Proteasome inhibitors are novel biologically targeted anti-cancer drugs. The first-in-class proteasome inhibitor Bortezomib (BZ, also called Velcade) was approved for use in multiple myeloma (MM) patients in US in 2003, and in Europe in 2004 (1). During last five years, the use of BZ in cancer treatment has been significantly extended. It is currently used for both the initial therapy and salvage therapy of recurrent/relapsed MM as well as mantle cell lymphoma (MCL), two commonly diagnosed hematological malignancies that have a combined prevalence of more than 85,000 cases in the United States alone (1). BZ has been also extensively tested in clinical trials for the treatment of large variety of solid tumors that showed promising results. BZ is a reversible inhibitor of the 26S proteasome. After a single treatment, there is inhibition of proteasome activity followed by the recovery. Thus, BZ must be delivered to cancer patients by i.v. injection every 72 hrs., a procedure that allows sustained targeting of the 26S proteasome activity. (2-4). However, there are dose-limiting toxicities in patients that include neurotoxicity, fatigue, diarrhea, and cutaneous toxicity. Relevant to this proposal are the severe adverse cutaneous effects including rash, cutaneous vasculitis, and dermatitis that affect 10-15 % of BZ treated patients (5-8). Yet, BZ treatment effects on the skin are poorly characterized and mechanism(s) of these adverse effects are unknown. Intravenous BZ delivery has also been used successfully for experimental anti-cancer therapy in mice (3, 4). We asked if we could recapitulate the cutaneous effects of BZ in a mouse model. In our pilot experiment, we treated (C57BL/6 x DBA) Fl female mice intravenously with a therapeutic dose of BZ (MTD, 1 mg/kg; Ref. 3). We observed extensive recruitment of mast cells to the skin accompanied by modest inflammatory infiltration and pronounced epidermal hyperplasia 24 hrs. after treatment (Figure 1). Most of these mast cells showed typical indices of cell activation as measured by the appearance of multiple granules that are released from the cells (Figure 1). Such granules are characteristic of mast cells. They are present in the cytoplasm of an intact, unactivated cell and contain a number of pre-formed pro-inflammatory mediators, including histamine, proteases and cytokines. Release of these cytokines can strongly impact the inflammatory response. These experiments were repeated using mice from different strains (C57BL/6, FVB, SENCAR) as well as using alternative routes of treatment including topical application of high doses of BZ (5-10 ug/animal in acetone). We obtained similar results in these repeated experiments (data not shown). Thus, this BZ-induced mast cell recruitment and epidermal hyperplasia is not strain-specific and is observed under multiple delivery modes. These are novel observations and further study of this phenomenon could ultimately lead to information that will impact our ability to prevent/treat BZ induced cutaneous toxicity

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Center Core Grants (P30)
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Special Emphasis Panel (ZAR1-KM-D (M1))
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Northwestern University at Chicago
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