Basis for dosing time-dependent change in the anti-tumor effect of imatinib in mice.
Basis for dosing time-dependent change in the anti-tumor effect of imatinib in mice.
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DOI：
10.1016/j.bcp.2006.08.002
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发表时间：
2006-11
影响因子：
5.8
通讯作者：
Hiroo Nakagawa;Takako Takiguchi;Mariko Nakamura;A. Furuyama;S. Koyanagi;H. Aramaki;S. Higuchi;S. Ohdo
中科院分区：
文献类型：
--
作者：
Hiroo Nakagawa;Takako Takiguchi;Mariko Nakamura;A. Furuyama;S. Koyanagi;H. Aramaki;S. Higuchi;S. Ohdo
由于多种受体酪氨酸激酶参与肿瘤进展的机制，因此预期开发临床上有用的酪氨酸激酶抑制剂作为治疗恶性癌症的治疗剂。伊马替尼甲磺酸盐，称为格列卫或STI-571，是一种抑制具有酪氨酸激酶活性的各种受体功能的分子，如Abl、bcr-abl嵌合产物、KIT和血小板衍生生长因子（PDGF）受体。在这项研究中，我们研究了给药时间对伊马替尼抑制小鼠肿瘤生长能力的影响。将荷瘤小鼠圈养在标准化光/暗循环条件下（07：00 h开灯，19：00 h关灯），随意进食和饮水。在小鼠中植入的肿瘤细胞的生长通过施用伊马替尼（50 mg/kg，i. p.）比在黑暗早期给药时更有效。抗肿瘤作用的给药时间依赖性与伊马替尼诱导的抗血管生成作用的给药时间依赖性平行。伊马替尼对PDGF受体酪氨酸激酶活性的抑制作用随给药时间而变化，但对KIT和Abl无抑制作用。伊马替尼诱导的血小板衍生生长因子受体活性抑制作用的给药时间依赖性与其抗肿瘤作用密切相关。我们的研究结果表明，伊马替尼的抗肿瘤疗效增强时，血小板衍生生长因子受体活性增加的药物管理。通过优化给药方案，可以预期药物的有效治疗效果。
Because a variety of receptor tyrosine kinases are involved in the mechanism of tumor progression, the development of a clinically useful tyrosine kinase inhibitor is expected as a therapeutic agent for the treatment of malignant cancers. Imatinib mesylate, known as Gleevec or STI-571, is a molecule that inhibits the function of various receptors with tyrosine kinase activity, such as Abl, the bcr–abl chimeric product, KIT, and platelet-derived growth factor (PDGF) receptors. In this study, we investigated the influence of dosing time on the ability of imatinib to inhibit tumor growth in mice. Tumor-bearing mice were housed under standardized light/dark cycle conditions (lights on at 07:00h, off at 19:00h) with food and water ad libitum. The growth of tumor cells implanted in mice was more severely inhibited by the administration of imatinib (50mg/kg, i.p.) in the early light phase than when it was administered in the early dark phase. The dosing time-dependency of anti-tumor effects was parallel to that of imatinib-induced anti-angiogenic effect. The inhibitory effect of imatinib on tyrosine kinase activity of PDGF receptors, but not of KIT and Abl, varied according to its administration time. The dosing time-dependency of imatinib-induced inhibition of PDGF receptor activity was closely related to that of its anti-tumor effects. Our results suggest that the anti-tumor efficacy of imatinib is enhanced by administering the drug when PDGF receptor activity was increased. The potent therapeutic efficacy of the drug could be expected by optimizing the dosing schedule.