Background: Hair loss (alopecia) is a much-feared effect of many chemotherapy protocols and is one of the most distressing aspects of cancer therapy. Because of the rapid proliferation rate of hair matrix keratinocytes during hair shaft production, the hair follicle represents a """"""""by-stander"""""""" target for many chemotherapeutic agents. However, molecular mechanisms that control the response of human hair follicle to chemotherapy are poorly understood. Therefore, our long-term objectives are to develop a complex of models for studying the response of human hair follicle to chemotherapy and to design novel approaches to prevent chemotherapy-induced hair loss. Our general strategy is to focus on the p53 transcription factor, which mediates apoptosis and growth arrest induced by chemotherapy and is essential for chemotherapy-induced hair loss in mice. p53 is mutated in over 50% of human cancers and may be considered as a target for local pharmacological suppression to prevent or reduce chemotherapy-induced hair loss in patients with p53-negative tumors. Hypothesis: p53 mediates chemotherapy-induced hair loss in human hair follicles and local temporary p53 blockade by specific antagonists would constitute an effective preventive treatment for chemotherapy-induced hair loss in patients with p53 negative tumors. Purpose: 1) Develop a complex of models for studying the response of human hair follicles to chemotherapy and: a) analyze the expression of p53 and p53 target genes in human hair follicles after application of a variety of chemotherapeutic agents, b) define the effects of synthetic antagonists that temporary inhibit p53 activity on the response of human hair follicles to chemotherapy. 2) Determine whether the local treatment by p53 inhibitors that focused on preventing chemotherapy-induced hair loss would affect anti-tumor activity of the chemotherapeutic agents. 3) Define whether local temporary inhibiting p53 function to prevent chemotherapy-induced hair loss would induce long-term genomic instability and lead to the formation of secondary skin tumors. SIGNIFICANCE: Understanding the role for p53 and its target genes in the pathobiology of chemotherapy-induced hair loss would allow using their synthetic antagonists to manage this devastating side-effect of cancer treatment. Patients with many forms of p53-negative cancers treated by chemotherapy may ultimately benefit from this study.
| Sharov, Andrey A; Sharova, Tatyana Y; Mardaryev, Andrei N et al. (2006) Bone morphogenetic protein signaling regulates the size of hair follicles and modulates the expression of cell cycle-associated genes. Proc Natl Acad Sci U S A 103:18166-71 |
| Sharov, Andreya; Tobin, Desmond J; Sharova, Tatyana Y et al. (2005) Changes in different melanocyte populations during hair follicle involution (catagen). J Invest Dermatol 125:1259-67 |
| Sharov, Andrei A; Siebenhaar, Frank; Sharova, Tatyana Y et al. (2004) Fas signaling is involved in the control of hair follicle response to chemotherapy. Cancer Res 64:6266-70 |
