Differential Effects of Thalidomide on Angiogenesis and Tumor Growth in Mice

Thalidomide, clinically used as an antiinflammatory and antitumoral drug, inhibited sponge-induced angiogenesis when administered systemically (100 mg/kg^–1) in mice. However, it failed to inhibit solid Ehrlich tumor in the same mouse strain. We have used functional, biochemical and histological parameters to assess neovascularization and fibrovascular tissue infiltration of the mice sponge granuloma. The neovascularization growth as detected by development of blood flow and hemoglobin content extracted from the implants showed that thalidomide inhibited fibrovascular tissue formation by 40%. The functional and biochemical parameters correlated well with the histological study. Thalidomide had no inhibitory effect in the development of Ehrlich tumor. The detection of this selective action using the same animal strain bearing two different processes, supports the hypothesis that rather than species specificity, thalidomide is tissue specific. This approach may be used to identify the specificity of other therapeutic agents against distinct angiogenesis-dependent diseases.     

单疗程沙利度胺联合CTOD方案治疗多发性骨髓瘤22例

目的评价沙利度胺联合CTOD(环磷酰胺、吡柔比星、长春新碱、地塞米松)化疗方案治疗多发性骨髓瘤22例的疗效和不良反应。方法22例患者均给予小剂量沙利度胺联合化疗,沙利度胺的剂量为50～200mg/d,环磷酰胺(CTX)500～600mg/m2×1d,吡柔比星(THP)20mg/m2×(2～3)d;长春新碱(VCR)2mg/m2×1d,地塞米松(Dex)10～15mg/m2×(5～7)d;每2～3月重复,有效可继续化疗2～4次。结果患者一疗程总有效率为90.90%(完全缓解率为4.54%,部分缓解率86.36%),主要不良反应为骨髓抑制,白细胞和血小板分别在化疗后第5～12天、第5～14天降到最低值,外周血象一般在11～15d恢复正常。不良反应不明显,无1例患者因化疗发生不良反应而死亡。结论沙利度胺联合CTOD化疗方案治疗多发性骨髓瘤的较理想方案。     

三氧化二砷联合沙利度胺对骨髓增生异常综合征的调节作用

目的 探讨三氧化二砷联合沙利度胺对骨髓增生异常综合征(MDS)的调节作用.方法 将46例MDS患者随机分为2组,每组23例.治疗组给予三氧化二砷及沙利度胺,对照组仅给予三氧化二砷.治疗2个月后评估2组总体疗效,比较血红蛋白(Hb)、中性粒细胞绝对值(ANC)、血小板计数(PLT)、骨髓原始细胞比例及不良反应的差异.结果 治疗组总有效率显著高于对照组.治疗组Hb、ANC、PLT水平及骨髓原始细胞比例的改善程度均显著大于对照组.2组不良反应发生率无显著差异.结论 与单独应用三氧化二砷相比,三氧化二砷联合沙利度胺可显著改善MDS患者三系血细胞,降低骨髓原始细胞比例,提高近期疗效,且不增加不良反应.     

Thalidomide-dexamethasone versus Interferon-alpha-dexamethasone as maintenance treatment after ThaDD induction for multiple myeloma: a prospective, multicentre, randomised study

Maintenance therapy was explored in multiple myeloma (MM) patients after conventional thalidomide, dexamethasone and pegylated liposomal doxorubicin (ThaDD). Patients with newly or relapsed MM obtaining at least minor response after 6 ThaDD courses, were randomised to receive α-interferon (IFN) 3 MU 3 times a week or thalidomide 100 mg daily until relapse. Both groups also received pulsed dexamethasone 20 mg 4 d a month. Fifty-one patients were randomized in the IFN-dexamethasone (ID) arm and 52 in the thalidomide-dexamethasone (TD) arm. The characteristics of two groups were similar. A significantly better 2-years progression-free survival (PFS; 63% vs. 32%; P  = 0·024) and overall survival (84% vs. 68%; P  = 0·030) was observed in the thalidomide arm. In high-risk patients and in those achieving less than very good partial response after induction, TD fared better in term of PFS. Main side effects were peripheral neuropathy and constipation in TD group, fatigue, anorexia and haematological toxicity in ID arm. There was a 21% probability of discontinuation at 3 years in the thalidomide arm and 44% in the IFN arm ( P  = 0·014). Low-dose thalidomide plus pulsed low-dose dexamethasone after conventional thalidomide combination-based therapy was also feasible in the long term, enabling significantly better residual disease control if compared with a standard maintenance therapy.     

沙利度胺对大鼠颈动脉损伤后新生内膜形成的影响

目的：观察沙利度胺局部给药对大鼠颈动脉损伤后新生内膜形成和血管再狭窄的影响,并探讨其可能机制。方法：48只SD大鼠随机分成假手术组（A组）、单纯手术组（B组）和沙利度胺组（C组）,A组仅分离和结扎右颈外动脉,B组和C组行右颈总动脉血管成形术,C组在损伤血管局部给予沙利度胺。在术后7d和14d分别测定血清中血管内皮生长因子（VEGF）和肿瘤坏死因子（TNF）-α水平、观察血管内膜损伤后形态学变化、用免疫组织化学法观察组织VEGF和巨噬细胞表达水平。结果：在血管损伤后14d,B组VEGF和TNF-α水平明显高于A组和C组（P〈0．01）,B组管腔面积明显缩小（P〈0．01）,而新生内膜面积明显增加（P〈0．01）,同时B组血管内膜VEGF和巨噬细胞的表达亦较A组和B组增加（P〈0．01）。结论：沙利度胺局部给药可抑制血管损伤后新生内膜形成和血管再狭窄的发生。     

Impact of prior therapies on the relative efficacy of bortezomib compared with dexamethasone in patients with relapsed/refractory multiple myeloma

This subgroup analysis of the phase III APEX (Assessment of Proteasome Inhibition for Extending Remissions) trial examined whether prior exposure to specific therapies affected the relative efficacy of bortezomib versus dexamethasone in relapsed/refractory myeloma. Time to progression and overall survival were superior with bortezomib in all subgroups, with no evidence of interaction between any prior therapies and assignment to study therapy. Patients with prior thalidomide exposure had worse outcomes overall, but neither prior thalidomide nor prior autologous stem cell transplantation affected the relative efficacy of bortezomib versus dexamethasone. These results confirm the superiority of bortezomib over dexamethasone, regardless of prior exposure to specific therapies (clinicaltrials.gov: NCT00048230).     

Thalidomide and lenalidomide in multiple myeloma

Multiple myeloma is a treatable but not necessarily a curable plasma-cell cancer. After decades of minimal progress, two new classes of drugs with novel mechanisms of action - immunomodulatory drugs (thalidomide and lenalidomide) and proteasome inhibitors (bortezomib) - have been introduced for the treatment of this disease. Thalidomide and lenalidomide have shown great activity as single agents and in combination with glucocorticoids for the treatment of chemotherapy-refractory myeloma. Thalidomide - and more recently lenalidomide - in combination with dexamethasone have shown promising results as induction therapy. These drugs can easily be combined with other chemotherapeutic agents to potentiate the anti-myeloma effect. The immunomodulatory function of these drugs can be successfully exploited to control residual disease during remission. Thus, both thalidomide and lenalidomide have ushered in a new era of optimism in the management of this incurable cancer.     

反应停联合VAD方案治疗多发性骨髓瘤疗效评价

目的探讨反应停(沙立度胺)联合VAD(长春新碱、阿霉素、地塞米松)方案治疗多发性骨髓瘤的临床疗效。方法治疗组:反应停100mg/d开始,逐渐增至400mg/d或不能耐受,持续使用,联合VAD化疗。对照组:常规VAD方案化疗。对两组临床疗效进行对比分析。结果治疗组接近完全缓解(nCR)3例,部分缓解(PR)20例,总有效率(ORR)76.7%;对照组nCR1例,PR8例,ORR45.0%。治疗组疗效优于对照组,差异具有统计学意义(P0.05)。结论反应停联合VAD治疗多发性骨髓瘤疗效高、不良反应少,值得推广。