• 【对硼替佐米的反应和多发性骨髓瘤中成骨细胞的活化。】 复制标题 收藏 收藏
    DOI:10.3816/CLM.2006.n.047 复制DOI
    作者列表:Zangari M,Yaccoby S,Cavallo F,Esseltine D,Tricot G
    BACKGROUND & AIMS: :Histomorphometry and biochemical markers of bone turnover have shown that, although osteoclast activity is increased in multiple myeloma (MM), mostly through the receptor activator of nuclear factor-kappaB ligand/osteoprotegerin axis, the key element in vivo to determine the presence or absence of osteolytic lesions resides on the presence and activity of osteoblasts. The loss of bone observed in MM is the result of an uncoupling of bone formation and bone resorption. Bortezomib is a first-in-class proteasome inhibitor developed as an antineoplastic agent with marked activity in relapsed/refractory MM. Response to bortezomib has been related to a significant increase in alkaline phosphatase (ALP). Increased ALP in patients responding to bortezomib was associated with a parallel increase in bone-specific ALP and parathyroid hormone, suggesting that response to bortezomib in MM is closely associated with osteoblastic activation. Variation in markers of osteoblastic activation (such as ALP) have also predicted response and response duration in patients with myeloma treated with bortezomib (P < 0.0001). This clinical observation has been confirmed in an experimental mouse model for primary human myeloma. The consequences of increased bone anabolism on myeloma growth need to be closely evaluated in prospective trials.
    背景与目标: :骨形态学的骨形态计量学和生化标记表明,尽管破骨细胞活性在多发性骨髓瘤(MM)中增加,但主要是通过核因子-κB配体/骨保护素轴的受体激活剂,这是体内确定是否存在的关键因素溶骨性病变的原因在于成骨细胞的存在和活性。在MM中观察到的骨骼损失是骨骼形成与骨骼吸收解耦的结果。硼替佐米是一流的蛋白酶体抑制剂,被开发为在复发/难治性MM中具有显着活性的抗肿瘤药。对硼替佐米的反应与碱性磷酸酶(ALP)的显着增加有关。对硼替佐米治疗的患者的ALP升高与骨特异性ALP和甲状旁腺激素的同时升高相关,这表明MM对硼替佐米的反应与成骨细胞活化密切相关。成骨细胞活化标志物(例如ALP)的变化还预测了硼替佐米治疗的骨髓瘤患者的反应和反应持续时间(P <0.0001)。这项临床观察已在原发性人类骨髓瘤的实验小鼠模型中得到证实。骨合成代谢增加对骨髓瘤生长的影响需要在前瞻性试验中进行仔细评估。
  • 【硼替佐米是一种新的治疗弹状浆细胞样树突状细胞瘤的方法。】 复制标题 收藏 收藏
    DOI:10.3324/haematol.2017.169326 复制DOI
    作者列表:Philippe L,Ceroi A,Bôle-Richard E,Jenvrin A,Biichle S,Perrin S,Limat S,Bonnefoy F,Deconinck E,Saas P,Garnache-Ottou F,Angelot-Delettre F
    BACKGROUND & AIMS: :Blastic plasmacytoid dendritic cell neoplasm is an aggressive hematologic malignancy with a poor prognosis. No consensus regarding optimal treatment modalities is currently available. Targeting the nuclear factor-kappa B pathway is considered a promising approach since blastic plasmacytoid dendritic cell neoplasm has been reported to exhibit constitutive activation of this pathway. Moreover, nuclear factor-kappa B inhibition in blastic plasmacytoid dendritic cell neoplasm cell lines, achieved using either an experimental specific inhibitor JSH23 or the clinical drug bortezomib, interferes in vitro with leukemic cell proliferation and survival. Here we extended these data by showing that primary blastic plasmacytoid dendritic cell neoplasm cells from seven patients were sensitive to bortezomib-induced cell death. We confirmed that bortezomib efficiently inhibits the phosphorylation of the RelA nuclear factor-kappa B subunit in blastic plasmacytoid dendritic cell neoplasm cell lines and primary cells from patients in vitro and in vivo in a mouse model. We then demonstrated that bortezomib can be associated with other drugs used in different chemotherapy regimens to improve its impact on leukemic cell death. Indeed, when primary blastic plasmacytoid dendritic cell neoplasm cells from a patient were grafted into mice, bortezomib treatment significantly increased the animals' survival, and was associated with a significant decrease of circulating leukemic cells and RelA nuclear factor-kappa B subunit expression. Overall, our results provide a rationale for the use of bortezomib in combination with other chemotherapy for the treatment of patients with blastic plasmacytoid dendritic cell neoplasm. Based on our data, a prospective clinical trial combining proteasome inhibitor with classical drugs could be envisaged.
    背景与目标: :弹性浆细胞样树突状细胞瘤是一种侵袭性血液恶性肿瘤,预后较差。目前尚无关于最佳治疗方式的共识。靶向核因子-κB途径被认为是一种有前途的方法,因为据报道,原生质浆样树突状细胞瘤表现出该途径的组成性激活。此外,使用实验性特异性抑制剂JSH23或临床药物硼替佐米可达到的抑制浆液样树突状树突状细胞瘤细胞系中核因子κB的作用,在体外干扰白血病细胞的增殖和存活。在这里,我们通过显示来自7名患者的原发性母细胞浆样树突状细胞瘤细胞对硼替佐米诱导的细胞死亡敏感而扩展了这些数据。我们证实硼替佐米有效抑制小鼠模型中体外和体内来自患者的原始浆细胞样树突状细胞瘤细胞系和原代细胞中RelA核因子-κB亚基的磷酸化。然后,我们证明了硼替佐米可以与其他化疗方案中使用的其他药物联用,以改善其对白血病细胞死亡的影响。确实,当将来自患者的原发性母细胞浆样树突状细胞瘤移植到小鼠体内时,硼替佐米治疗可显着提高动物的存活率,并且与循环白血病细胞和RelA核因子-κB亚基表达的显着降低有关。总体而言,我们的结果为将硼替佐米与其他化学疗法联合用于治疗原发性浆细胞样树突状细胞瘤患者提供了理论依据。根据我们的数据,可以设想将蛋白酶体抑制剂与经典药物联合使用的前瞻性临床试验。
  • 【硼替佐米在肝细胞癌中诱导肿瘤特异性细胞死亡和生长抑制,并改善肝纤维化。】 复制标题 收藏 收藏
    DOI:10.1007/s00535-012-0675-z 复制DOI
    作者列表:Saeki I,Terai S,Fujisawa K,Takami T,Yamamoto N,Matsumoto T,Hirose Y,Murata Y,Yamasaki T,Sakaida I
    BACKGROUND & AIMS: BACKGROUND:Human hepatocellular carcinoma (HCC) is highly ubiquitinated. The ubiquitination is important to the generatation of HCC. The antitumor and antifibrosis effects of an ubiquitin-proteasome system inhibitor, bortezomib, on HCC with liver cirrhosis (LC) were analyzed in vitro and in vivo. METHODS:The effect of bortezomib was analyzed in the rat hepatocarcinogenesis model using a DEN and CDAA diet (DEN/CDAA model), which shows severe LC and generation of HCC. The decrease of GST-P-positive foci and HCC were analyzed in vivo. Cell death was analyzed by cell death detection kit. Liver fibrosis was checked by sirius-red staining and α-smooth muscle actin staining. The in vitro study involved 3 HCC cell lines (HepG2, HuH7, and HLF) and primary rat and human hepatocytes. The proliferation rate of the HCC cell line was analyzed using the MTT assay and FACS analysis. The toxicity of bortezomib was checked using the LDH release assay for primary human and rat hepatocytes. RESULTS:In the rat hepatocarcinogenesis model, bortezomib prevented the development of preneoplastic lesions during the early stages of hepatocarcinogenesis and specifically induced cell death in HCC. Furthermore, bortezomib inhibited cell proliferation and induced tumor-specific cell death in HCC cell lines with decrease of cyclin D1 and phospho-Rb expression. Further, bortezomib showed no hepatotoxicity of primary rat and human hepatocytes, suggesting that it might be an HCC-specific drug. Bortezomib also prevented the activation of hepatic stellate cells and inhibited the liver fibrosis of the DEN/CDAA model. CONCLUSIONS:Bortezomib appears to be an ideal target drug for HCC with LC.
    背景与目标: 背景:人类肝细胞癌(HCC)高度泛素化。泛素化对于肝癌的产生很重要。在体外和体内分析了泛素-蛋白酶体系统抑制剂硼替佐米对肝硬化肝细胞癌的抗肿瘤和抗纤维化作用。
    方法:使用DEN和CDAA饮食(DEN / CDAA模型)分析了硼替佐米在大鼠肝癌模型中的作用,该模型显示出严重的LC和肝癌的产生。体内分析了GST-P阳性灶和HCC的减少。通过细胞死亡检测试剂盒分析细胞死亡。肝纤维化通过天青红色染色和α-平滑肌肌动蛋白染色检查。体外研究涉及3种HCC细胞系(HepG2,HuH7和HLF)以及原代大鼠和人类肝细胞。使用MTT测定和FACS分析来分析HCC细胞系的增殖速率。硼替佐米的毒性使用LDH释放测定法对原代人和大鼠肝细胞进行了检查。
    结果:在大鼠肝癌发生模型中,硼替佐米预防了肝癌发生早期肿瘤前病变的发展,并特异性地诱导了肝癌细胞的死亡。此外,硼替佐米可抑制HCC细胞株的细胞增殖并诱导肿瘤特异性细胞死亡,并降低细胞周期蛋白D1和磷酸化Rb的表达。此外,硼替佐米未显示对原代大鼠和人肝细胞有肝毒性,表明它可能是HCC特异性药物。硼替佐米还阻止了肝星状细胞的活化,并抑制了DEN / CDAA模型的肝纤维化。
    结论:硼替佐米似乎是LC伴肝癌的理想靶标药物。
  • 【使用基于硼替佐米的诱导疗法治疗的多发性骨髓瘤患者之间的细菌感染:亚洲癌症中心的真实经验。】 复制标题 收藏 收藏
    DOI:10.1016/j.clml.2019.12.024 复制DOI
    作者列表:Soekojo CY,Low JZ,Oh J,Ooi M,De Mel S,Chng WJ
    BACKGROUND & AIMS: BACKGROUND:The treatment landscape for multiple myeloma (MM) has progressed significantly, and over the past decade, bortezomib-based induction therapy has been a standard of care. However, the practice of antibacterial prophylaxis during induction therapy has been diverse. The aim of our study is to evaluate the proportion of patients with febrile episodes and bacteremia among patients with MM, during the first 12 weeks of bortezomib-based induction therapy, without routine fluoroquinolone prophylaxis, but with routine Pneumocystis Carinii prophylaxis (mostly with trimethoprim-sulfamethoxazole), in a region with high fluoroquinolone resistance rate. Of note, these patients have direct access to health care facilities and timely supportive care. PATIENTS AND METHODS:We evaluated newly diagnosed MM patients from 2014 to 2018 receiving bortezomib-based induction therapy for the proportion of patients who had febrile episodes and bacteremia in the first 12 weeks of bortezomib-based induction therapy. We also evaluated if there were factors associated with increased febrile episodes including age, absolute neutrophil count, creatinine clearance, M-band level at diagnosis, nadir platelet count, International Staging System, and Revised International Staging System. RESULTS:Of the 108 evaluable patients, there were a total of 25 (23.1%) patients who had febrile episodes, and 1 (0.9%) patient who had bacteremia during the first 12 weeks of bortezomib-based induction therapy. All patients recovered well. No deaths were seen. Febrile episodes were associated with lower absolute neutrophil count (P = .036), renal impairment (P = .013), and ISS stage (P = .026). CONCLUSION:The proportion of patients with significant bacterial infection during the first 12 weeks of bortezomib-based induction therapy without routine fluoroquinolone prophylaxis, but with routine Pneumocystis Carinii prophylaxis (mostly with trimethoprim-sulfamethoxazole), is low in a population with adequate access to health care facilities and timely supportive care.
    背景与目标: 摘要背景:多发性骨髓瘤(MM)的治疗领域已取得重大进展,并且在过去的十年中,基于硼替佐米的诱导治疗已成为治疗的标准。但是,在诱导疗法中进行抗菌预防的方法多种多样。我们研究的目的是评估在基于硼替佐米的诱导治疗的前12周,没有常规氟喹诺酮预防措施,但有常规肺囊虫Carinii预防措施(主要是甲氧苄氨嘧啶,氟喹诺酮耐药率较高的区域。值得注意的是,这些患者可以直接使用卫生保健设施并及时获得支持治疗。
    患者和方法:我们评估了2014年至2018年接受基于硼替佐米为基础的诱导治疗的新诊断MM患者在基于硼替佐米为基础的诱导治疗的前12周中出现高热发作和菌血症的患者的比例。我们还评估了是否有与高热发作相关的因素,包括年龄,绝对中性粒细胞计数,肌酐清除率,诊断时的M带水平,最低点血小板计数,国际分期系统和修订的国际分期系统。
    结果:在108名可评估的患者中,在基于硼替佐米的诱导治疗的前12周中,共有25例(23.1%)出现高热发作,1例(0.9%)出现菌血症。所有患者康复良好。没有看到死亡。高热发作与较低的绝对中性粒细胞计数(P = .036),肾功能不全(P = .013)和ISS分期(P = .026)有关。
    结论:在以硼替佐米为基础的诱导治疗的前12周,未常规预防氟喹诺酮但常规预防卡氏肺孢子虫(主要采用甲氧苄啶-磺胺甲基异恶唑)的患者中,发生严重细菌感染的患者比例较低。护理设施和及时的支持性护理。
  • 【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。

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