Treatment with the tumor necrosis factor-alpha-inducing drug 5,6-dimethylxanthenone-4-acetic acid enhances the antitumor activity of the photodynamic therapy of RIF-1 mouse tumors.
Treatment with the tumor necrosis factor-alpha-inducing drug 5,6-dimethylxanthenone-4-acetic acid enhances the antitumor activity of the photodynamic therapy of RIF-1 mouse tumors.
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发表时间：
2003-11
期刊：
影响因子：
11.2
通讯作者：
D. Bellnier;S. Gollnick;S. Camacho;W. Greco;R. Cheney
中科院分区：
文献类型：
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作者：
D. Bellnier;S. Gollnick;S. Camacho;W. Greco;R. Cheney
DMXAA（5，6-二甲基咕吨酮-4-乙酸）是一种抗血管剂，至少部分通过诱导肿瘤坏死因子（TNF）-α发挥其抗肿瘤作用。光动力疗法（PDT），即用可见光激活肿瘤组织中的光反应药物，在临床上用于控制实体恶性肿瘤。先前已经显示，通过腹膜内施用重组人TNF-α，PDT在小鼠中被增强。在这里，我们研究了DMXAA作为移植的鼠RIF-1肿瘤的基于Photofrin的PDT的改性剂的活性。整个研究中使用的DMXAA剂量（20 mg.kg（-1））对肿瘤生长几乎没有影响。DMXAA和PDT的组合导致肿瘤体积的减小和再生长的显著延迟，给出了2.81的PDT剂量修正因子。这种增强被认为是强烈的时间表依赖性。当在肿瘤局部照射前1-3小时给予DMXAA时，达到最显著的反应;在PDT光递送+/-24小时内的其他间隔观察到较少的活性。使用2小时的DMXAA光间隔，组织学检查显示，与单独给予任何一种药物的肿瘤相比，给予联合治疗的肿瘤中血管计数（CD 31免疫染色）和明显坏死（H&E）显著减少。相反，联合治疗后24小时，瘤周组织仍然完整。在低剂量PDT后，DMXAA没有增加对正常小鼠足的损伤（1.5 mg.kg（-1）Photofrin）;然而，当DMXAA与高剂量PDT组合时，正常组织光毒性有所增强。DMXAA加低剂量PDT（1.5 mg.kg（-1）Photofrin）后的抗肿瘤作用似乎依赖于TNF-α，因为针对该细胞因子的中和抗体将肿瘤反应降低至对照水平。DMXAA本身在RIF-1肿瘤中诱导TNF-α，而PDT没有。然而，在DMXAA后加入PDT导致TNF-α降低，表明联合治疗的增强的抗肿瘤活性不仅仅归因于PDT对细胞因子的诱导比单独使用DMXAA增加。这些观察结果表明，一个有前途的新的联合治疗具有相当大的治疗优势。
DMXAA (5,6-dimethylxanthenone-4-acetic acid) is an antivascular agent that exerts its antitumor effect at least partly through the induction of tumor necrosis factor (TNF)-alpha. Photodynamic therapy (PDT), the activation of a photoreactive drug in tumor tissue with visible light, is used clinically to control solid malignancies. PDT has been shown previously to be potentiated, in mice, by the i.p. administration of recombinant human TNF-alpha. Here, we investigated the activity of DMXAA as a modifier of Photofrin-based PDT of implanted murine RIF-1 tumors. The DMXAA dose (20 mg.kg(-1)) used throughout this study had little effect on tumor growth. The combination of DMXAA and PDT led to a reduction in tumor volume and significant delays in regrowth, giving a PDT-dose modification factor of 2.81. This enhancement was found to be strongly schedule dependent. The most pronounced responses were achieved when DMXAA was administered 1-3 h before the local illumination of the tumors; less activity was observed at other intervals within +/-24 h of PDT-light delivery. Using a 2-h DMXAA-light interval, histological examination showed significantly reduced blood vessel counts (CD31 immunostaining) and marked necrosis (H&E) in the tumors given combination therapy compared with the tumors given either agent alone. Conversely, peritumoral tissue was still intact 24 h after the combined therapy. DMXAA did not augment the damage to normal mouse feet after low-dose PDT (1.5 mg.kg(-1) Photofrin); however, there was some enhancement of normal tissue phototoxicity when DMXAA was combined with high-dose PDT. The antitumor effect after DMXAA plus low-dose PDT (1.5 mg.kg(-1) Photofrin) appeared to be dependent on TNF-alpha because neutralizing antibodies to this cytokine reduced the tumor response to control levels. DMXAA by itself induced TNF-alpha in RIF-1 tumors whereas PDT did not. However, the addition of PDT after DMXAA resulted in decreases in TNF-alpha, suggesting that the enhanced antitumor activity of the combination therapy was not attributable simply to an increased induction of the cytokine by PDT over that from DMXAA alone. These observations suggest a promising new combination therapy with considerable therapeutic advantage.