Ｒａｓ関連蛋白およびＢＣＲ／ＡＢＬダブルブロックによるフィラデルフィア染色体陽性白血病の治療

Abstract

Imatinib mesylate, a competitive inhibitor for of ABL tyrosine kinase, is highly active against Philadelphia-positive (Ph+) chronic myelocytic leukemia. However, recent studies demonstrated the existence of primary and/or acquired imatinib-resistant Ph+ clones those would affect the treatment outcome. For the development of the strategies those strengthen the effect of imatinib, we selected Ras related proteins as an alternative molecular target, because these proteins enhance the oncogenetic property of BCR/ABL as downstream signaling effector. Based on the previous findings showing the inhibitory effect for Ras related proteins of the third-generation bisphosphonate, zoledronate (ZOL), we examined its anti-leukemic potencies and the combination effect with imatinib against Ph+ leukemia both in vivo and in vitro. ZOL showed a time- and concentration-dependent anti-proliferative effect in all examined leukemic cell lines by inducing apoptosis. During the apoptotic execution, ZOL inactivated Ras related proteins via prevention of the posttranslational prenylation. The combination of imatinib and ZOL showed the synergistic anti-proliferative effects against Ph+ leukemic cell lines in vitro, and, intriguingly, this combination could prolong the survival of mice xenografted with Ph+ BV173 cell line in comparison with mice treated with imatinib or ZOL alone. These suggest that ZOL is a potent anti-leukemic agent that synergistically augments the effect of imatinib.