Associate Provost for Research Boston University Medical Campus
NCI - National Cancer Institute	Research Resources

Abstract

Abstract: DESCRIPTION (provided by applicant): 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.

Thesaurus Terms:
alopecia, disease /disorder prevention /control, drug adverse effect, drug screening /evaluation, inhibitor /antagonist, neoplasm /cancer chemotherapy, p53 gene /protein
antineoplastic, apoptosis, combination chemotherapy, disease /disorder model, hair follicle, model design /development, skin neoplasm
SCID mouse, clinical research, human subject, immunocytochemistry, morphometry, polymerase chain reaction, terminal nick end labeling, tissue /cell culture, western blotting

Institution:	BOSTON UNIVERSITY MEDICAL CAMPUS
	715 ALBANY ST, 560
	BOSTON, MA 021182394
Fiscal Year:	2005
Department:	DERMATOLOGY
Project Start:	16-JUN-2003
Project End:	31-MAY-2007
ICD:	NATIONAL CANCER INSTITUTE
IRG:	ZRG1