國立臺灣大學醫學院外科曾勝弘2006-07-262018-07-112006-07-262018-07-112005-07-31http://ntur.lib.ntu.edu.tw//handle/246246/24543本研究計畫為三年計畫，主要在探討GM-CSF、IL-12及IL-18免疫基因療法，以及抗血 管生成基因療法等不同作用機轉的組合基因療法對於神經膠質瘤的療效。第一年我們建立 多種重組腺病毒，包括Ad/IL-12、Ad/IL-18、Ad/Endo、Ad/G+E，其titer在1011-1012 pfu。接 著進行動物實驗，以這些重組腺病毒，單獨或合併，來治療腦瘤，結果發現對照組及Ad/IL-18 組大鼠全部死亡，Ad/IL-12組有50%存活率，Ad/ME組有30%存活率，Ad/IL-12+Ad/IL-18 有50%存活率，Ad/IL-12+Ad/ME有70%存活率，Ad/IL-18+Ad/ME有30%存活率， Ad/IL-12+Ad/IL-18+Ad/ME有70%存活率。Ad/IL-12、Ad/IL-12+Ad/IL-18、 Ad/IL-12+Ad/ME、Ad/IL-12+Ad/IL-18+Ad/ME組都比對照組存活率高(P<0.05)；但 Ad/IL-18、Ad/ME、Ad/IL-18+ Ad/ME組則與對照組存活率沒有差別(P>0.05)；此外， Ad/IL-12+Ad/IL-18+Ad/ME組比Ad/IL-18、Ad/ME、Ad/IL-18+Ad/ME組存活率高(P<0.05)， 但與Ad/IL-12、Ad/IL-12+Ad/IL-18、Ad/IL-12+Ad/ME則無差別(P>0.05)。這結果証明單獨 以Ad/IL-12治療對於腦部神經膠質瘤有療效，但單獨以Ad/IL-18治療則沒有療效，合併二者 並無加成效果。此外，合併Ad/IL-12及Ad/ME則有加成效果，但再加上Ad/IL-18則亦未能提 高療效。因此第二年我們調整方向，探討合併GM-CSF、IL-12及IL-18免疫療法，以及抗血 管生成基因療法等不同作用機轉的組合基因療法對於神經膠質瘤的療效。結果發現Ad/G+E 組(K組)大鼠有50%存活率(死亡大鼠存活時間為20.6±3.0天)，Ad/IL-12+Ad/ G+E組(L組)大鼠 有60%存活率(死亡大鼠存活時間為24.5±3.1天)，Ad/IL-18+Ad/ G+E組(M組)大鼠有50%存活 率(死亡大鼠存活時間為22.2±2.7天)，Ad/IL-18+Ad/IL-12+Ad/ G+E組(N組)大鼠有80%存活 率(死亡大鼠存活時間為29.5±0.7天)。這幾組的存活率都比對照組高度(P<0.05)，但與 Ad/IL-12、Ad/IL-12+Ad/IL-18、Ad/IL-12+Ad/ME、Ad/IL-12+Ad/IL-18+Ad/ME等組之間並 無差別(P>0.05)。Ad/IL-18+Ad/IL-12+Ad/ G+E組(N組)的存活率比Ad/IL-18+Ad/ME(I組)的存 活率高(P=0.03)，且大鼠存活時間比除了Ad/IL-12+Ad/IL-18+Ad/ME(I組)之外的各組長 (P<0.05)。這須結果証明合併GM-CSF、IL-12及IL-18免疫基因療法，以及抗血管生成基因 療法等不同作用機轉的組合基因療法對於神經膠質瘤有加成的療效。This 3-year project is intended to investigate the effects of combined granulocyte-macrophage colony-stimulating factor (GM-CSF)-, interleukin-12 (IL-12)- and IL-18-based gene therapy and anti-angiogenesis gene therapy on the intracerebral gliomas in rats. In the first year, we constructed several recombinant adenoviral vectors, including Ad/IL-12, Ad/IL-18, Ad/Endo, Ad/G+E with the titers in the range of 1011 to 1012 pfu. Then these adenoviral vectors were used to treat the intracerebral gliomas. All the control rats and the rats treated with Ad/IL-18 died. By contrast, the survival rate of the rats treated with Ad/IL-12 was 50%, Ad/ME was 30%, Ad/IL-12+Ad/IL-18 was 50%, Ad/IL-12+Ad/ME was 70%, Ad/IL-18+Ad/ME was 30%, and Ad/IL-12+Ad/IL-18+Ad/ME was 70%. The Ad/IL-12, Ad/IL-12+Ad/IL-18, Ad/IL-12+Ad/ME, and Ad/IL-12+Ad/IL-18+Ad/ME groups had higher survival rate than the control groups (P<0.05). However, the Ad/IL-18, Ad/ME, Ad/IL-18+ Ad/ME groups showed no significant difference from the control groups (P>0.05). on the other hand, Ad/IL-12+Ad/IL-18+Ad/ME group had higher survival rate than Ad/IL-18, Ad/ME, or Ad/IL-18+Ad/ME groups (P<0.05), but showed no difference from the Ad/IL-12, Ad/IL-12+Ad/IL-18, or Ad/IL-12+Ad/ME groups (P>0.05). The results indicated that Ad/IL-12 alone was effective for the treatment of intracerebral gliomas, by contrast, Ad/IL-18 had no therapeutic effect on the glioma. Combined Ad/IL-12 and Ad/IL-18 showed no synergistic effects. Combined Ad/IL-12 and Ad/ME shoed synergistic effects on the intracerebral gliomas, however, addition of Ad/IL-18 did not enhance the therapeutic effects. In the second year, we modified the strategies and included the adenoviral vector carrying granulocyte-macrophage colony-stimulating factor (GM-CSF) and endostatin (Ad/G+E) in the treatment methods. We found that the survival rate of the rats treated with Ad/G+E was 50%, Ad/IL-12+Ad/G+E was 60%, Ad/IL-18+Ad/G+E組 was 50%, Ad/IL-18+Ad/IL-12+Ad/G+E was 80%. The survival rate of these groups was significantly higher than that of the control group (P<0.05); however, was not different from that of the groups treated with Ad/IL-12, Ad/IL-12+Ad/IL-18, Ad/IL-12+Ad/ME, Ad/IL-12+Ad/IL-18+Ad/ME (P>0.05). By contrast, the survival rate of the group treated with Ad/IL-18+Ad/IL-12+Ad/G+E was higher than that of the group treated with Ad/IL-18+Ad/ME (P=0.03). Furthermore, the survival time of the group treated with Ad/IL-18+Ad/IL-12+Ad/G+E was longer than that of all tested groups (P<0.05) except the group treated with Ad/IL-12+Ad/IL-18+Ad/ME. The results suggested that combination of GM-CSF, IL-12, and IL-18-based immunogene therapy and the anti-angiogenesis therapy had synergistic therapeutic effects on gliomas.application/pdf105333 bytesapplication/pdfzh-TW國立臺灣大學醫學院外科神經膠質瘤免疫基因療法抗血管生成基因療法granulocyte-macrophage colony-stimulating factorinterleukin-12interleukin-18endostatin腺病毒載體gliomaimmunogene therapyanti-angiogenesis gene therapygranulocyte-macrophage colony-stimulating factoradenoviral vectorreporthttp://ntur.lib.ntu.edu.tw/bitstream/246246/24543/1/932314B002043.pdf