SKI-606, a Src/AbI inhibitor with in vivo activity in colon tumor xenograft models
SKI-606, a Src/AbI inhibitor with in vivo activity in colon tumor xenograft models
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DOI：
10.1158/0008-5472.can-04-2484
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发表时间：
2005-06-15
期刊：
影响因子：
11.2
通讯作者：
Boschelli, F
中科院分区：
文献类型：
--
作者：
Golas, JM;Lucas, J;Boschelli, F
Src表达上调是人类癌症中的常见事件。在结直肠癌中，Src水平升高是预后不良的指标，并且进展为转移性疾病与Src活性的显著增加相关。因此，我们检测了SKI-606（Src和Ab 1激酶的有效抑制剂）在体外和皮下对结肠肿瘤细胞系的活性。肿瘤异种移植模型。SKI-606抑制HT 29细胞Src自磷酸化，IC 50接近0.25 μ mol/L。类似浓度的抑制剂可降低粘着斑激酶（Src底物）Tyr（925）的磷酸化。塑料上的抗增殖活性与HT 29或Colo 205细胞中的S，re抑制无关（IC（50）s，分别为1.5和2.5 μ mol/L），尽管亚微摩尔浓度的SKI-606抑制软琼脂中HT 29细胞集落的形成。SKI-606还引起松散聚集的Colo 205球状体凝聚成致密球状体。以最低有效剂量对裸鼠经口给药时，观察到血浆峰浓度接近3 μ mol/L，口服生物利用度为18%，t（1/2）为8.6小时。SKI-606在s.c.结肠肿瘤异种移植物模型中，并导致HT 29和Colo 205肿瘤中Tyr（418）上Src自磷酸化的显著减少。SKI-606在每天一次给药时抑制HT 29肿瘤生长，而每天两次给药对于抑制Colo 205、HCT 116和DLD 1肿瘤生长是必要的。这些结果支持开发SKI-606作为治疗结肠直肠癌的治疗剂。
Src up-regulation is a common event in human cancers. In colorectal cancer, increased Src levels are an indicator of poor prognosis, and progression to metastatic disease is associated with substantial increases in Src activity. Therefore, we examined the activity of SKI-606, a potent inhibitor of Src and Ab1 kinases, against colon tumor lines in vitro and in s.c. tumor xenograft models. SKI-606 inhibited Src autophosphorylation with an IC50 of similar to 0.25 mu mol/L in HT29 cells. Phosphorylation of Tyr(925) of focal adhesion kinase, a Src substrate, was reduced by similar concentrations of inhibitor. Antiproliferative activity on plastic did not correlate with S, re inhibition in either HT29 or Colo205 cells (IC(50)s, 1.5 and 2.5 mu mol/L, respectively), although submicromolar concentrations of SKI-606 inhibited HT29 cell colony formation in soft agar. SKI-606 also caused loosely aggregated Colo205 spheroids to condense into compact spheroids. On oral administration to nude mice at the lowest efficacious dose, peak plasma concentrations of similar to 3 mu mol/L, an oral bioavailability of 18%, and a t(1/2) of 8.6 hours were observed. SKI-606 was orally active in s.c. colon tumor xenograft models and caused substantial reductions in Src autophosphorylation on Tyr(418) in HT29 and Colo205 tumors. SKI-606 inhibited HT29 tumor growth on once daily administration, whereas twice daily administration was necessary to inhibit Colo205, HCT116, and DLD1 tumor growth. These results support development of SKI-606 as a therapeutic agent for treatment of colorectal cancer.