Published online before print September 6, 2007

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(American Journal of Pathology. 2007;171:1153-1167.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.061164

Dissecting the Impact of Chemotherapy on the Human Hair Follicle

A Pragmatic in Vitro Assay for Studying the Pathogenesis and Potential Management of Hair Follicle Dystrophy

Enik Bodó^*, Desmond J. Tobin, York Kamenisch, Tamás Bíró, Mark Berneburg, Wolfgang Funk^¶ and Ralf Paus^*

From the Department of Dermatology,^* University Hospital Schleswig-Holstein, University of Lübeck, Lübeck, Germany; the Department of Dermatology, Eberhard Karls University, Tübingen, Germany; Klinik Dr. Kozlowski,^¶ Munich, Germany; Medical Biosciences Research, School of Life Sciences, University of Bradford, Bradford, United Kingdom; and the Department of Physiology, University of Debrecen, Debrecen, Hungary

Chemotherapy-induced alopecia represents one of the major unresolved problems of clinical oncology. The underlying molecular pathogenesis in humans is virtually unknown because of the lack of adequate research models. Therefore, we have explored whether microdissected, organ-cultured, human scalp hair follicles (HFs) in anagen VI can be exploited for dissecting and manipulating the impact of chemotherapy on human HFs. Here, we show that these organ-cultured HFs respond to a key cyclophosphamide metabolite, 4-hydroperoxycyclophosphamide (4-HC), in a manner that resembles chemotherapy-induced HF dystrophy as it occurs in vivo: namely, 4-HC induced melanin clumping and melanin incontinence, down-regulated keratinocyte proliferation, massively up-regulated apoptosis of hair matrix keratinocytes, prematurely induced catagen, and up-regulated p53. In addition, 4-HC induced DNA oxidation and the mitochondrial DNA common deletion. The organ culture system facilitated the identification of new molecular targets for chemotherapy-induced HF damage by microarray technology (eg, interleukin-8, fibroblast growth factor-18, and glypican 6). It was also used to explore candidate chemotherapy protectants, for which we used the cytoprotective cytokine keratinocyte growth factor as exemplary pilot agent. Thus, this novel system serves as a powerful yet pragmatic tool for dissecting and manipulating the impact of chemotherapy on the human HF.