沙立度胺对乳腺癌细胞血管内皮生长因子表达的影响

目的 观察沙立度胺对人乳腺癌细胞系MCF-7、MDA-MB-231细胞血管内皮生长因子(VEGF)表达的抑制作用.方法 应用半定量逆转录-聚合酶链反应(RT-PCR)技术,分别观察沙立度胺对MCF-7和MDA-MB-231细胞VEGF表达的抑制作用.结果 沙立度胺在50μg/L明显抑制两株细胞VEGF mRNA的表达,但浓度增高到100μg/L抑制VEGF mRNA表达的作用反而减弱.结论 沙立度胺在一定浓度范围内能抑制乳腺癌细胞VEGF mRNA的表达.     

沙利度胺联合LD-Arac治疗高危骨髓增生异常综合征27例

目的观察沙利度胺及小剂量阿糖胞苷(LD-Arac)治疗高危骨髓增生异常综合征的疗效,研究高危MDS的治疗方法。方法对27例高危骨髓增生异常综合征患者,应用LD-Arac10～15mg/m2,每12h1次皮下注射,15～21天1疗程,间隔10～15天重复。沙利度胺100mg·d-1,早、晚2次口服,无严重副作用者每周递增50mg·d-1,最大剂量300mg·d-1。结果完全缓解12例(44%),部分缓解6例(22%),3例进步,6例无效,总有效率66%。9例(33%)在治疗中转化为急性白血病。结论LD-Arac和沙利度胺治疗高危MDS确有明显疗效,无严重骨髓抑制,无感染及出血,明显改善高危MDS病人的预后。     

沙利度胺对小鼠皮肤移植的影响

目的观察沙利度胺对小鼠皮肤移植物存活及生长情况的影响,探讨沙利度胺在抗同种异体排斥反应中的作用。方法建立Balb/c小鼠到C57BL/6小鼠的皮肤移植模型,将模型小鼠随机分为3组,每组12只,对照组腹腔注射吐温-80溶液+0.9%氯化钠注射液(1∶999),200 mL.kg-1.d-1;环孢素A组腹腔注射环孢素A,10 mg.kg-1.d-1;沙利度胺组腹腔注射沙利度胺,200 mg.kg-1.d-1。分别于实验第7,9,11天取小鼠皮肤移植物进行病理检测,观察各组移植物平均存活时间。结果对照组小鼠移植物平均存活时间为8.2 d,环孢素A组平均为13.5 d,沙利度胺组平均为13.2 d,环孢素A组与沙利度胺组均明显高于对照组(P<0.05),环孢素A组与沙利度胺组之间差异无显著性(均P>0.05)。第7,9,11天各组移植皮片病理检测结果显示,随着时间的延长,各组均可见移植皮下淋巴细胞浸润,腺体及毛细血管破坏逐渐加重;其中对照组皮下组织破坏严重,沙利度胺组皮下组织破坏明显减轻,环孢素A组皮下组织破坏最轻。结论沙利度胺能延长Balb/c小鼠到C57BL/6小鼠皮肤移植物的存活时间,具有一定的临床应用前景。     

沙利度胺对血液肿瘤患者内皮细胞功能的影响

目的探讨沙利度胺对血液肿瘤患者内皮细胞功能的影响。方法检测和比较32例血液肿瘤患者服用沙利度胺前后内皮细胞功能指标：血浆内皮素-1（ET-1）、血管内皮生长因子（VEGF）、组织因子（TF）、凝血酶调节蛋白（riM）、凝血因子V、血管性血友病因子（vWF）、抗凝血酶（AT）、组织型纤溶酶原激活物（tPA）及纤溶酶原激活物抑制物-1（PAI-1）的活性。结果服用沙利度胺后血液肿瘤患者体内的VEGF、TF、TM、vWF、AT活性明显降低（P〈0．05或P〈0．01），而血浆ET-1水平比治疗前显著升高（P〈0．05），其余指标无明显改变（P〉0．05）。结论沙利度胺可以影响内皮细胞功能，抑制新生血管的增生，从而在血液肿瘤治疗中发挥作用。     

Continuous low dose Thalidomide: a phase II study in advanced melanoma, renal cell, ovarian and breast cancer

To grow and metastasize, solid tumours must develop their own blood supply by neo-angiogenesis. Thalidomide inhibits the processing of mRNA encoding peptide molecules including tumour necrosis factor-alpha (TNF-alpha) and the angiogenic factor vascular endothelial growth factor (VEGF). This study investigated the use of continuous low dose Thalidomide in patients with a variety of advanced malignancies. Sixty-six patients (37 women and 29 men; median age, 48 years; range 33-62 years) with advanced measurable cancer (19 ovarian, 18 renal, 17 melanoma, 12 breast cancer) received Thalidomide 100 mg orally every night until disease progression or unacceptable toxicity was encountered. Three of 18 patients with renal cancer showed partial responses and a further three patients experienced stabilization of their disease for up to 6 months. Although no objective responses were seen in the other tumour types, there were significant improvements in patients' sleeping (P < 0.05) and maintained appetite (P < 0.05). Serum and urine concentrations of basic fibroblast growth factor (bFGF), TNF-alpha and VEGF were measured during treatment and higher levels were associated with progressive disease. Thalidomide was well tolerated: Two patients developed WHO Grade 2 peripheral neuropathy and eight patients developed WHO grade 2 lethargy. No patients developed WHO grade 3 or 4 toxicity. Further studies evaluating the use of Thalidomide at higher doses as a single agent for advanced renal cancer and in combination with biochemotherapy regimens are warranted.     

The ratio between CD4+ and CD8+ cells in the peripheral blood of patients with hematological malignancies is not altered by thalidomide

Thalidomide is thought to have anti-angiogenic and immunomodulatory properties, including suppression of tumor necrosis factor-alpha, effects on interleukins and interferons, down-regulation of some cell adhesion molecules, and changes in the proportion of lymphocyte subsets. It is unclear whether the clinical response to thalidomide in patients with multiple myeloma (MM), idiopathic myelofibrosis (IM), and myelodysplastic syndromes (MDS) is related to its ability to inhibit angiogenesis or its immunomodulatory effects. We examined the effect of thalidomide on T-lymphocyte subsets in 18 patients with MDS, 6 patients with MM, 4 patients with IM, and 3 patients with angioimmunoblastic lymphoma (AILD). These patients had either a relapse or progressive disease following cytotoxic chemotherapy including high-dose chemotherapy with autologous stem cell support. Thalidomide was first administered at 100 mg/day p.o. and increased to 400 mg/day. T-lymphocyte subsets (CD4 + , CD8 + ) were measured by fluorescence-activated cell sorter (FACS) before and during treatment with thalidomide. Twenty-six of 31 patients responded to thalidomide, most of them achieving partial remission. The median concentration of CD4 + cells was 443/μl, the median of CD8 + cells was 359/μl (CD3 992/μl). In our cohort, no significant changes in absolute numbers or proportions of CD3 + (P = 0.12), CD4 + (P = 0.668), or CD8 + (P = 0.143) cells were observed following the treatment with thalidomide. Although the CD4/CD8 ratio declined from 1.6 to 1.0 during 3 months of thalidomide treatment, this had no statistical significance (P = 0.1). Our findings show that an effect of thalidomide on the T lymphocytes studied is unlikely to be of major importance for the clinical effects.     

Effects of thalidomide and pentobarbital on neuronal activity in the preoptic area during sleep and wakefulness in the cat

To test the hypothesis that sleep produced by thalidomide, unlike that of pentobarbital, is associated with increased neuronal activity in the preoptic area (POA), the spontaneous activity of 96 POA neurons was recorded in chronically prepared cats during alert wakefulness (W), deep slow-wave sleep (SWS), and REM sleep in a drug-free preparation and after administration of thalidomide (4mg/kg) and pentobarbital (4 or 8 mg/kg). Thalidomide, unlike pentobarbital, at a dose that significantly increased the amount of SWS, failed to depress neuronal activity in the POA compared to drug-free controls. Mean discharge rates during thalidomide treatment were similar to drug-free rates. In contrast, rates during low-dose pentobarbital treatment were significantly less than those of drug-free and thalidomide-treated animals. Rates during high-dose pentobarbital treatment were significantly less than those in all other groups. Thalidomide, compared with the other groups, in addition to increasing the amount of SWS, significantly increased the total amount of REM sleep as well as REM sleep as a percent of total sleep, but did not produce ataxia or behavioral excitement. These results do not confirm the initial hypothesis, but suggest that hypnotic drugs that do not depress neuronal activity in the POA may be devoid of some of the unwanted side effects often associated with the more commonly prescribed hypnotic medications.     

Modulation of thalidomide pharmacokinetics by cyclophosphamide or 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in mice: the role of tumour necrosis factor

Purpose There is considerable current interest in the use of thalidomide as a single agent or in combination with drugs such as cyclophosphamide in the treatment of multiple myeloma and other cancers. Our previous work has shown that thalidomide potentiates the antitumour activity of both cyclophosphamide and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) against murine Colon 38 tumours. In both of these cases, thalidomide extends the half-life (t_1/2) of the other drug. We wished to determine whether cyclophosphamide and DMXAA altered the t_1/2 of thalidomide. Since both thalidomide and DMXAA modulate tumour necrosis factor (TNF), we also wished to determine the role of TNF in this interaction.Methods Mice with Colon 38 tumours were treated with cyclophosphamide (220 mg/kg) and/or thalidomide (20 mg/kg) or DMXAA (25 mg/kg) and thalidomide (100 mg/kg), combinations that have previously demonstrated synergistic activity. Plasma and tumour tissue drug concentrations were analysed by high-performance liquid chromatography. To determine the role of TNF, similar experiments were performed using mice defective in the TNF gene (TNF^–/–) or the TNF receptor-1 gene (TNFR1^–/–).Results Coadministration of cyclophosphamide increased the thalidomide t_1/2 by 3.9- and 3.6-fold, respectively, in plasma and tumour tissue, with a corresponding increase in the concentration-time curve (AUC). The corresponding values following coadministration of DMXAA were 3.0- and 4.6-fold, respectively. Coadministration of cyclophosphamide had similar effects on thalidomide t_1/2 in C57Bl/6, TNF^–/– and TNFR1^–/– mice, while coadministration of DMXAA did not alter the t_1/2 or AUC in TNF^–/– and TNFR1^–/– mice.Conclusions Both cyclophosphamide and DMXAA have a pharmacokinetic interaction with thalidomide, increasing t_1/2 and AUC. TNF mediates the effect of DMXAA on thalidomide pharmacokinetics but not that of cyclophosphamide.This work was supported by the Auckland Medical Research Foundation, the Marsden Fund and the Auckland Cancer Society. Francisco Chung is a recipient of an Asian Development Bank Scholarship.     

Cyclooxygenase inhibitors and thalidomide ameliorate vincristine-induced hyperalgesia in rats

In this study ibuprofen (50.0 mg/kg, i.p.), rofecoxib (10.0 mg/kg, i.p.) and thalidomide (50.0 mg/kg, oral) were shown to prevent vincristine-induced mechanical hyperalgesia. Sprague-Dawley rats were injected every other day with vincristine (0.1 mg/kg) over 13 days. The animals were cotreated daily with vehicle (saline), ibuprofen, rofecoxib or thalidomide throughout the period of vincristine treatment. Mechanical withdrawal threshold to punctuate and radiant heat stimuli were determined prior to and then on alternate days throughout the treatment period. Vincristine vehicle-treated animals developed marked mechanical hyperalgesia from day 5 of chemotherapy and this lasted until the end of the experiment. Thermal thresholds were not altered by the administration of vincristine vehicle. Animals in the vincristine vehicle group neither gained nor lost weight during the treatment period. All three active drugs showed an antihyperalgesic effect on the responses to mechanical stimulation of the hind paw that was significant from day 5 for ibuprofen and thalidomide and from day 7 for rofecoxib. Thermal thresholds increased after the administration of both the NSAIDs and thalidomide. Rofecoxib was the only drug to show any beneficial effect in protecting the animals from failure to gain body weight.     

Novel Therapies in Multiple Myeloma

The discovery of the activity of thalidomide in myeloma in the late 1990s transformed the therapy of myeloma dramatically. Apart from providing a useful treatment option for patients with myeloma, it has spurred clinical investigation of several other nonchemotherapeutic agents for this disease. These active, promising agents include CC-5013 (a thalidomide analog) and bortezomib (a proteasome inhibitor), as well as other agents, such as arsenic trioxide, ENMD 0995 and 2-methoxyestradiol. Preliminary data show that a number of these agents are active in treating disease that has relapsed after conventional chemotherapy as well as after high-dose therapy and transplantation, and some agents are active even after other novel agents have failed. The only novel drug that is commercially available currently is thalidomide, which has a therapeutically relevant benefit at all stages of the disease. A therapeutic trial of thalidomide is essential for all patients with myeloma. There are in vitro and in vivo data showing synergy between some of the novel agents. Although these novel drugs are typically used for treating disease that is refractory to or has relapsed after cytotoxic therapy, it is likely that they will start being used as part of frontline therapy, either by themselves or in combination with chemotherapy.