TREATMENT OF CTCL WITH O6 BENZYLGUANINE/BCNU

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DESCRIPTION: Cutaneous T-cell lymphoma (CTCL) includes myosis fungoides and its leukemic cariant, the Sezary syndrome. CTCL is a neoplasm of mature, CD4+ memory T cells that traffick between the skin and peripheral lymph nodes via the lymphatics and blood even in the very early, limited patch/plaque (Stage IA) phase of disease. Current therapy for CTCL is suboptimal. Median survival ranges from 12 years for early stage disease to only two years for advanced cases. The chloro-ethylnitrosurea, BNCU, has proven efficacy against CTCL by both the topical and intravenous routes of administration. Nevertheless, not all patients respond, most responders relapse within one-to-two years, and dose is limited by cutaneous and/or systemic toxicity. O6 benzylguanine (O6BG) potentiates the cytotoxicity of BCNU by directly inhibiting the enzyme O6-alkylguanine DNA alkyltransferase (AGT) that normally repairs DNA adducts produced by BCNU. The current application is translational research designed to apply recent advances in our understanding of CTCL tumor biology and the modulation of AGT activity to the development of novel CTCL therapy. Preliminary studies in other cancers demonstrate that O6BG can effectively deplete tumor AGT in vivo and that O6BG/BCNU combination therapy can be administered with acceptable toxicity levels. Furthermore, the applicant has shown that CTCL tumor cells contain significant levels of AGT. Based on these observations, he hypothesizes that O6BG/BCNU combination therapy will be more effective against CTCL than BCNU alone. The major objectives in this Phase I clinical trial are: 1) to determine the time course of AGT depletion by O6BG in CTCL skin lesions, and 2) to determine the cutaneous and systemic toxicity of O6BG/BCNU combination therapy when low dose BCNU is administered either topically or systemically in a dose escalation study. The minor objectives are to determine the clinical response, lesional infiltrate density, lesional tumor clone density and lesional host density. The long-term objective is to design O6BG/BCNU combination therapy regimes for CTCL that have increased efficacy and decreased toxicity relative to other established topical and systemic treatments.