OSAKI Tokio Kochi Medical School, Department of Oral Surgery, Professor, 医学部, 教授 (70031995)
UETA Eisaku Kochi Medical School, Department of Oral Surgery, Research Associate, 医学部・附属病院, 助手 (10203431)
YAMAMOTO Tetsuya Kochi Medical School, Department of Oral Surgery, Assistant Professor, 医学部・附属病院, 講師 (00200824)
|Budget Amount *help
¥3,600,000 (Direct Cost : ¥3,600,000)
Fiscal Year 1999 : ¥1,600,000 (Direct Cost : ¥1,600,000)
Fiscal Year 1998 : ¥2,000,000 (Direct Cost : ¥2,000,000)
To induce apoptosis sufficient for cancer control, we investigated the role of reactive oxygen intermediates (ROI) and their scavengers in induction of apoptosis of squamous cell carcinoma (SCC) cells. The results obtained are as follows ;
1, The SCC lines, which were established from oral SCCs, revealed almost same activities of catalase, gluthatione peroxidase, and Cu, Zn-superoxide dismutase (SOD). However, Mn-SOD activities differed largely among the cell lines.
2, SCC lines with a high Mn-SOD activity were more resistant to 5-FU and γ-rays than those with a low Mn-SOD activity, and the Mn-SOD activities were inversely correlated with apoptosis by 5-FU and γ-rays.
3, Apoptosis was closely correlated with the intracellular and intra-mitochondrial ROI (HィイD22ィエD2OィイD22ィエD2) levels, which were parallel with the decrease of mitochondrial membrane potential, release of cytochrome c, caspase-3 activation, and DNA fragmentation.
4, By treatment with 5-FU and γ-rays, Mn-SOD-mRNA expression and Mn-SOD activities were increased in all SCC lines.
5, Mn-SOD-antisense-transfected SCC cells were more strongly induced to apoptosis after treatment with 5-FU and γ -rays compared with wild SCC cells.
6, Subcutaneous tumors in nu/nu mice, in which Mn-SOD-antisense-transfected SCC cells were transplanted, were more sensitive to γ-rays and 5-FU than tumors of non-transfected SCC cells.
These results indicate that ROI play an important role in apoptosis induced by 5-FU and γ-rays and that among the ROI scavengers, Mn-SOD is the strongest inhibitor of apoptosis. Therefore, as the effective SCC therapy, inactivation of ROI scavengers, especially, Mn-SOD, is proposed.