TREATMENT OF CTCL WITH O6 BENZYLGUANINE/BCNU

描述：皮肤T细胞淋巴瘤（CTCL）包括蕈样肌炎和 它的白血病变种塞扎里综合征 CTCL是一种成熟的肿瘤， CD 4+记忆T细胞在皮肤和外周淋巴之间运输 即使在非常早期， 斑块/斑块（IA期）阶段。 目前CTCL的治疗方法是 次优 中位生存期从早期疾病的12年到 晚期病人只判两年 氯乙基亚硝基脲，BNCU， 经局部和静脉途径证实对CTCL有效， 局 然而，并非所有患者都有反应，大多数反应者 在一到两年内复发，剂量受到皮肤和/或 全身毒性 O 6苄基鸟嘌呤（O 6 BG）可增强 BCNU通过直接抑制酶O 6-烷基鸟嘌呤DNA烷基转移酶 (AGT)通常修复BCNU产生的DNA加合物。 当前 应用是旨在应用最新进展的转化研究， 我们对CTCL肿瘤生物学和AGT活性调节的理解 新CTCL疗法的发展。 其他方面的初步研究 癌症证明O 6 BG可以有效地消耗体内肿瘤AGT， O 6 BG/BCNU联合治疗可以以可接受的 毒性水平。 此外，申请人已经表明，CTCL肿瘤细胞 含有大量的AGT 根据这些观察，他 假设O 6 BG/BCNU联合治疗将更有效 比单独使用BCNU更有效 本I期临床试验的主要目的 试验是：1）确定CTCL中O 6 BG消耗AGT的时间过程 皮肤病变，和2）确定皮肤和全身毒性 O 6 BG/BCNU联合治疗，当给予低剂量BCNU时， 局部或全身给药。 次要目标 是为了确定临床反应，病灶浸润密度， 病变肿瘤克隆密度和病变宿主密度。 长期 目的是设计O 6 BG/BCNU联合治疗CTCL的方案， 相对于其他已建立的药物， 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.