DRUG SEQUENCING RESISTANCE IN MULTIPLE MYELOMA

描述：(申请人简介)多发性骨髓瘤是一种不治之症 在标准剂量化疗的情况下，接受治疗的中位生存期 大概3年左右了。为了改善患者的预后， 多发性骨髓瘤大剂量自体干细胞化疗方案 已经采取了救援行动，并表现出完全的应答率 40%-50%。然而，在无进展生存方面缺乏一个平台期 大剂量化疗表明，更有效的药物组合包括 需要新的抗肿瘤药物。这个应用程序的一个主要假设是 抗肿瘤药物的顺序和时机在杀灭过程中很重要 体内骨髓瘤细胞的数量。临床前数据表明，大剂量的 烷化剂和拓扑异构酶II的化疗顺序 抑制剂和拓扑异构酶II抑制剂是一种合理的方法 可能表现出协同活性。患者未能及时就诊的主要原因 对抗肿瘤药物的反应是由于固有的或获得性的药物 抵抗。很可能体内骨髓瘤细胞的耐药性是 由于多种抗性机制的同时表达，可能 包括DNA拓扑异构酶的扰动。第二个主要假设是 本应用是拓扑异构酶I和II的改变(内容， 位置和活性)与骨髓瘤细胞的耐药性有关 活着。针对这两个假设，本文提出了四个具体目标。1.至 确定大剂量方案的毒性和潜在疗效 先是马法兰，然后是拓扑替康，然后是VP-16磷酸(MTV) 外周血干细胞挽救治疗多发性骨髓瘤2. 大剂量拓扑替康、马法兰的药动学研究 和VP-16磷酸，并研究其药代动力学关系。 考虑到这种疗法的疗效和毒性。3.研究 在体外产生的假说是特定的给药顺序 作为烷化剂的抗肿瘤药物，然后是拓扑异构酶I抑制剂 其次是拓扑异构酶II抑制剂在体内具有生化合理性 治疗多发性骨髓瘤。4.确定角色(S) DNA拓扑异构酶I的定量、定性和分布变化， II-α和II-β在多发性骨髓瘤临床耐药中的作用 接受大剂量MTV方案治疗的患者。

DESCRIPTION: (Applicant's Abstract) Multiple myeloma is an incurable disease with standard dose chemotherapy, having a median survival with treatment of about three years. In an effort to improve the outcome for patients with multiple myeloma, high-dose chemotherapy regimens with autologous stem cell rescue have been undertaken and have demonstrated complete response rates of 40-50%. However, the lack of a plateau in progression free survival after high-dose chemotherapy suggests that more effective drug combinations involving new antitumor agents are needed. A major hypothesis of this application is that the sequencing and timing of the antitumor agents is important in the killing of myeloma cells in vivo. The preclinical data suggest that a high-dose chemotherapy sequence of alkylating agent followed by topoisomerase II inhibitor followed by topoisomerase II inhibitor is a reasonable approach and may demonstrate synergistic activity. The major reason that patients fail to respond to antineoplastic agents is because of intrinsic or acquired drug resistance. It is likely that the drug resistance of myeloma cells in vivo is due to the concurrent expression of multiple mechanisms of resistance, perhaps including perturbations in DNA topoisomerases. The second major hypothesis of this application is that alterations in topoisomerase I and II (content, location and activity) are involved in the drug resistance of myeloma cells in vivo. Four specific aims are proposed to address these two hypotheses. 1. To establish the toxicity and potential efficacy of a high-dose regimen sequenced as melphalan followed by topotecan followed by VP-16 phosphate (MTV) followed by peripheral blood stem cell rescue in the treatment of multiple myeloma. 2. To evaluate the pharmacokinetic profiles of intensive-dose topotecan, melphalan and VP-16 phosphate and to investigate the pharamcodynamic relationships with respect to the efficacy and toxicity of this regimen. 3. To examine the hypothesis generated in vitro that the specific sequence of administration of antineoplastic agents as alkylator followed by topoisomerase I inhibitor followed by topoisomerase II inhibitor has a biochemical justification in vivo in the treatment of multiple myeloma. 4. To determine the role(s) of quantitative, qualitative, and distributive alterations in DNA topoisomerase I, II-alpha and II-beta in the clinical drug resistance of multiple myeloma in patients who have been treated with the high-dose MTV regimen.