A PHASE I STUDY OF HYDROXYUREA AND PENTOXIFYLLINE FOR TREATMENT OF GLIOBLASTOMA

胶质母细胞瘤放射治疗后的存活率仍被限制在9至12个月。抑制DNA修复的药物代表了一类新的放射增敏剂，目前正在探索用于治疗胶质母细胞瘤。羟基尿素(HU)是一种公认的放射增敏剂，在用于持续输注的静脉制剂中尚未商业化。支持包括DNA修复抑制在内的各种可能的放射增敏机制的体外数据表明，如果治疗的肿瘤暴露在稳定的浓度而不是团注浓度下，这种药物将是最有效的。此外，其快速的半衰期和清除将需要频繁的口服剂量才能达到稳定的浓度。因此，我们将HU作为持续静脉输液进行管理。HU与其他修复抑制剂如阿糖胞苷、阿糖胞苷和戊茶碱(PTF)有协同作用。PTF是一种具有血液流变学活性的甲基黄嘌呤类似物，在体外是一种有效的放射增敏剂和修复抑制剂。在这项研究中，HU是通过持续输注PTF给每天接受两次放射治疗的胶质母细胞瘤患者进行PTF的I期剂量递增。-胶质母细胞瘤，己酮可可碱，-人体

Survival following radiotherapy for glioblastoma remains limited to 9 to 12 months. Agents which inhibit DNA repair represent a novel class of radiosensitizers which are currently being explored in the treatment of Glioblastoma. Hydroxyurea (Hu) is a recognized radiosensitizer which is not commercially available in an iv preparation for continuous infusion. In vitro data supporting the various possible mechanisms of radiosensitization including DNA repair inhibition, suggest that this agent would be most effective if a treated tumor were exposed to steady rather than bolus concentrations. In addition, its rapid half life and clearance would require frequent oral dosing to achieve steady state concentrations. We are thus administering Hu as a continuous IV infusion. Hu is synergistic with other repair inhibitors such as Ara-c, Ara-a, and Pentoifylline (PTF). PTF is a methylxanthine analog with hemorrheologic activity which is a potent radiosensitizer and repair inhibitor in vitro. In this study, Hu is being given via continuous infusion with PTF in a phase I dose escalation of PTF to patients receiving twice daily radiotherapy for glioblastoma. - Glioblastoma, Pentoxifylline, - Human Subjects