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Epidermal Growth Factor Receptor Blockade in Combination with Conventional Chemotherapy Inhibits Soft Tissue Sarcoma Cell Growth In vitro and In vivo

Authors' Affiliations: Departments of ¹ Surgical Oncology, ² Cancer Biology, ³ Medical Oncology, and ⁴ Pathology and ⁵ Division of Quantitative Sciences, University of Texas M. D. Anderson Cancer Center, Houston, Texas; and ⁶ Department of Radiation Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania

Requests for reprints: Dina Lev, Department of Cancer Biology, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1104, Houston TX 77030. Phone: 713-792-1637; Fax: 713-563-1185; E-mail: dlev{at}mdanderson.org.

Purpose: The epidermal growth factor receptor (EGFR) is highly expressed in many human soft tissue sarcomas (STS). However, EGFR blockade has not apparently been used for human STS therapy; therefore, we examined the in vitro and in vivo effects and the underlying mechanisms before considering EGFR blockade as a therapy for STS patients.

Experimental Design: Human STS tissues and cell lines were used to study EGFR expression and activation. Western blot analysis was used to evaluate effects of EGFR activation on downstream signaling. Cell culture assays were used to assess the effect of EGF stimulation as well as EGFR blockade (using an EGFR tyrosine kinase inhibitor, Iressa; AstraZeneca) on STS cell growth, apoptosis, and chemosensitivity. An in vivo study (HT1080 human fibrosarcoma cell line in nude/nude mice: Iressa, doxorubicin, Iressa + doxorubicin, vehicle) was used to examine tumor growth; pEGFR, proliferating cell nuclear antigen, and terminal deoxyribonucleotide transferase–mediated nick-end labeling staining helped assess the effect of therapy in vivo on STS EGFR activation, proliferation, and apoptosis.

Results: EGFR was expressed and activated in STS cell lines and tumors, probably due to ligand binding rather than EGFR mutation. Stimulation caused activation of AKT and mitogen-activated protein kinase pathways. EGFR blockade inhibited these effects and also caused increased apoptosis, a p53-independent G₀-G₁ cell cycle arrest, and decreased cyclin D1 expression. In vivo, Iressa + doxorubicin had markedly synergistic anti-STS effects.

Conclusion: EGFR blockade combined with conventional chemotherapy results in anti-human STS activity in vitro and in vivo, suggesting the possibility that combining these synergistic treatments will improve anti-STS therapy.

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				W. Ren, B. Korchin, G. Lahat, C. Wei, S. Bolshakov, T. Nguyen, W. Merritt, A. Dicker, A. Lazar, A. Sood, et al. Combined Vascular Endothelial Growth Factor Receptor/Epidermal Growth Factor Receptor Blockade with Chemotherapy for Treatment of Local, Uterine, and Metastatic Soft Tissue Sarcoma Clin. Cancer Res., September 1, 2008; 14(17): 5466 - 5475. [Abstract] [Full Text] [PDF]