The vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid improves the antitumor efficacy and shortens treatment time associated with Photochlor-sensitized photodynamic therapy in vivo.
The vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid improves the antitumor efficacy and shortens treatment time associated with Photochlor-sensitized photodynamic therapy in vivo.
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DOI：
10.1111/j.1751-1097.2008.00395.x
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发表时间：
2009-01
影响因子：
3.3
通讯作者：
Bellnier DA
中科院分区：
文献类型：
--
作者：
Seshadri M;Bellnier DA
在这份报告中，我们研究了光动力疗法（PDT）与5，6-二甲基氧杂蒽酮-4-乙酸（DMXAA），目前正在进行临床评价的血管破坏剂相结合的抗肿瘤活性。用PDT治疗皮下携带CT-26结肠癌的BALB/c小鼠，使用第二代二氢卟酚基敏化剂2-[1-己氧基乙基]-2-去乙烯基焦脱镁叶绿酸-a（Photochlor），加或不加DMXAA。将长期（60天）治疗结局、肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）诱导、血管损伤（微血管密度，MVD）作为终点进行评价。此外，使用磁共振成像（MRI）和足部反应测定评价治疗选择性。观察到低剂量DMXAA和PDT（48 J cm−2，112 mW cm−2）组合的高度协同相互作用，导致约60%的长期治愈。该联合治疗方案的PDT疗程的持续时间仅为7分钟，而选择单药PDT疗程以获得等效治愈率的持续时间为152分钟。与长期PDT单药治疗相比，DMXAA +短期PDT治疗后的MRI显示瘤周水肿明显减少。类似地，DMXAA + PDT对正常小鼠足组织的光毒性显著低于单独PDT。联合治疗后4 h观察到细胞因子TNF-α和IL-6的诱导增加（P < 0.001），随后观察到广泛的血管损伤，表现为联合治疗后24 h MVD显著降低。总之，与DMXAA组合的光氯敏化PDT在临床上可行的照明方案下表现出上级的功效和改善的选择性。目前正在计划对这种新型联合策略进行临床评价。
In this report, we examined the antitumor activity of photodynamic therapy (PDT) in combination with 5,6-dimethylxanthenone- 4-acetic acid (DMXAA), a vascular disrupting agent currently undergoing clinical evaluation. BALB/c mice bearing subcutaneous CT-26 colon carcinomas were treated with PDT using the second-generation chlorin-based sensitizer, 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (Photochlor) with or without DMXAA. Long-term (60-days) treatment outcome, induction of tumor necrosis factor-alpha (TNF-α) and interleukin- 6 (IL-6), vascular damage (microvessel density, MVD) were evaluated as endpoints. In addition, treatment selectivity was evaluated using magnetic resonance imaging (MRI) and the foot response assay. A highly synergistic interaction was observed with the combination of low-dose DMXAA and PDT (48 J cm−2 at 112 mW cm−2) resulting in ~60% long-term cures. The duration of the PDT session for this combination therapy protocol was only 7 min, while the duration of a monotherapy PDT session, selected to yield the equivalent cure rate, was 152 min. MRI showed markedly less peritumoral edema after DMXAA + short-duration PDT compared with long-duration PDT monotherapy. Similarly, DMXAA + PDT caused significantly less phototoxicity to normal mouse foot tissue than PDT alone. Increased induction of cytokines TNF-α and IL-6 (P < 0.001) was observed at 4 h followed by extensive vascular damage, demonstrated by a significant reduction in MVD at 24 h after combination treatment. In conclusion, Photochlorsensitized PDT in combination with DMXAA exhibits superior efficacy and improved selectivity with clinically feasible illumination schemes. Clinical evaluation of this novel combination strategy is currently being planned.
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DOI：
10.1016/s0360-3016(02)03920-2
发表时间：
2002-12-01
影响因子：
7
作者：
Baguley, BC;Ching, LM
通讯作者：
Ching, LM
影响因子：
3.3
作者：
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影响因子：
9.7
作者：
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Valentini, G