沙利度胺联合曲安奈德抑制人脐静脉内皮细胞增殖的研究

目的:研究沙利度胺(thalidomide)联合曲安奈德对人脐静脉内皮细胞(HUVEC)的药物作用.方法:Ⅰ型胶原酶消化法原代培养HUVEC, Ⅷ因子相关抗原检测法鉴定细胞.沙利度胺溶于0.5%二甲基亚砜(DMSO)中,分为3组.A组为沙利度胺组,分4个浓度梯度,分别为10、25、50和75 mg/L;B组为沙利度胺+曲安奈德组,为含1 mg/L曲安奈德的各浓度沙利度胺;C组为对照组.HUVEC传代植入96孔板,细胞密度为1×10~4/mL,过夜,加入不同浓度的药物,处理72 h; 在酶标仪570 nm波长处读取吸光度(A)值. 结果: 2组药物均对HUVEC的增殖有明显的抑制作用 (P < 0.01),抑制作用与药物浓度呈正相关;与A组相比,B组对HUVEC抑制作用更强(P < 0.05).结论:沙利度胺及曲安奈德对血管内皮细胞增殖有明显作用,这两类药物在治疗新生血管性疾病中可发挥一定作用.     

High complete remission rate and durable remissions achieved with rational use of autologous stem‐cell transplantation,thalidomide maintenance,and non‐myeloablative allogeneic transplantation in patients with multiple myeloma

Abstract: Autologous stem‐cell transplantation (ASCT) has emerged as the standard approach in patients with multiple myeloma, although it is unlikely to achieve cure. Thalidomide maintenance and non‐myeloablative allogeneic transplantation (NST) may increase complete remission (CR) rate and increase overall survival. In this study, 35 ASCT and 10 NST were performed in 33 patients. Patients, who were resistant or relapsed following ASCT, underwent NST if they had an HLA‐matched sibling, otherwise treated with a second ASCT. Thalidomide was started as maintenance after ASCT. After first transplantation, three patients underwent second ASCT and 10 patients underwent NST. Following first transplantation, CR rate was 39% and increased to 60% (overall response 93%) with addition of thalidomide, bortezomib, and second transplantation. CR was durable in 14 (42%) patients. During a median follow‐up of 24 months, 18 patients progressed and nine patients died. The 100‐d transplant‐related mortality was <5%. The four‐yr progression‐free survival (PFS) was 52.4%. In conclusion, ASCT followed by thalidomide and NST in resistant patients can lead to high CR and PFS rates. As a second transplantation has not been performed routinely, patients having durable CR had a chance to avoid or delay a second transplantation without compromising disease control.     

From the bench to the bedside: emerging new treatments in multiple myeloma

Within the last decade, several novel classes of anti-myeloma therapeutics have become available. The clinical successes achieved by thalidomide, lenalidomide, and the proteasome inhibitor bortezomib, and in particular the ability of these agents to lead to major clinical responses in patients resistant to conventional or high-dose chemotherapy, have highlighted the importance of expanding further the spectrum of classes of agents utilized for the treatment of myeloma. Herein, we review the current status for the development of novel anti-myeloma agents, with emphasis on classes of therapeutics which have already translated into clinical trials or those in advanced stages of preclinical development. These include second-generation proteasome inhibitors (NPI-0052 and PR-171), heat shock protein 90 (hsp90) inhibitors, 2-methoxyestradiol, histone deacetylase (HDAC) inhibitors (e.g. SAHA and LBH589), fibroblast growth factor receptor 3 (FGF-R3) inhibitors, insulin-like growth factor 1 receptor (IGF-1R) inhibitors, mTOR inhibitors, monoclonal antibodies, and agents specifically targeting the tumor microenvironment, such as defibrotide.     

Combination of thalidomide and cisplatin in an head and neck squamous cell carcinomas model results in an enhanced antiangiogenic activity in vitro and in vivo

Thalidomide is an immunomodulatory, antiangiogenic drug. Although there is evidence that it might be more effective in combination with chemotherapy the exact mechanism of action is unclear. Therefore, we investigated its effect in combination with metronomically applied cisplatin in a xenotransplant mouse model characteristic for advanced head and neck squamous cell carcinomas, its possible synergistic action in vitro, and which tumor-derived factors might be targeted by thalidomide. Although thalidomide alone was ineffective, a combined treatment with low-dose cisplatin inhibited significant tumor growth, proliferation and angiogenesis in vivo as well as migration and tube formation of endothelial cells in vitro. Noteworthy, the latter effect was enhanced after coapplication of cisplatin in nontoxic doses. An inhibitory effect on tumor cell migration was also observed suggesting a direct antitumor effect. Although thalidomide alone did not influence cell proliferation, it augmented antiproliferative response after cisplatin application emphasizing the idea of a potentiated effect when both drugs are combined. Furthermore, we could show that antiangiogenic effects of thalidomide are related to tumor-cell derived factors including vascular endothelial growth factor, basic fibroblast growth factor, hepatocyte growth factor and Il-8 some known and with, granulocyte colony stimulating growth factor and granulocyte macrophage colony stimulating growth factor, some new target molecules of thalidomide. Altogether, our findings reveal new insights into thalidomide-mediated antitumor and antiangiogenic effects and its interaction with cytostatic drugs.     

Emergence of central nervous system myeloma in the era of novel agents

Although multiple myeloma (MM) remains an incurable disease, considerable improvements in survival have been made with the introduction of autologous stem cell transplantation and new drugs. Central nervous system (CNS) MM is a rare complication associated with poor survival. Historically, CNS disease developed early in the course of MM; however recently, patients often present with CNS disease following multiple lines of therapy. It is hypothesized that exposure to novel agents (thalidomide, lenalidomide and bortezomib) changes the natural history of MM, increasing the lifetime risk of CNS disease. We analysed the baseline characteristics, treatment and outcome data of patients who presented with CNS MM at Peter MacCallum Cancer Centre between 2001 and 2010. Seven patients were identified, from 2005 onwards. All patients were Durie–Salmon stage IIIA or IIIB and International Staging System Scores I to III at baseline. All had received at least three lines of therapy, including high‐dose chemotherapy with autologous stem cell transplantation and a novel agent, prior to developing CNS MM. Median time from diagnosis to CNS disease was 24 months (range 10–42). All patients died after developing CNS disease with median survival post‐CNS disease of 2 months (range 1–23). The incidence of CNS MM is increasing, and time to development of CNS manifestations is prolonging, associated with increased use of high‐dose chemotherapy and novel agents. Whether this is due to improved overall survival or specific characteristics of these therapies is not clear. Despite the availability of novel agents, survival after CNS MM remains poor. Copyright © 2011 John Wiley & Sons, Ltd.     

沙利度胺联合TACE序贯适形放疗治疗原发性肝癌的疗效

目的：评价沙利度胺联合肝动脉栓塞化疗（trancather arterial chemoembolization,TACE）序贯适形放疗治疗原发性肝癌的疗效.方法：符合入组条件的中晚期肝癌患者77例随机分为治疗组（A组）38例和对照组（B组）39例,A组为沙利度胺联合TACE序贯适形放疗.沙利度胺：口服剂量为200mg/d,同时联合TACE,TACE用药选用吉西他滨0.8-1.4g,栓塞剂选用碘化油、明胶海绵.4周后如无放疗禁忌症,行肝部肿瘤立体定向适形放疗,分割剂量为3.0-5.0Gy,50％等剂量线包绕P-GTV,边缘剂量30-40Gy.放疗结束后继续予沙利度胺维持治疗,维持量达（200-300） mg/d,服药至少3个月以上.B组单纯行TACE序贯适形放疗,方案及剂量同上.结果：近期疗效两组无完全缓解（CR）病例.A组有效率为51.6％;B组有效率为43.8％,两组差异无显著性（P＞0.05）.A组和B组患者的中位生存期分别为17个月、14个月,A组半年、1年、2年生存率分别为93.5％、61.3％、22.6％;B组半年、1年、2年生存率分别为87.5％、59.3％、15.6％.口服沙利度胺3个月以上患者与对照组病例相比,生存期有显著性差异（P＜0.05）.放疗联合TACE、口服沙利度胺组,与未接受放疗患者相比,其生存期有显著性差异（P＜0.05）.治疗组严重皮疹发生率为5.3％,严重嗜睡、头晕发生率为10.5％.结论：沙利度胺联合TACE序贯适形放疗治疗原发性肝癌能延长患者生存期,适形放疗有可能在综合治疗肝癌中发挥重要作用.     

沙利度胺联合肝动脉化疗栓塞治疗中晚期肝癌的临床研究

探讨沙利度胺(TLD)联合肝动脉化疗栓塞(TACE)治疗中晚期原发性肝癌的临床疗效及不良反应。120例患者随机分为观察组和对照组各60例,观察组在TACE基础上加口服TLD,对照组不用TLD。近期疗效显示,观察组肿瘤完全缓解(CR)8例,部分缓解(PR)45例,无变化(SD)4例,进展(PD)3例,总有效率为88.3%,对照组为65.0%(P=0.037)。两组未见严重不良反应发生。随访3年,观察组1、2和3年生存率分别为75.0%、69.8%和55.2%;对照组为48.3%、42.9%和33.3%,P<0.05。初步研究结果提示,应用TLD联合TACE治疗中晚期原发性肝癌疗效明显,不良反应轻,具有较好的临床应用价值。