O6-BENZYLGUANINE AND BCNU IN CUTANEOUS T-CELL LYMPHOMA

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。本试验的主要目的是：1)确定静脉注射120 mg/m2的o6苄基鸟嘌呤后，皮肤t细胞淋巴瘤患者皮损处o6烷基鸟嘌呤DNA烷基转移酶（AGT）耗损的动力学；2)确定低剂量BCNU在O6benzylguanine 120 mg/m2后，每两周局部给药时的毒性。在治疗的第一个疗程中，将在基线和输注O6benzylguanine后的6小时、24小时和1周进行病灶皮肤活检。这些样品将使用酶分析、Western blot分析和定量免疫组织学分析AGT消耗。BCNU将在6苄鸟嘌呤后1小时局部给药。这将每2周重复一次，直到患者退出试验。BCNU将从10毫克开始，并在每个指定剂量水平上增加10毫克。BCNU不会在个别患者中升级。只要没有观察到剂量限制性毒性，剂量水平将在3例患者的连续队列中逐步提高。如果在最初以一定剂量水平治疗的3名患者中观察到1例剂量限制性毒性，则必须在没有进一步剂量限制性毒性的情况下以该剂量水平治疗另外3名患者，以便剂量可以继续增加。如果在一个剂量水平上观察到两例剂量限制性毒性，则已超过最大耐受剂量，必须以以前的剂量水平治疗共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.