HTLV-1 associated adult T- cell leukemia is a disease characterized by monoclonal proliferation of CD 4+, CD 25+ T-lymphocytes. HTLV-1 infection is endemic in Japan, the Caribbean Islands, the southeastern part of the United States and in Central Africa. In New York City, a large number of HTLV-1 positive individuals have been identified in the borough of Brooklyn. Approximately 10% of people that are seropositive for the HTLV-1 virus go on to develop ATLL. The prognosis of ATLL is poor with median survival of 6.2 months for acute type, 10.2 for lymphomatous type and 24.3 months for the chronic type. Current therapy consists of various combinations of chemotherapeutic agents resulting in some partial or complete response and then rapid relapse. There is currently no effective therapy for relapsed HTLV-1 associated ATLL. There is need to better understand the molecular mechanisms involved in HTLV-1 associated adult T-cell leukemia and to find new forms of therapy that would improve the outlook of this disease. The investigator has chosen to study the role of retinoic acid in the treatment of this disease. Recent reports indicate antiproliferative effects of retinoids against HTLV-1 infected human T-cell leukemia cell lines and also against peripheral blood mononuclear cells (PBMC) obtained from patients with HTLV-1 associated adult T-cell leukemia. Three types of retinoids are being used widely in laboratory and clinical research. These are all-trans retinoic acid, 9-cis retinoic acid and 13-cis retinoic acid. These retinoids act by binding to specific retinoic acid receptors all-trans retinoic acid preferentially binds to the retionic acid receptor (RAR) type receptor, while 9-cis retinoic acid binds to both RAR and retionid X receptor (RXR) receptors. The target receptor for 13-cis retinoic acid is currently unknown. It is proposed to study HTLV-1 positive cell lines and fresh cells from patients with HTLV-1 associated adult T-cell leukemia for: 1) the effects of retinoids on cell growth; and 2) the expression of retinoid receptors which may mediate response to retinoids. The applicant will also study the possible pathways of cellular response to retinoids in adult T-cell leukemia/lymphoma by assessing changes in cellular processes known to be important in ATLL leukermogenesis. Finally, a Phase II clinical trial of 13-cis retinoic acid will be conducted in patients with ATLL.
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