McGary Eric C, Weber Kristy, Mills Lisa, Doucet Michelle, Lewis Valerie, Lev Dina Chelouche, Fidler Isaiah J, Bar-Eli Menashe
Department of Cancer Biology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77054,USA.
Clin Cancer Res. 2002 Nov;8(11):3584-91.
Osteosarcoma is an aggressive primary bone cancer characterized by expression of platelet-derived growth factor (PDGF) and its cognate receptor. Coexpression of the growth factor and receptor suggests their role in autocrine or paracrine growth mechanisms. It has been reported previously that STI571 has specific activity in inhibiting select tyrosine kinase receptors, including PDGF and c-Kit. Osteosarcomas express low levels of c-Kit but abundant levels of PDGF receptor (PDGFR).
To investigate the potential of STI571 as therapy for osteosarcoma, we studied its effects on PDGF-mediated cell growth in vitro and in an in vivo mouse model.
PDGF acted as a potent mitogen in a dose-dependent manner in two osteosarcoma cell lines. STI571 (1.0 micro M) inhibited both PDGFR-alpha and PDGFR-beta phosphorylation and the downstream phosphorylation targets extracellular signal-regulated kinase and Akt. STI571 also inhibited PDGF-mediated growth and induced apoptosis in vitro as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and terminal deoxynucleotidyl transferase-mediated nick end labeling staining. To study the effect of STI571 alone or in combination with Taxol in an in vivo model, an osteosarcoma cell line (KRIB) was transplanted into the tibia of athymic nude mice. Mice were treated with STI571 (50 mg/kg p.o. q M-F), Taxol (8 mg/kg i.p. weekly), or STI571 plus Taxol for 6 weeks. There was no significant difference in tumor size between treatment and control mice. Aberrant signaling pathways downstream of the PDGFR in the v-Ki-ras oncogene-transformed KRIB cell line may in part explain this finding.
Our data demonstrate that STI571 inhibits PDGF-mediated growth and leads to apoptosis of osteosarcoma cells in vitro by selective inhibition of the PDGFR tyrosine kinase. The effectiveness of STI571 in our studies suggests targeting of PDGFRs as a novel treatment for osteosarcoma.
骨肉瘤是一种侵袭性原发性骨癌，其特征在于血小板衍生生长因子（PDGF）及其同源受体的表达。生长因子和受体的共表达表明它们在自分泌或旁分泌生长机制中的作用。先前已有报道称，STI571在抑制包括PDGF和c-Kit在内的特定酪氨酸激酶受体方面具有特异性活性。骨肉瘤中c-Kit表达水平低，但血小板衍生生长因子受体（PDGFR）水平丰富。
为了研究STI571作为骨肉瘤治疗方法的潜力，我们在体外和体内小鼠模型中研究了其对PDGF介导的细胞生长的影响。
在两种骨肉瘤细胞系中，PDGF以剂量依赖性方式作为一种有效的促有丝分裂原。STI571（1.0微摩尔）抑制PDGFR-α和PDGFR-β的磷酸化以及下游磷酸化靶点细胞外信号调节激酶和Akt。通过3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四氮唑溴盐测定法和末端脱氧核苷酸转移酶介导的缺口末端标记染色确定，STI571在体外也抑制PDGF介导的生长并诱导细胞凋亡。为了在体内模型中研究单独使用STI571或与紫杉醇联合使用的效果，将一种骨肉瘤细胞系（KRIB）移植到无胸腺裸鼠的胫骨中。小鼠接受STI571（50毫克/千克口服，每周一至周五）、紫杉醇（8毫克/千克腹腔注射，每周一次）或STI571加紫杉醇治疗6周。治疗组和对照组小鼠的肿瘤大小没有显著差异。v-Ki-ras癌基因转化的KRIB细胞系中PDGFR下游异常的信号通路可能部分解释了这一发现。
我们的数据表明，STI571通过选择性抑制PDGFR酪氨酸激酶，在体外抑制PDGF介导的生长并导致骨肉瘤细胞凋亡。STI571在我们研究中的有效性表明，靶向PDGFRs作为骨肉瘤的一种新治疗方法。
