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Hum. Reprod. Advance Access originally published online on June 17, 2004
Human Reproduction 2004 19(9):1957-1967; doi:10.1093/humrep/deh355
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Human Reproduction vol. 19 no. 9 © European Society of Human Reproduction and Embryology 2004; all rights reserved

The AG1478 tyrosine kinase inhibitor is an effective suppressor of leiomyoma cell growth

Asher Shushan1,3, Nathan Rojansky1, Neri Laufer1, Benjamin Y. Klein2, Zipora Shlomai2, Rubina Levitzki2, Zipora Hartzstark2 and Hannah Ben-Bassat2

1 Department of Obstetrics and Gynecology and 2 Laboratory of Experimental Surgery, Hadassah University Hospital, PO Box 12000, Jerusalem 91120, Israel

3 To whom correspondence should be addressed. Email: shush{at}cc.huji.ac.il

BACKGROUND: Uterine leiomyomas are the most common benign smooth muscle cell tumours in women. Formation of leiomyomas, still not completely understood, is viewed as a multistep process, with involvement of ovarian steroid hormones, cytokines and growth factors. Our study aimed to identify tyrosine kinase inhibitors as potential ‘signal transduction therapeutics’ for leiomyomas, underlying the effect of ovarian steroidal hormones. METHODS: The selective epidermal growth factor (EGF) receptor blocker AG1478 was evaluated as a potential target, since EGF has been shown to mediate estrogen action and to play a crucial role in regulating leiomyoma growth. Paired cultures of leiomyoma and normal myometrium samples were established and the suppressive effect of AG1478 on the cells prior and subsequent to steroidal hormone treatment was examined: cell proliferation, recovery after treatment, cell cycle analysis and immunochemical analysis of relevant proteins. RESULTS: Leiomyoma cell growth is effectively blocked by AG1478 and is unaffected by the presence of physiological concentrations of progesterone and estradiol. AG1478 (10 µM) completely suppressed proliferation and the cells did not recover after cessation of treatment. CONCLUSION: The growth-arresting properties of AG1478, unaffected by ovarian steroidal hormones, identify it as a potential lead agent for the non-surgical management of uterine leiomyomas.

Key words: AG1478/growth suppression/leiomyomas/protein tyrosine kinase (PTK) inhibitors/signal transduction therapy


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