The influence of the combined treatment with Vadimezan (ASA404) and taxol on the growth of U251 glioblastoma xenografts.
The influence of the combined treatment with Vadimezan (ASA404) and taxol on the growth of U251 glioblastoma xenografts.
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DOI：
10.1186/1471-2407-12-242
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发表时间：
2012-06-13
期刊：
影响因子：
3.8
通讯作者：
Niedermann G
中科院分区：
文献类型：
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作者：
Milanović D;Braun F;Weber W;Grosu AL;Behe M;Niedermann G
多形性胶质母细胞瘤（GBM）最重要的生物学特征之一是高血管密度。Vadimezan（ASA 404，DMXAA）属于小分子血管破坏剂（VDA）类别，可导致已建立的肿瘤血管破坏和随后的肿瘤出血性坏死。其选择性抗血管作用是通过瘤内诱导多种细胞因子介导的，包括肿瘤坏死因子-α（TNF-α）、粒细胞集落刺激因子（G-CSF）、白细胞介素6（IL-6）和巨噬细胞炎症蛋白1α（MIP-1α）。临床前研究表明，ASA 404与紫杉烷类化合物具有协同作用。在这项研究中，我们研究了ASA 404和紫杉醇治疗荷U251人胶质母细胞瘤异种移植瘤的小鼠是否具有协同作用。通过使用18F-FDG PET（氟脱氧葡萄糖-正电子发射断层扫描）成像测量肿瘤大小和代谢活性的变化来评估治疗反应。将U251细胞s.c.在NMRI-Foxn 1 nu无胸腺雌性裸鼠的右后肢中。将动物随机分为4组（7-9只动物/组）进行治疗：对照组、紫杉醇组、ASA 404组和ASA 404+紫杉醇组。动物接受单剂量的紫杉醇（10 mg/kg）、ASA 404（27.5 mg/kg）或紫杉醇（10 mg/kg）加ASA 404（27.5 mg/kg）腹膜内给药; ASA 404在紫杉醇治疗后24小时给药。ASA 404治疗后4和24 h（紫杉醇治疗后28和48 h）进行18 F-FDG PET扫描。与未治疗的对照组相比，紫杉醇治疗不影响肿瘤生长。用单剂量ASA 404单独或与紫杉醇组合治疗动物引起肿瘤生长的显著延迟。联合治疗并没有减少异种移植物的生长显着超过ASA 404单独，但肿瘤18 F-FDG摄取的早期变化之前，随后的生长抑制。在联合治疗的情况下，在治疗结束时测定的肿瘤重量较低。ASA 404单独或与紫杉醇联合治疗在我们的胶质母细胞瘤模型中显示出抗肿瘤作用，可能是通过破坏血管。这种化合物的抗癌作用的意义需要进一步的临床前研究。18F-FDG PET似乎是在治疗过程中早期监测ASA 404治疗的有前途的工具。
One of the most important biological characteristics of Glioblastoma multiforme (GBM) is high vascular density. Vadimezan (ASA404, DMXAA) belongs to the class of small molecule vascular disrupting agents (VDA) that cause disruption of established tumor vessels and subsequent tumor hemorrhagic necrosis. Its selective antivascular effect is mediated by intratumoral induction of several cytokines including tumor necrosis factor-α (TNF-α), granulocyte-colony-stimulating factor (G-CSF), interleukin 6 (IL-6) and macrophage inflammatory protein 1α (MIP-1α). Preclinical studies have demonstrated that ASA404 acts synergistically with taxanes. In this study, we investigated if treatment of mice bearing U251 human glioblastoma xenografts with ASA404 and taxol may be synergistic. Therapy response was evaluated by measuring changes in tumor size and metabolic activity using 18F-FDG PET (Fluorodeoxyglucose - positron emision tomography) imaging. U251 cells were inoculated s.c. in the right hind limb of NMRI-Foxn1nu athymic female nude mice. Animals were randomly assigned into 4 groups (7–9 animals/group) for treatment: control, taxol, ASA404, and ASA404 plus taxol. The animals received either a single dose of taxol (10 mg/kg), ASA404 (27.5 mg/kg), or taxol (10 mg/kg) plus ASA404 (27.5 mg/kg) administered i.p.; ASA404 was administred 24 h after the treatment with taxol. 4 and 24 h after treatment with ASA404 (28 and 48 h hours after treatment with taxol) 18 F-FDG PET scans were performed. The treatment with taxol did not affect the tumor growth in comparison to untreated controls. The treatment of animals with single dose ASA404 alone or in combination with taxol caused a significant delay in tumor growth. The combined treatment did not decrease the growth of the xenografts significantly more than ASA404 alone, but early changes in tumor 18 F-FDG uptake preceded subsequent growth inhibition. The tumor weights, which were determined at the end of treatment, were lower in case of combined treatment. The treatment with ASA404 alone or in combination with taxol showed antitumoral effects in our glioblastoma model probably through destruction of blood vessels. The implications for the anticancer effect of this compound warrant further preclinical studies. 18F-FDG PET appears to be a promising tool to monitor treatment with ASA404 early in the course of therapy.
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影响因子：
8.8
作者：
McKeage, M. J.;Von Pawel, J.;Reck, M.;Jameson, M. B.;Rosenthal, M. A.;Sullivan, R.;Gibbs, D.;Mainwaring, P. N.;Serke, M.;Lafitte, J-J;Chouaid, C.;Freitag, L.;Quoix, E.
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15.9
作者：
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影响因子：
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通讯作者：
Rojiani, AM
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影响因子：
8.8
作者：
Ching, LM;Cao, Z;Kieda, C;Zwain, S;Jameson, MB;Baguley, BC
通讯作者：
Baguley, BC
影响因子：
8.8
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