Inhibition of tyrosine kinases PDGFR and C-Kit by imatinib mesylate interferes with postnatal testicular development in the rat
Inhibition of tyrosine kinases PDGFR and C-Kit by imatinib mesylate interferes with postnatal testicular development in the rat
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DOI：
10.1111/j.1365-2605.2007.00755.x
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发表时间：
2007-08-01
影响因子：
--
通讯作者：
Jahnukainen, Kirsi
中科院分区：
文献类型：
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作者：
Nurmio, Mirja;Toppari, Jorma;Jahnukainen, Kirsi
酪氨酸激酶受体c-KIT及其与配体干细胞因子(SCF)的相互作用在睾丸发育过程中起着至关重要的作用。C-KIT对间质细胞的发育和精原细胞的迁移、增殖和存活具有重要作用。血小板衍生生长因子(PDGF)及其酪氨酸激酶受体(PDGFR)在间质细胞和肌样细胞的发育中起重要作用。化疗药物甲磺酸伊马替尼(STI571，Glivec；诺华)抑制这两种酪氨酸激酶受体。出生后第5~7天给未成熟雄性大鼠(SD)注射伊马替尼(150 mg/kg)3d，可延缓生殖系干细胞库的形成，抑制A型精原细胞的增殖，并诱导生殖细胞凋亡。PDGFR介导的间充质肌样前体细胞增殖也减少，生精索长度缩短。然而，在11周龄时，暴露的动物附睾精子计数正常，而血浆黄体生成素和卵泡刺激素水平显著增加。伊马替尼是研究男性生殖系干细胞库的出生后形成和决定最终睾丸大小的因素的良好工具。由于人类睾丸的发育是由相同的机制控制的，因此需要对灵长类动物和人类模型进行进一步的研究，以探索伊马替尼是否也会影响儿童的睾丸。
The tyrosine kinase receptor c-kit and its interaction with the ligand, stem cell factor (SCF), play an essential role in the developing testis. C-kit is important for the development of the Leydig cells and for the migration, proliferation and survival of spermatogonia. Platelet-derived growth factor (PDGF) and its tyrosine kinase receptor (PDGFR) are important for the development of Leydig cells and myoid cells. The chemotherapeutic agent, imatinib mesylate (STI571, Glivec; Novartis) inhibits both of these tyrosine kinase receptors. Three-day treatment of immature male rats (SD) with imatinib (150 mg/kg) on postnatal days 5-7 delayed the formation of germ-line stem cell pool, reduced proliferation of type A spermatogonia and induced germ cell apoptosis. PDGFR-mediated proliferation of mesenchymal myoid precursors was also decreased and the length of the seminiferous cord was reduced. However, at the age of 11 weeks the exposed animals had normal epididymal sperm counts, whereas plasma levels of luteinizing hormone and follicle stimulating hormone were significantly increased. Imatinib serves as a good tool to study postnatal formation of the male germ-line stem cell pool and factors determining the final testicular size. As development of the human testis is controlled by the same mechanisms, further studies with primate and human models are needed to explore whether imatinib affects the testis in children as well.