Kawamoto Teruya, Akisue Toshihiro, Marui Takashi, Nakatani Tetsuya, Hitora Toshiaki, Fujita Ikuo, Kurosaka Masahiro, Yamamoto Tetsuji
Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
Anticancer Res. 2004 Sep-Oct;24(5A):2675-9.
Malignant fibrous histiocytoma (MFH) is one of the most common high-grade sarcomas in bone and soft tissue and, due to its chemo-resistance, the prognosis of the disease is poor. ST1571 is a tyrosine kinase inhibitor that was initially developed as a BCR/ABL inhibitor for chronic myeloid leukemia patients. STI571 also selectively inhibits platelet-derived growth factor receptors (PDGFRs) and c-kit. We examined the expression of PDGFRs and c-kit in human MFH cell lines, and the effect of STI571 on cell proliferation.
Four human MFH cell lines (TNMY1, GBS-1, Nara-F and Nara-H) were used. mRNA expression of the receptor tyrosine kinases (PDGFRs and c-kit) was analyzed using reverse transcription-polymerase chain reaction, and the inhibitory effect of STI571 on cell proliferation was analyzed using the MTS assay technique.
PDGFRalpha mRNA was expressed in TNMY1 and GBS-1, and PDGFRbeta and c-kit mRNAs were expressed in TNMY1, GBS-1 and Nara-F. All three of these mRNAs were absent in Nara-H. STI571 inhibited cell proliferation of TNMY1, GBS-1 and Nara-F in a dose- and time-dependent manner, but cell proliferation of Nara-H was not inhibited by ST1571 at concentrations of 10 microM or less.
STI571 significantly inhibited proliferation of the three human MFH cell lines that expressed mRNAs of target receptor tyrosine kinases. The inhibitory effect of ST1571 on cell proliferation in these three cell lines might be due to decreased tyrosine kinase activity. STI571 might be a potent chemotherapeutic agent for human MFHs.
恶性纤维组织细胞瘤（MFH）是骨骼和软组织中最常见的高级别肉瘤之一，因其具有化疗耐药性，该疾病的预后较差。ST1571是一种酪氨酸激酶抑制剂，最初作为慢性粒细胞白血病患者的BCR/ABL抑制剂开发。STI571还可选择性抑制血小板衍生生长因子受体（PDGFRs）和c-kit。我们检测了人MFH细胞系中PDGFRs和c-kit的表达，以及STI571对细胞增殖的影响。
使用了四种人MFH细胞系（TNMY1、GBS-1、奈良-F和奈良-H）。采用逆转录-聚合酶链反应分析受体酪氨酸激酶（PDGFRs和c-kit）的mRNA表达，采用MTS检测技术分析STI571对细胞增殖的抑制作用。
TNMY1和GBS-1中表达PDGFRα mRNA，TNMY1、GBS-1和奈良-F中表达PDGFRβ和c-kit mRNA。奈良-H中这三种mRNA均未表达。STI571以剂量和时间依赖性方式抑制TNMY1、GBS-1和奈良-F的细胞增殖，但在浓度为10μM或更低时，ST1571未抑制奈良-H的细胞增殖。
STI571显著抑制了三种表达靶受体酪氨酸激酶mRNA的人MFH细胞系的增殖。ST1571对这三种细胞系细胞增殖的抑制作用可能是由于酪氨酸激酶活性降低。STI571可能是一种有效的人MFH化疗药物。
