Novel HER2 selective tyrosine kinase inhibitor, TAK-165, inhibits bladder, kidney and androgen-independent prostate cancer in vitro and in vivo
Novel HER2 selective tyrosine kinase inhibitor, TAK-165, inhibits bladder, kidney and androgen-independent prostate cancer in vitro and in vivo
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DOI：
10.1111/j.1442-2042.2006.01342.x
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发表时间：
2006-05-01
影响因子：
2.6
通讯作者：
Namiki, Mikio
中科院分区：
文献类型：
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作者：
Nagasawa, Joji;Mizokami, Atsushi;Namiki, Mikio
目的：TAK-165是一种新的人表皮生长因子受体2（HER 2）酪氨酸激酶强效抑制剂。一些报告表明HER 2在膀胱癌、肾细胞癌（RCC）和雄激素非依赖性前列腺癌中表达。因此，我们研究了TAK-165对这些泌尿系癌细胞的抗肿瘤作用。材料和方法：进行Western印迹分析，以确认HER 2在细胞系中的表达。为了研究体外疗效，用不同浓度的TAK-165处理细胞72 h，然后使用血细胞计数器计数。然后计算IC 50值。在异种移植模型中，肿瘤体积达到200-300 mm 3后，小鼠连续14天经口给予TAK-165 10 mg/kg/天或20 mg/kg/天或生理盐水（n = 6-8）。结果：在HT 1376、UMUC 3、T24（膀胱）、ACHN（肾脏）、DU 145、LNCaP、LN-REC 4（前列腺）中观察到HER 2表达。尽管与BT474（一种强烈表达HER 2的乳腺癌细胞系）相比，这些细胞中的表达水平较弱。在膀胱癌细胞系中，IC 50从0.09变化到大于25 μ mol/L。ACHN细胞在体外的敏感性较低。所研究的前列腺癌细胞系均敏感（IC_（50）0.053-4.62 μ mol/L）。在异种移植模型中，TAK-165给药显著抑制UMUC-3、ACHN和LN-REC 4的生长。治疗14天后，UMUC 3、ACHN和LN-REC 4的抗肿瘤效应（T/C [%] = TAK-165治疗肿瘤的生长/对照肿瘤的平均生长× 100）分别为22.9%、26.0%和26.5%。结论：TAK-165可能是治疗膀胱癌、肾癌和雄激素非依赖性前列腺癌的一种有希望的新药。
Purpose: TAK-165 is a new potent inhibitor of human epidermal growth factor receptor 2 (HER2) tyrosine kinase. Several reports suggest HER2 expression in bladder cancer, renal cell carcinoma (RCC) and androgen-independent prostate cancer. We therefore investigated the antitumor effect of TAK-165 on these urological cancer cells.Materials and methods: Western blot analysis was performed to confirm HER2 expression in cell lines. To study in vitro efficacy, cells were treated with TAK-165 at various concentrations for 72 h and then counted using a hemocytometer. Then the IC50 value was calculated. In the xenograft model, after the tumor reached 200-300 mm(3) in volume, mice were orally administered TAK-165 10 mg/kg per day or 20 mg/kg per day or saline for 14 consecutive days (n = 6-8).Results: HER2 expression was observed in HT1376, UMUC3, T24 (bladder), ACHN (kidney), DU145, LNCaP, LN-REC4 (prostate). although the expression level in these cells was weak compared with BT474 (a breast cancer cell line which expresses HER2 strongly). IC50 was varied from 0.09 to greater than 25 mu mol/L in the bladder cancer cell line. ACHN cells were less sensitive in vitro. The prostate cancer cell lines studied were all sensitive (IC50 0.053-4.62 mu mol/L). In the xenograft model, treatment with TAK-165 significantly inhibited growth of UMUC-3, ACHN, and LN-REC4. The antitumor effect (T/C [%] = growth of TAK-165 treated tumor/average growth of control tumor x 100) after 14 days treatment were 22.9%, 26.0%, and 26.5% in UMUC3, ACHN and LN-REC4, respectively.Conclusions: TAK-165 may be a hopeful new agent for bladder, kidney and androgen-independent prostate cancer.