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Rapamycin Selectively Inhibits the Growth of Childhood Rhabdomyosarcoma Cells through Inhibition of Signaling via the Type I Insulin-like Growth Factor Receptor¹

Department of Molecular Pharmacology [M. B. D., P. D., G. S. G., P. J. H.], St. Jude Children's Research Hospital, Memphis, Tennessee 38105; Department of Experimental Oncology [D. N. S.], St. Jude Children's Research Hospital, Memphis, Tennessee 38105; Department of Pharmacology [P. J. H.], University of Tennessee College of Medicine, Memphis, Tennessee 38163, Department of Pediatrics [D. N. S.], University of Tennessee College of Medicine, Memphis, Tennessee 38163; and Department of Biomolecular Discovery, SmithKline Beecham, King of Prussia, Pennsylvania 19406-0939 [R. K. J.]

² To whom requests for reprints should be addressed, at Department of Molecular Pharmacology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105.

We show that cell lines derived from childhood alveolar rhabdomyosarcoma (RMS) are very sensitive to the growth-inhibitory effects of the immunosuppressive agent rapamycin (RAP), compared to other human cell lines (50% inhibitory concentration range of 0.1-8 ng/ml, compared to 1280 to > 10,000 ng/ml). Our data suggest that the sensitivity of RMS lines is due to RAP inhibition of insulin-like growth factor 1 receptor-mediated signaling, which is essential for continued proliferation of RMS cells. The embryonal RMS line Rhl, which was resistant to RAP in serum-containing medium (50% inhibitory concentration, 4180 ng/ml), was highly sensitive under autocrine conditions of growth, indicating that resistance was due to paracrine signaling pathways insensitive to RAP action. FK506 reversed RAP action in all cell lines, indicating a dependence on complex-ing with the cytosolic FK506-binding protein for activity.

¹ This work was supported in part by United States Public Health Service Awards CA23099 and CA21675 (Cancer Center Support Core) from the National Cancer Institute and by the American Lebanese Syrian Associated Charities.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 12/ 9/93. Accepted 1/ 5/94.

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