TREATMENT OF CTCL WITH O6 BENZYLGUANINE/BCNU

描述：皮肤T细胞淋巴瘤(CTCL)包括菌样肉芽肿和 它的白血病癌症，塞萨里综合征。CTCL是一种成熟的、 在皮肤和外周淋巴之间运输的CD4+记忆T细胞 结节通过淋巴管和血液，即使在很早期，也有限 斑块/斑块(IA期)疾病阶段。目前治疗CTCL的方法是 不太理想。中位生存期从早期疾病的12年到 高级病例只有两年。氯乙基亚硝脲，BNCU， 外用和静脉给药治疗CTCL已证实有效 行政管理。然而，并不是所有的患者都有反应，大多数应答者 在一到两年内复发，剂量受皮肤和/或 全身毒性。O6-苄基鸟嘌呤(O6BG)增强细胞毒作用 BCNU通过直接抑制酶O6-烷基鸟嘌呤DNA烷基转移酶 (AGT)通常修复BCNU产生的DNA加合物。海流 应用是翻译研究，旨在将最新进展应用于 我们对CTCL肿瘤生物学和AGT活性调节的认识 为新型CTCL疗法的发展做出贡献。在其他方面的初步研究 癌症研究表明，O6BG在体内可以有效地耗尽肿瘤AGT，并 O6BG/BCNU联合治疗可接受 毒性水平。此外，申请人还表明，CTCL肿瘤细胞 含有显著水平的AGT。基于这些观察，他 假设O6BG/BCNU联合治疗将更有效 对抗CTCL，而不是单独使用BCNU。这个I期临床的主要目标 实验内容为：1)O6BG对CTCL中AGT耗竭的时程测定 皮肤损害，以及2)确定其皮肤和全身毒性 小剂量BCNU联合O6BG/BCNU治疗 局部或系统地进行剂量递增研究。次要目标 是为了确定临床反应，皮损浸润物密度， 皮损肿瘤克隆密度和皮损宿主密度。长期的 目的：设计O6BG/BCNU联合治疗CTCL的方案。 与其他已建立的药物相比，具有更高的疗效和更低的毒性 局部和全身治疗。

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.