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Enhancement of antitumor activity of anticancer drugs and irradiation in head and neck cancer

增强抗癌药物的抗肿瘤活性和头颈癌的放射治疗

基本信息

批准号：
07671890
负责人：
NISHIDA Shozo
金额：
$ 1.34万
依托单位：
Kinki University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07671890/
关键词：
apoptosis Mn-SOD CuZn-SOD SOD Apoptosis 頭頸部腫瘍

项目摘要

It has been reported that radicals play some role in the induction of apoptosis by irradiation or TNFa. However, the body has scavengers of these radicals. In the present study, we attempted to investigate the effect of inhibition of these scavengers, particularly of cytoplasmic Cu, Zn-SOD that scavenge oxygen radicals, and the induction of apoptosis. Apoptosis was confirmed by the formation of an apoptosis body observed by light microscopy and fragmentation of DNA detected by agarose gel electrophoresis. Treatment of DDC caused a significant decrease in SOD activity. As the SOD activity decreased, the appearance of an apoptosis body increased in frequency. Pretreatment of NAC decreased induction of apoptosis by DDC.The above results suggested that elevation of intracytoplasmic oxygen radicals relative to decrease in the activity of Cu, Zn-SOD may lead to the induction of apoptosis.Some malignant tumors are resistant to TNF-alpha or several antineoplastic agents which exert antitumoral effects mediated by the radicals. One predicted reason for this resistance is induction of an mitochondrial enzyme, Mn-SOD,which scavenges O_2 radicals by TNF-alpha. We investigated whether or not inhibition of this induction recovers the antitumoral effects of TNF-alpha. In the cell strain cultivated in a medium containing TNF-alpha, there were no dead cells. Addition of TNF-alpha significantly increased both the concentration and activity of Mn-SOD,which indicated the induction of Mn-SOD by TNF-alpha in the cell strain. This induction was inhibited by the addition of inhibitor. Further addition of TNF-alpha after the addition of inhibitor caused cell death in 50.3% of the cells.

据报道，自由基在辐射或TNFa诱导细胞凋亡中发挥一定作用。然而，身体有这些自由基的清除剂。在本研究中，我们试图研究这些清除剂的抑制作用，特别是清除氧自由基的细胞质 Cu、Zn-SOD 的抑制作用以及诱导细胞凋亡的作用。通过光学显微镜观察凋亡体的形成和琼脂糖凝胶电泳检测DNA片段化来证实细胞凋亡。 DDC 治疗导致 SOD 活性显着降低。随着SOD活性降低，凋亡体的出现频率增加。 NAC预处理降低了DDC对细胞凋亡的诱导作用。上述结果表明，相对于Cu、Zn-SOD活性的降低，细胞质内氧自由基的升高可能导致细胞凋亡的诱导。一些恶性肿瘤对TNF-α或几种抗肿瘤药物具有耐药性，这些抗肿瘤药物通过自由基介导发挥抗肿瘤作用。这种抵抗的一个预测原因是线粒体酶 Mn-SOD 的诱导，它通过 TNF-α 清除 O_2 自由基。我们研究了抑制这种诱导是否可以恢复 TNF-α 的抗肿瘤作用。在含有TNF-α的培养基中培养的细胞株中，没有死亡细胞。 TNF-α的添加显着提高了细胞株中Mn-SOD的浓度和活性，表明TNF-α对细胞株中Mn-SOD的诱导作用。通过添加抑制剂来抑制这种诱导。添加抑制剂后进一步添加TNF-α导致50.3%的细胞死亡。