|Budget Amount *help
¥13,800,000 (Direct Cost : ¥13,800,000)
Fiscal Year 1999 : ¥6,600,000 (Direct Cost : ¥6,600,000)
Fiscal Year 1998 : ¥7,200,000 (Direct Cost : ¥7,200,000)
Highly augmented cytopathic effect of a fiber-mutant E1B-defective adenovirus for gene therapy of glioma. Cancer Res., 1999. An E1B 55-kDa gene-defective adenovirus(Adv), ONYX-015, has been reported to be a highly useful replication-competent Adv that shows cytopathic effect for cancers with an abnormal p53 gene, without damaging normal tissues. In this study, we combined this Adv (Adv-E1Adb) with a fiber mutation, F/K20, which has a stretch of 20 lysine residues added at the COO-H-terminus of the fiber and shows high transduction efficiency to gliomas. In U-373 MG glioma cells, the transduction efficiency of Adv-F/K20 for lacZ was nine times higher than that of the Adv with wild-type fiber (Adv-F/wt) for lacZ. At a multiplicity of infection of 30, the replication efficiency of Adv-E1AdB-F/K20 was 11 times higher than that of Adv-E1AdB with wt fiber (Adv-E1AdB-F/wt). The ED50 value of AdvE1AdB-F/K20 to U-373 MG cells, which is a measure of the in vitro cytopathic effect, was 32 times g
reater than that of Adv-E1AdB-F/wt. Injection of Adv-E1AdB-F/K20 suppressed the in vivo growth of tumors. The antitumoral effect of Adv-E1AdB-F/K20 was remarkably stronger than that of Adv-E1AdB-F/wt. A greater quantity of replicated virus protein (hexon) by infection with Adv-E1AdB-F/K20 was demonstrated in vitro and in vivo, compared with that of Adv-E1AdB-F/wt. In conclusion, gene therapy using Adv-E1AdB-F/K20, which drastically augmented the antitumoral effect of Adv-E1AdB, will be promising therapeutic approach for gliomas.
Adenovirus-mediated transfer of p33ィイD1INGィエD1 with p53 drastically augments apoptosis in gliomas. Cancer Res., 1999. The p53 tumor suppressor gene is an important target for the gene therapy of cancers, and clinical trials targeting this gene have been conducted. Some cancers, however, are refractory to p53 gene therapy. Therefor, it has been combined with other therapies including chemotherapy and radiotherapy to enhance the cytopathic effect of p53 induction. The p33ィイD1ING1ィエD1 gene cooperates with p53 to block cell proliferation. In this study, we investigated whether adenovirus (Adv)-mediated co-induction of p33ィイD1ING1ィエD1 and p53 enhances apoptosis in glioma cells (U251 and U-373MG), which showed no genetic alterations but low expression levels of p33ィイD1ING1ィエD1. Co-infection of Adv-p33 and Adv-MBP-p53 at the same MOIs induced drastically enhanced apoptosis in both cell lines. Our results indicated that this co-infection approach can be used as a modality for the gene therapy of gliomas, sparing damage to normal tissues.
3. Anti-oncogeneを用いた遺伝子治療 a.p53によるアポトーシスは、p33^<ING>併用で増強された。 b.p53制限増殖型Adv-F/K20は脳腫瘍治療に著効を示した。
4. 神経におけるBcl-2 familyの役割 a.Bax高発現で細胞がアポトーシスになるかネクローシスになるかは、BaxとBcl-X_Lの発現のバランスにより決まる。b.アポトーシス抑制作用はBcl-X_Lの方がBcl-2より有効である。 Less