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Tumor Necrosis Factor- and Interleukin-1 Antagonists Alleviate Inflammatory Skin Changes Associated with Epidermal Growth Factor Receptor Antibody Therapy in Mice

¹ Research Division, ImClone Systems, a wholly-owned subsidiary of Eli Lilly & Company, New York, New York; ² Bristol Myers Squibb Pharmaceutical Research Institute, Bristol-Myers Squibb Co., Princeton, New Jersey; ³ Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York; and ⁴ Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania

Requests for reprints: James R. Tonra, ImClone Systems, 180 Varick Street, New York, NY 10014. Phone: 646-638-6411; Fax: 212-645-2054; E-mail: james.tonra{at}imclone.com.

Key Words: EGFR • acneiform rash • TNF • IL-1 • skin

Cancer patients receiving epidermal growth factor receptor (EGFR) antibody therapy often experience an acneiform rash of uncertain etiology in skin regions rich in pilosebaceous units. Currently, this condition is treated symptomatically with very limited, often anecdotal success. Here, we show that a monoclonal antibody targeting murine EGFR, ME1, caused a neutrophil-rich hair follicle inflammation in mice, similar to that reported in patients. This effect was preceded by the appearance of lipid-filled hair follicle distensions adjacent to enlarged sebaceous glands. The cytokine tumor necrosis factor- (TNF), localized immunohistochemically to this affected region of the pilosebaceous unit, was specifically up-regulated by ME1 in skin but not in other tissues examined. Moreover, skin inflammation was reduced by cotreatment with the TNF signaling inhibitor, etanercept, indicating the involvement of TNF in this inflammatory process. Interleukin-1, a cytokine that frequently acts in concert with TNF, is also involved in this process given the efficacy of the interleukin-1 antagonist Kineret. Our results provide a mechanistic framework to develop evidence-based trials for EGFR antibody–induced skin rash in patients with cancer. [Cancer Res 2009;69(14):5643–7]