New anti-angiogenesis agents: review of the clinical experience with carboxyamido-triazole (CAI), thalidomide, TNP-470 and interleukin-12

Angiogenesis was postulated to be a critical prognostic factor and therapeutic focus for malignancy more than two decades ago. Recent studies indicate quantitative assessments of microvessel count to be an independent prognostic variable for disease-free and overall survival in a wide variety of tumors, and that angiogenesis may be a feasible target against which to intervene pharmacologically. Several new and old agents have been found to have anti-angiogenic activity and have reached clinical trial. This review will focus on four agents under investigation in the US: carboxyamido-triazole (CAI), thalidomide, TNP-470 and interleukin (IL)-12. CAI, originally identified for its anti-invasive capacity, has been shown to inhibit tumor and endothelial cell proliferation by inhibition of calcium uptake. It is administered orally, is generally well tolerated, and has been shown to induce disease stabilization and occasional reductions in tumor mass. Thalidomide was shown to inhibit growth factor-induced neovessel formation, a process that can also explain its earlier devastating clinical toxicity. It is administered orally, and is currently in phase II clinical trials for prostate cancer, glioblastoma multiforme and breast cancer. TNP-470 is a fumagillin analog that has been shown in in vivo models to be a potent inhibitor of angiogenesis at concentrations that are cytostatic to endothelial cells and tumor cells. Lastly, IL-12 may exert its anti-angiogenic effects through activation of interferon- to up-regulate interferon-inducible protein-10, an anti-angiogenic cytokine. Phase I clinical trials of IL-12 have shown disease stabilization in several tumor types in response to s.c. administration or using genetically engineered IL-12-expressing patient fibroblasts. These promising new agents join the matrix metalloproteinase inhibitors as important new drugs in the anti-cancer armamentarium.     

The effects of selective cytokine inhibitory drugs (CC-10004 and CC-1088) on VEGF and IL-6 expression and apoptosis in myeloma and endothelial cell co-cultures

Myeloma cells and human umbilical vein endothelial cells (HUVECs) were co-cultured to model in vitro the interactions between myeloma and endothelium, and treated with thalidomide and two selective cytokine inhibitory drugs (SelCIDs, phosphodiesterase-4 inhibitors). Flow cytometry and enzyme-linked immunosorbent assay were used to assess production of two key cytokines--vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6)--and apoptosis in co-cultured HUVECs and myeloma cells. VEGF was produced by both myeloma cells and HUVECs, while IL-6 was almost exclusively produced by endothelial cells. In co-culture, there was significant up-regulation of VEGF and IL-6 production compared with the sum of separate myeloma and endothelial cell cultures. SelCIDs markedly inhibited production of both cytokines in co-cultures, with CC-10004 being more potent than CC-1088. In addition, SelCIDs induced myeloma cell apoptosis. Apoptosis in co-cultured myeloma cells was significantly lower than in those cultured separately, suggesting that co-culture partially protected myeloma cells from drug-induced apoptosis. This protective effect was probably due to IL-6 produced by endothelial cells in co-culture as addition of anti-IL-6 neutralizing antibody, but not anti-VEGF antibody, abrogated it. In conclusion, SelCIDs can exert their anti-myeloma activity through two mechanisms, i.e. inhibition of VEGF and IL-6 production by interacting myeloma and endothelium and induction of myeloma cell apoptosis.     

环孢素A联合沙利度胺治疗骨髓增生异常综合征对T细胞亚群影响的初步研究

为探讨环孢素A联合沙利度胺治疗骨髓增生异常综合征对T细胞亚群的影响,我们对2007年6月至2012年6月我院血液内科门诊和住院低中危MDS患者22例,在给予环孢素A联合沙利度胺治疗前后,应用流式细胞仪对于患者和健康志愿者外周血标本进行T淋巴细胞亚群检测。我们发现:CD4+T细胞在MDS患者外周血的百分比低于正常对照组(P<0.05),CD4/CD8比值与正常对照组相比有显著性差异(P<0.05)。治疗显效组患者治疗后的CD4+T细胞百分率增高(P<0.05),CD8+T细胞百分率减低(P<0.01),CD4/CD8比值在治疗前后有显著性差异(P<0.05)。在治疗前,无效组和显效组在T细胞总数百分率,CD4+T、CD8+T细胞百分率以及CD4/CD8的比值均有统计学意义(P<0.05)。由此我们认为,MDS患者存在T淋巴细胞亚群免疫失调,细胞免疫功能紊乱。CsA以及沙利度胺治疗MDS的机制可能与Th,Ts细胞比率改变有关。     

Thalidomide in consecutive multiple myeloma patients: single-center analysis on practical aspects, efficacy, side effects and prognostic factors with lower thalidomide doses

Purpose: In this single‐center analysis, we assessed whether lower thalidomide doses are feasible and result in favourable treatment response in multiple myeloma (MM) patients. Results: Between May 2001 and October 2006, 38 consecutive MM patients received thalidomide. Their median age was 62.4 yr, all had stage II/III MM and 31.6% had deletion 13q14 (del13q14). Prior to thalidomide, patients had received a median of two treatment lines. The median thalidomide dose was 100 mg/d (range 50–800) and the median treatment duration was 34 wk. The median cumulative thalidomide dose was 24 g. Sixteen patients received thalidomide as a single agent and 22 in combination (+dexamethasone n = 18; others n = 4). The median time‐to‐treatment failure (TTF) after thalidomide initiation was 30.4 wk. Analysis of prognostic factors showed a significantly prolonged TTF without del13q14 (38.1 vs. 8.9 wk with del13q14; P = 0.006). Our analysis of TTF between thalidomide given alone vs. in combinations showed a better TTF for the combination (23.6 vs. 30.6 wk), albeit not reaching significance (P = 0.20). Other parameters, such as age, stage, and prior SCT showed no difference in TTF. Peripheral polyneuropathy (PNP) frequencies were increased with longer (>28 wk) and increased cumulative thalidomide doses (>40 g), which emphasizes (a) the need to carefully escalate thalidomide from 50 to 200 mg/d, thereby reducing side effects and increasing patient compliance, and (b) that PNP occurs more frequently with longer and higher thalidomide doses. Conclusion: The strategy to lower thalidomide doses seems a feasible and attractive approach in MM patients, this being currently tested in prospective randomized trials.     

白桦脂酸联合沙利度胺诱导U266细胞凋亡机制研究

目的：探讨白桦脂酸联合沙利度胺诱导多发性骨髓瘤（ MM）U266细胞凋亡的机制。方法：分别用白桦脂酸（20、40、60和80 mg/L,白桦脂酸组）、沙利度胺（10、50和100 mg/L,沙利度胺组）及白桦脂酸（40 mg/L）联合沙利度胺（联合组,白桦脂酸40 mg/L,沙利度胺10、50和100 mg/L）分别处理U266细胞,同期设对照组;MTT法和流式细胞术分别检测不同浓度白桦脂酸组、沙利度胺组及联合组U266细胞增殖抑制率和凋亡率;Real-time PCR检测4组U266细胞中Survivin、Cyto-C、Bcl-2、Bax mRNA的表达,蛋白免疫印迹法检测4组U266细胞中Survivin、Cyto-C、Bcl-2、Bax蛋白表达水平。结果：随着白桦脂酸浓度的增加,U266细胞增殖抑制率增加,差异有统计学意义（ P＜0.05）,最适浓度为40 mg/L;与沙利度胺组相比,联合组U266细胞的增殖抑制率和凋亡率明显升高,差异具有统计学意义（ P＜0.05）;与沙利度胺组或白桦脂酸组相比,联合组 U266细胞中Survivin、Bcl-2 mRNA的表达明显降低,Cyto-C和Bax mRNA表达明显升高,差异具有统计学意义（ P＜0.05）;与沙利度胺、白桦脂酸组相比,联合组U266细胞中Survivin、Bcl-2蛋白表达明显降低,Cyto-C和Bax蛋白表达明显升高,差异具有统计学意义（ P＜0.05）。结论：白桦脂酸联合沙利度胺可以促进多发性骨髓瘤U266细胞凋亡,其机制可能与凋亡分子Survivin、Bcl-2、Cyto-c和Bax相关。     

Low-dose vs. high-dose thalidomide for advanced multiple myeloma: a prospective trial from the Intergroupe Francophone du Myélome

This multicentre prospective randomised trial compared the efficacy and safety of two doses of thalidomide in patients with relapsed or refractory myeloma. The study was designed to test the non-inferior efficacy and to confirm the better tolerability of low-dose thalidomide as compared to a higher dose. Four hundred patients were randomly assigned to receive either 100 or 400 mg/day of thalidomide. Dexamethasone treatment was added in both arms for patients with stable disease or treatment failure at 12 weeks. The primary endpoint was 1-year overall survival (OS). Thalidomide 100 mg/day was better tolerated than 400 mg/day with less high-grade somnolence, constipation, nausea/vomiting and peripheral neuropathy (P < 0.001, P = 0.007, P = 0.03 and P = 0.007, respectively). In the per-protocol population (PP), the estimated 1-year OS rates were of 74.5% (n = 149) and 67.3% (n = 156) in the 400 and 100 groups, respectively. The upper limit of the difference between these rates was of 15.6% higher than the non-inferiority acceptable limit of 12.75%, and the hypothesis of non-inferiority of 100 could not be established (P = 0.14). On the other hand, when intent-to-treat (ITT) population was analysed, the non-inferiority was demonstrated because the 1-year OS rates were of 72.8% (n = 195) and 68.8% (n = 205) in the same groups, leading to an upper limit of the difference of 11.49% lower than the non-inferiority acceptable limit. In addition, in patients alive 12 weeks postrandomisation and those who received thalidomide plus dexamethasone, there were no significant differences in response rates, time to progression, progression-free survival and OS between the two groups. Collectively, low-dose thalidomide 100 mg/day has significant activity in advanced myeloma with an improved safety profile and can be a good salvage therapy in combination with dexamethasone.     

Design,synthesis, biological evaluations,molecular docking,and in vivo studies of novel phthalimide analogs

A series of novel phthalimide analogs containing an indole or brominated indole moiety were synthesized and their antimicrobial activity was evaluated. Compound 8 showed a broad spectrum activity, revealing 53–67% of erythromycin activity on the tested bacteria and 60–70% of miconazole activity on the tested fungi. Anticancer activity was evaluated on the cell lines HepG2, MCF‐7, A549, H1299, and Caco2. The results revealed that the new phthalimide analog 8 has broad‐spectrum anticancer activity toward all the tested cancer cell lines, followed by compound 11 , which showed good activity toward all the tested cell lines except for MCF‐7. The ability of the promising analogs 5 , 8 , and 11 to bind to topoisomerase II DNA gyrase was investigated. Caspase‐3 activation and Bcl‐2 assay of the best active derivatives 8 , 11 in addition to compound 5 were evaluated. The antifibrotic activity was studied in an in vivo model and the histopathological studies revealed that treatment with the new compound 8 improved the fibrotic liver tissues to normality.

     

沙利度胺联合其他药品治疗类风湿关节炎的系统评价

目的 系统评价沙利度胺联合其他药品治疗类风湿关节炎的有效性与安全性。方法 检索2017年9月1日前发表在PubMed、Medline、Web of Science及中国知网（CNKI）、中国生物医学文献数据库（CBM）、维普数据库（VIP）、万方数据库中相关的随机对照试验（RCTs）,应用State 14.0软件进行Meta-分析。结果 共纳入15篇相关文献,累计1 246例患者。Meta-分析结果显示,联用沙利度胺组在有效率（OR=2.71,95% CI=1.87~3.93,P<0.05）、关节肿胀数（OR=1.68,95% CI=0.99~2.37,P<0.05）、关节压痛数（OR=2.22,95% CI=1.31~3.14,P<0.05）、红细胞沉降率（OR=12.93,95% CI=10.26~15.60,P<0.05）等方面疗效均优于对照组。在不良反应发生率方面,联用沙利度胺组与对照组比较无显著性差异（OR=0.93,95% CI=0.66~1.32,P>0.05）。结论 联用沙利度胺在类风湿关节炎的治疗中有积极作用。