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Development of a Conditional In vivo Model to Evaluate the Efficacy of Small Molecule Inhibitors for the Treatment of Raf-Transformed Hematopoietic Cells

Departments of ¹ Blood and Marrow Transplantation and ² Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas and ³ Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, North Carolina

Requests for reprints: Michael Andreeff, Department of Blood and Marrow Transplantation, 1515 Holcombe Boulevard, Unit 448, Houston, TX 77030. Phone: 713-792-7260; Fax: 713-794-4747; E-mail: mandreef{at}mdanderson.org.

Conditionally active forms of the Raf proteins (Raf-1, B-Raf, and A-Raf) were created by ligating NH₂-terminal truncated activated forms () to the estrogen receptor (ER) hormone-binding domain resulting in estradiol-regulated constructs (Raf:ER). These different Raf:ER oncoproteins were introduced into the murine FDC-P1 hematopoietic cell line, and cells that grew in response to the three Raf:ER oncoproteins were isolated. The ability of FDC-P1, Raf-1:ER, A-Raf:ER, and B-Raf:ER cells to form tumors in severe combined immunodeficient mice was compared. Mice injected with Raf:ER cells were implanted with ß-estradiol pellets to induce the Raf:ER oncoprotein. Cytokine-dependent parental cell lines did not form tumors. Implantation of ß-estradiol pellets into mice injected with Raf:ER cells significantly accelerated tumor onset and tumor size. The recovered Raf:ER cells displayed induction of extracellular signal-regulated kinase (ERK) in response to ß-estradiol stimulation, indicating that they had retained conditional activation of ERK even when passed through a severe combined immunodeficient mouse. The Raf:ER cells were very sensitive to induction of apoptosis by the mitogen-activated protein/ERK kinase (MEK) 1 inhibitor CI1040 whereas parental cells were much less affected, demonstrating that the MEK1 may be useful in eliminating Ras/Raf/MEK–transformed cells. Furthermore, the effects of in vivo administration of the MEK1 inhibitor were evaluated and this inhibitor was observed to suppress the tumorigenicity of the injected cells. This Raf:ER system can serve as a preclinical model to evaluate the effects of signal transduction inhibitors which target the Raf and MEK proteins.

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