Transcutaneous application of CO2 enhances the antitumor effect of radiation therapy in human malignant fibrous histiocytoma.
Transcutaneous application of CO2 enhances the antitumor effect of radiation therapy in human malignant fibrous histiocytoma.
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DOI：
10.3892/ijo.2014.2476
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发表时间：
2014-08
影响因子：
5.2
通讯作者：
Y. Onishi;T. Akisue;Teruya Kawamoto;T. Ueha;H. Hara;Mitsunori Toda;Risa Harada;M. Minoda;M. Morishita;R. Sasaki;K. Nishida;R. Kuroda;M. Kurosaka
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文献类型：
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作者：
Y. Onishi;T. Akisue;Teruya Kawamoto;T. Ueha;H. Hara;Mitsunori Toda;Risa Harada;M. Minoda;M. Morishita;R. Sasaki;K. Nishida;R. Kuroda;M. Kurosaka
肉瘤由于缺氧而相对具有抵抗力。我们先前证实经皮二氧化碳疗法可减少人类恶性纤维组织细胞瘤（MFH）的缺氧状况。因此，我们假设经皮CO（2）治疗可以增强放射治疗对人MFH的抗肿瘤作用。我们的目的是评估经皮CO2治疗对使用MFH的X射线照射的抗肿瘤疗效的影响。首先，在体外研究中，我们评估了凋亡活性和活性氧（ROS）的生产，使用流式细胞仪和免疫印迹分析在24小时后，在三种不同的氧条件下（常氧，复氧和缺氧）的X射线照射。此外，在体内研究中，将24只背部皮下接种MFH肿瘤的雄性无胸腺BALB/c裸小鼠随机分为四组：对照组、CO（2）组、X射线照射组和联合组（CO（2）和X射线照射）。治疗每周进行两次，持续2周，总共四次。计算肿瘤体积。所有肿瘤均切除，并使用流式细胞术和免疫印迹分析来评估凋亡活性、ROS产生、相关蛋白和HIF-1α表达。体外实验结果表明，X射线照射后，常氧和复氧条件下MFH细胞凋亡和ROS生成均明显高于缺氧条件下（P<0.01）。在体内研究中，联合组的肿瘤体积分别减少到对照组、CO2组和X射线组的28%、42%和47%（P<0.05）。与对照组、CO（2）组和X射线组相比，联合组的凋亡活性和ROS产生显著增加，而HIF-1α表达降低。经皮CO（2）系统增强了X射线照射的抗肿瘤作用，可能成为克服人类恶性肿瘤放射抵抗的新的治疗工具。
Sarcomas are relatively resistant because of hypoxia. We previously demonstrated that the transcutaneous CO(2) therapy reduced hypoxic conditions in human malignant fibrous histiocytoma (MFH). Therefore, we hypothesized that transcutaneous CO(2) therapy could enhance the antitumor effect of radiation therapy in human MFH. Our purpose was to evaluate the effects of transcutaneous CO(2) therapy on the antitumor efficacy of X-ray irradiation using MFH. First, in an in vitro study, we assessed apoptotic activity and reactive oxygen species (ROS) production using flow cytometric and immunoblot analysis at 24 h after X-ray irradiation under three different oxygen conditions (normoxic, reoxygenated and hypoxic). In addition, in the in vivo study, 24 male athymic BALB/c nude mice with MFH tumors that were inoculated in the dorsal subcutaneous area were randomized into four groups: control, CO(2), X-ray irradiation and combination (CO(2) and X-ray irradiation). Treatments were performed twice weekly for 2 weeks, four times in total. Tumor volume was calculated. All tumors were excised and apoptotic activity, ROS production, related proteins and HIF-1α expression were assessed using flow cytometric and immunoblot analysis. The in vitro study revealed that X-ray irradiation induced increased apoptosis and ROS production in MFH cells under normoxic and reoxygenated conditions relative to hypoxic conditions (P<0.01). In the in vivo study, tumor volume in the combination group was reduced to 28, 42 and 47% of that in the control, CO(2), and X-ray groups, respectively (P<0.05). Apoptotic activity and ROS production in the combination group were strongly increased with decreasing HIF-1α expression relative to the control, CO(2) and X-ray groups. The transcutaneous CO(2) system enhanced the antitumor action of X-ray irradiation and could be a novel therapeutic tool for overcoming radio-resistance in human malignancies.