O6-BENZYLGUANINE AND BCNU IN CUTANEOUS T-CELL LYMPHOMA

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。本试验的主要目的是：1）确定皮肤T细胞淋巴瘤患者静脉注射120 mg/m2 O 6苄基鸟嘌呤后皮肤病变中O 6烷基鸟嘌呤DNA烷基转移酶（AGT）耗竭的动力学; 2）确定120 mg/m2 O 6苄基鸟嘌呤后每两周局部给药一次低剂量BCNU的毒性。在第一个疗程期间，将在基线时以及O 6苄基鸟嘌呤输注后6小时、24小时和1周时获得病变皮肤活检。将使用酶试验、蛋白质印迹分析和定量免疫组织学分析这些样本的AGT消耗。在O 6苄基鸟嘌呤后1小时局部给予BCNU。这将每2周重复一次，直至患者退出试验。BCNU将从10 mg开始，并在每个指定剂量水平以10 mg增量增加。BCNU不会在个体患者中递增。只要未观察到剂量限制性毒性，将在3例患者的连续队列中递增剂量水平。如果在以某一剂量水平治疗的最初3例患者中观察到1例剂量限制性毒性，则必须以该剂量水平治疗最多3例患者，且无进一步的剂量限制性毒性，以便可以进行剂量递增。如果在一个剂量水平下观察到两例剂量限制性毒性，则超过了最大耐受剂量，必须在先前剂量水平下治疗总共6例患者，以确保其耐受性。GCRC用于药物给药和药代动力学。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The major objectives of this trial are to: 1) determine the kinetics of O6alkylguanine DNA alkyltransferase (AGT) depletion in skin lesions of patients with cutaneous T-cell lymphoma following intravenous administration of 120 mg/m2 of O6benzylguanine; and 2) determine the toxicity of low dose BCNU when administered topically on a biweekly schedule following 120 mg/m2 O6benzylguanine. During the first course of therapy, lesional skin biopsies will be obtained at baseline, and after O6benzylguanine infusion at 6 hrs, 24 hrs and 1 week. These samples will be analyzed for AGT depletion using an enzyme assay, Western blot analysis and quantitative immunohistology. BCNU will be administered topically 1 hr after O6benzylguanine. This will be repeated every 2 weeks until the patient is removed from the trial. BCNU will start at 10 mg, and increase by 10 mg increments at each assigned dose level. BCNU will not be escalated in individual patients. The dose level will be escalated in successive cohorts of three patients as long as no dose-limiting toxicity is observed. If one instance of dose-limiting toxicity is observed among the initial three patients treated at a dose level, then up to an additional 3 patients must be treated at that dose level with no further dose-limiting toxicity in order that dose escalation may proceed. If two instances of dose-limiting toxicity are observed at a dose level, the maximum tolerated dose has been surpassed, and a total of 6 patients must be treated at a previous dose level to assure its tolerability. The GCRC is used for drug administration and pharmacokinetics.