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Establishment of Antisense Therapy for Hematological Mailg-nancies Targeted Their Rearranged Genes.

针对血液肿瘤重排基因的反义疗法的建立。

基本信息

批准号：
09671094
负责人：
MAEKAWA Taira
金额：
$ 2.3万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09671094/
关键词：
antisense hematological malignancy leukemia gene rearrangement cell therapy

项目摘要

In this research project, we have clarified followings concerning the mechanism of suppression of the proliferation of human leukemic cells by antisense oligodeoxynucleotides (AS ODN) for rearranged and over-expressed oncogenes.1) BCR-ABL AS ODN could effectively suppress the proliferation of chronic myeloid leukemia (CML) cells by the induction of apoptosis of these leukemia cells. c-myc AS ODN could inhibit the proliferation of human leukemia cells HL6O, and the abrupt up-regulation of number of leukemia cells in G_1/S boundary. c-myc AS ODN also inhibited the proliferation of synovial cells from patients with rheumatoid arthritits and induced the apoptosis through Fas/Fas ligand system.2) We have established the synthesis and purification methods of AS ODN with chimeric backbone structure of phosphorothioate and phosphodiester linkages. The first three linkages of both 5'- and 3'-end are synthesized by phosphorothioate chemistry. We have shown these chimeric analogues were resistant to the degradation by nuclease.3) The above chimeric analogue have much less non-specific effects or aptamer effects that are often encountered when AS ODNs with all-phosphorothioate linkages are used.4) We have shown that AS ODNs with chimeric backbones against Bcl-2, c-myc, erythropoietin receptor, and stromal-derived factor 1 effectively work as functional antisense molecules, and we have found the novel target antisense sequence to reduce the Bcl-2 expression.

在本研究项目中，我们阐明了反义寡脱氧核苷酸（AS ODN）对重排和过表达癌基因抑制人白血病细胞增殖的机制。1) BCR-ABL AS ODN可通过诱导慢性髓系白血病（CML）细胞凋亡，有效抑制CML细胞的增殖。c-myc AS ODN能抑制人白血病细胞hl60的增殖，使G_1/S交界区白血病细胞数量突变上调。c-myc AS ODN还通过Fas/Fas配体系统抑制类风湿关节炎滑膜细胞的增殖并诱导细胞凋亡。2)建立了具有硫代磷和二酯键嵌合骨架结构的AS ODN的合成和纯化方法。5′端和3′端的前三个键都是通过硫代化学合成的。我们已经证明这些嵌合类似物能够抵抗核酸酶的降解。3)上述嵌合类似物具有更少的非特异性效应或适体效应，而当使用具有全硫代键的AS odn时，通常会遇到这种效应。4)我们已经发现，具有嵌合骨架的AS odn可以有效地对抗Bcl-2、c-myc、促红细胞生成素受体和基质衍生因子1，并且我们发现了新的靶向反义序列来降低Bcl-2的表达。