Okabe M, Kunieda Y, Miyagishima T, Kobayashi M, Kurosawa M, Itaya T, Sakurada K, Miyazaki T
Third Department of Internal Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
Leuk Lymphoma. 1993 Jul;10(4-5):307-16. doi: 10.3109/10428199309148553.
We investigated whether antisense oligodeoxynucleotides complementary to bcr/abl mRNA or protein kinase antagonists display antitumor activity on Ph1-positive leukemia cell lines. bcr/abl antisense oligomers showed inhibitory effects on the in vitro growth of Ph1-positive leukemia cell lines in liquid culture, and further displayed an inhibitory effect on transformed murine hematopoietic cells using transfection with a retroviral vector expressing P210bcr/abl oncoprotein. However, in vitro treatment with a bcr/abl antisense oligomer did not completely abolish the expression of bcr/abl mRNA and did not display the desired "killing effect" on Ph1-positive leukemia cells. On the other hand, investigation of the effect on Ph1-positive leukemia cells by various types of protein kinase antagonists revealed that herbimycin A, a protein tyrosine kinase antagonist, displays preferential and remarkable suppression of the growth of Ph1-positive leukemia cells and P210bcr/abl associated transformed cells by virtue of suppressing bcr/abl protein tyrosine kinase activity. These results may provide important future insights in developing a new category of antitumor therapy by targeting oncogene products.
我们研究了与bcr/abl信使核糖核酸互补的反义寡脱氧核苷酸或蛋白激酶拮抗剂是否对Ph1阳性白血病细胞系具有抗肿瘤活性。bcr/abl反义寡聚物对液体培养中Ph1阳性白血病细胞系的体外生长显示出抑制作用，并且在使用表达P210bcr/abl癌蛋白的逆转录病毒载体转染时，对转化的小鼠造血细胞进一步显示出抑制作用。然而，用bcr/abl反义寡聚物进行体外处理并没有完全消除bcr/abl信使核糖核酸的表达，并且对Ph1阳性白血病细胞没有显示出预期的“杀伤作用”。另一方面，对各种类型蛋白激酶拮抗剂对Ph1阳性白血病细胞的作用进行研究发现，蛋白酪氨酸激酶拮抗剂赫司特霉素A通过抑制bcr/abl蛋白酪氨酸激酶活性，对Ph1阳性白血病细胞和与P210bcr/abl相关的转化细胞的生长表现出优先且显著的抑制作用。这些结果可能为通过靶向癌基因产物开发新型抗肿瘤疗法提供重要的未来见解。
