Mechanisms of Resistance to Gemtuzumab Ozogamicin

吉妥珠单抗奥佐米星耐药机制

• 批准号: 6611369
• 负责人: IRWIN D BERNSTEIN
• 金额: $ 37.78万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6611369
• 关键词: DNA damage; NOD mouse; P glycoprotein; SCID mouse; acute myelogenous leukemia; antibody; antineoplastics; apoptosis; chemosensitizing agent; clinical research; clinical trial phase I; clinical trial phase II; cyclosporines; cytotoxicity; drug screening /evaluation; gene expression; human subject; human therapy evaluation; immunoconjugates; laboratory mouse; membrane transport proteins; multidrug resistance; neoplasm /cancer immunotherapy; neoplasm /cancer relapse /recurrence; patient oriented research; pharmacokinetics; polymerase chain reaction; protein structure function; tissue /cell culture

DESCRIPTION (PROVIDED BY APPLICANT): Gemtuzumab ozogamicin (GO), an immunoconjugate consisting of a highly potent calicheamicin derivative linked with a humanized anti-CD33 antibody, has proven safe and effective for treating patients with acute rnyeloid leukemia (AML) in relapse. However, the majority of patients fail to respond and our preliminary data implicate a role for proteins encoded by multidrug resistance (MDR) genes, in particular P-glycoprotein (Pgp). In vitro studies further indicate that GO-induced apoptosis of AML cells is enhanced by cyclosporine A (CSA), an agent known to modulate Pgp function. We hypothesize that MDR reversing agents will be beneficial in the setting of antibody-directed chemotherapy where effects of reversal agents would be expected to be limited to the target tissues. Thus, we propose to determine the role of MDR genes in inhibiting the cytotoxic effects of GO; and the effect of agents that reverse drug resistance, such as CSA, in enhancing GO-mediated cytotoxic efforts. These studies will evaluate transduced cell lines (Aim I) and primary AML blasts (Aim II). In phase I and II clinical trials, we will determine whether CSA can enhance the therapeutic effectiveness of GO in patients with relapsed AML (Aim III).

描述（由申请人提供）：gemtuzumab ozogamicin（GO），一个 由高度有效的calicheamicin衍生物链接的免疫偶联物 使用人源化抗CD33抗体，已被证明是安全有效的 急性rnyeloid白血病（AML）复发患者。但是，大多数 患者无法做出反应，我们的初步数据暗示了 蛋白质由多药耐药性（MDR）基因编码，特别是 P-糖蛋白（PGP）。体外研究进一步表明go诱导 环孢霉素A（CSA）增强了AML细胞的凋亡，一种已知的药物 调节PGP功能。 我们假设MDR逆转代理将在设置 抗体定向的化学疗法，逆转剂的影响将是 预计将仅限于目标组织。因此，我们建议确定 MDR基因在抑制GO的细胞毒性作用中的作用；以及 逆转耐药性（例如CSA）在增强GO介导的药物 细胞毒性努力。这些研究将评估转导的细胞系（AIM I） 和主要AML爆炸（AIM II）。在第一阶段和II临床试验中，我们将 确定CSA是否可以提高GO的治疗有效性 复发AML的患者（AIM III）。