Honma Y, Matsuo Y, Hayashi Y, Omura S
Department of Chemotherapy, Saitama Cancer Center Research Institute, Japan.
Int J Cancer. 1995 Mar 3;60(5):685-8. doi: 10.1002/ijc.2910600519.
The molecular basis of the Philadelphia chromosome (Ph1) is a structurally altered c-abl (bcr-abl) gene which encodes an abnormally large protein with protein tyrosine kinase activity. Herbimycin a, which effectively reduced intracellular phosphorylation by bcr-abl tyrosine kinase, preferentially inhibited the growth of Ph1-positive leukemia cell lines. Injection of Ph1-positive and -negative leukemia cell lines into mice with severe combined immunodeficiency (SCID) resulted in the death of all mice due to leukemia, although the severity of illness varied according to the cell lines used. Administration of herbimycin A significantly enhanced the survival of mice inoculated with the Ph1-positive leukemia cell lines tested but barely affected the survival of mice inoculated with the Ph1-negative leukemia cell lines tested. These results suggest that herbimycin A and related compounds may be useful for the treatment of Ph1-positive leukemia. The disease that developed using the Ph1-positive leukemia cell line NALM-20 resembled human Ph1-positive acute lymphoid leukemia. There was an inverse relationship between the survival time of mice and the number of cells inoculated. The SCID mouse-NALM-20 human leukemia chimera would be a good experimental model for screening tyrosine kinase inhibitors as therapeutic agents against Ph1-positive leukemia.
费城染色体（Ph1）的分子基础是一种结构改变的c-abl（bcr-abl）基因，它编码一种具有蛋白酪氨酸激酶活性的异常大的蛋白质。赫伯霉素A能有效降低bcr-abl酪氨酸激酶引起的细胞内磷酸化，优先抑制Ph1阳性白血病细胞系的生长。将Ph1阳性和阴性白血病细胞系注射到严重联合免疫缺陷（SCID）小鼠体内，所有小鼠均因白血病死亡，不过疾病的严重程度因所用细胞系而异。给予赫伯霉素A显著提高了接种测试的Ph1阳性白血病细胞系的小鼠的存活率，但对接种测试的Ph1阴性白血病细胞系的小鼠的存活率几乎没有影响。这些结果表明，赫伯霉素A及相关化合物可能对治疗Ph1阳性白血病有用。使用Ph1阳性白血病细胞系NALM-20引发的疾病类似于人类Ph1阳性急性淋巴细胞白血病。小鼠的存活时间与接种细胞数量之间存在反比关系。SCID小鼠-NALM-20人白血病嵌合体将是筛选酪氨酸激酶抑制剂作为抗Ph1阳性白血病治疗药物的良好实验模型。
