), AKT, or extracellular signal-regulated kinase 1/2 (ERK1/2). Molecular effects of bortezomib were further studied in SK-BR-3 and BT-474 cells because they share expression of EGFR and overexpression of HER-2 while, in contrast, SK-BR-3 cells were 200-fold more sensitive to this agent. Proteasome activity was inhibited to a similar extent in the two cell lines, and known proteasome substrates accumulated similarly. In SK-BR-3 cells, a marked inhibition of EGFR, HER-2, and AKT phosphorylation was observed at a clinically relevant concentration of bortezomib. In contrast, phosphorylation of Raf/mitogen-activated protein kinase kinase 1/2 (MEK 1/2)/ERK1/2 increased by bortezomib. In BT-474 cells, the effects were much less pronounced. Treatment of SK-BR-3 cells with bortezomib combined with pharmacologic inhibitors of EGFR, phosphatidylinositol 3'-kinase, or MEK resulted in modest or no enhancement of the effects on cell viability. Collectively, these results show that bortezomib has differential cellular and molecular effects in human breast cancer cells. The bortezomib-observed effects on signaling transduction molecules might be relevant to help to design mechanistic-based combination treatments.
    背景与目标: :蛋白酶体抑制剂硼替佐米对乳腺癌细胞的细胞和分子作用尚未明确。在此,在一组六个乳腺癌细胞系中,硼替佐米以浓度依赖性,时间依赖性和细胞系依赖性方式降低了生存能力。在另外三个耐药细胞系中的两个中,蛋白酶体活性相对较高。硼替佐米对细胞生存力的影响与HER-2,表皮生长因子受体(EGFR),AKT或细胞外信号调节激酶1/2(ERK1 / 2)的表达/磷酸化之间没有相关性。硼替佐米在SK-BR-3和BT-474细胞中的分子作用得到了进一步研究,因为它们共享EGFR的表达和HER-2的过表达,而SK-BR-3细胞对该剂的敏感性高200倍。 。蛋白酶体活性在两种细胞系中被抑制到相似的程度,并且已知的蛋白酶体底物也相似地积累。在SK-BR-3细胞中,在临床相关浓度的硼替佐米中观察到EGFR,HER-2和AKT磷酸化的明显抑制作用。相反,硼替佐米可增加Raf /丝裂原活化蛋白激酶激酶1/2(MEK 1/2)/ ERK1 / 2的磷酸化。在BT-474细胞中,这种作用不那么明显。用硼替佐米联合EGFR,磷脂酰肌醇3'-激酶或MEK的药物抑制剂治疗SK-BR-3细胞,对细胞生存力的影响没有或没有增强。总的来说,这些结果表明硼替佐米在人乳腺癌细胞中具有不同的细胞和分子效应。硼替佐米观察到的对信号转导分子的影响可能与帮助设计基于机制的联合治疗有关。

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