Divergent cytotoxic effects of PKC412 in combination with conventional antileukemic agents in FLT3 mutation-positive versus-negative leukemia cell lines
Divergent cytotoxic effects of PKC412 in combination with conventional antileukemic agents in FLT3 mutation-positive versus-negative leukemia cell lines
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DOI：
10.1038/sj.leu.2404593
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发表时间：
2007-05-01
期刊：
影响因子：
11.4
通讯作者：
Kano, Y.
中科院分区：
文献类型：
--
作者：
Furukawa, Y.;Vu, H. A.;Kano, Y.
FMS样酪氨酸激酶-3（FLT 3）是急性髓细胞白血病（AML）的一个新的治疗靶点，因为FLT 3突变是AML中最常见的遗传改变，与白血病发生直接相关。我们研究了FLT 3抑制剂PKC 412与8种常规抗白血病药物的细胞毒性相互作用（阿糖胞苷、阿霉素、伊达比星、米托蒽醌、依托泊苷、4-氢过氧-环磷酰胺、甲氨蝶呤和长春新碱）使用三种携带FLT 3突变的白血病细胞系（M0 LM 13、M0 LM 14和MV 4 -11）和五种没有FLT 3突变的白血病细胞系（KOPB-26、THP-1、BALL-1、KG-1和U937）。在等效线图分析中，PKC 412与除甲氨蝶呤外的所有研究药物均显示出对FLT 3突变细胞系的协同作用。相比之下，在没有FLT 3突变的白血病细胞系中，PKC 412对大多数药物具有相当大的拮抗作用，除了4-过氧化氢环磷酰胺和长春新碱。细胞周期分析显示，PKC 412诱导携带FLT 3突变的白血病细胞系G1期阻滞，而在FLT 3突变不存在的情况下，它将细胞阻滞在G2/M期，这可能是不同的细胞毒性相互作用的基础。这些结果表明，同时给予PKC 412和除甲氨蝶呤以外的其他药物对FLT 3突变阳性白血病临床有效，而对FLT 3突变阴性白血病几乎没有益处。我们的研究结果可能有助于设计基于PKC 412的联合化疗方案。
FMS-like tyrosine kinase-3 (FLT3) is a new therapeutic target for acute myelocytic leukemia (AML), because FLT3 mutations are the most common genetic alterations in AML and are directly related to leukemogenesis. We studied cytotoxic interactions of a FLT3 inhibitor, PKC412, with eight conventional antileukemic agents ( cytarabine, doxorubicin, idarubicin, mitoxantrone, etoposide, 4-hydroperoxy-cyclophosphamide, methotrexate and vincristine) using three leukemia cell lines carrying FLT3 mutations (MOLM13, MOLM14 and MV4-11) and five leukemia cell lines without FLT3 mutations (KOPB-26, THP-1, BALL-1, KG-1 and U937). PKC412 showed synergistic effects with all agents studied except methotrexate for FLT3-mutated cell lines in isobologram analysis. In contrast, PKC412 was rather antagonistic to most drugs, except for 4-hydroperoxy-cyclophosphamide and vincristine, in leukemia cell lines without FLT3 mutations. Cell-cycle analysis revealed that PKC412 induced G1 arrest in leukemia cell lines carrying FLT3 mutations, whereas it arrested cells in G2/M phase in the absence of FLT3 mutations, which may underlie the divergent cytotoxic interactions. These results suggest that the simultaneous administration of PKC412 and other agents except methotrexate is clinically effective against FLT3 mutation-positive leukemias, whereas it would be of little benefit for FLT3 mutation-negative leukemias. Our findings may be of help for the design of PKC412-based combination chemotherapy.