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The Antiproliferative Effects of Tyrosine Kinase Inhibitors Tyrphostins on a Human Squamous Cell Carcinoma in Vitro and in Nude Mice¹

Division of Endocrinology and Metabolism, Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284-7877 [T. Y., M. M. A., G. R. M.]; Rhone-Poulenc Rorer Central Research, Horsham, Pennsylvania 19044 [R. M. L., P. E. P., A. P. S., A. Z.]; and the Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel [A. L.]

Many human tumors of epithelial origin contain cells overexpressing the epidermal growth factor (EGF) receptor, and there is convincing evidence that cancer cell growth is correlated with the loss of the normal regulation of the EGF receptor signal transduction pathway. Some cancers are clearly dependent on activation of the EGF receptor for their proliferation. Recently, a class of compounds, tyrphostins, which inhibit the protein tyrosine kinase activity of the growth factor receptor, have been described. In this report, we have examined the antiproliferative effects of potent new tyrphostins on a well-characterized human squamous cell carcinoma in vitro and in vivo. We found that two of these compounds (RG-13022 and RG-14620) suppressed not only EGF-stimulated cancer cell proliferation in vitro but also tumor growth in nude mice. RG-13022 also increased the life span of these tumor-bearing nude mice. When administered to tumor-bearing nude mice together with monoclonal antibodies to the EGF receptor at a suboptimal dose which had no effect alone, inhibition of tumor growth was markedly enhanced. These data suggest that tyrphostins have potential as anticancer agents.

¹ This work was supported in part by Grants AR-28149, CA-40035, DE-08569, and DE-08526 from the NIH.

² To whom requests for reprints should be addressed, at Division of Endocrinology and Metabolism, Department of Medicine, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78284–7877.

Received 3/11/91. Accepted 6/ 6/91.

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