Mechanisms of Resistance to Gemtuzumab Ozogamicin

吉妥珠单抗奥佐米星耐药机制

• 批准号: 6798723
• 负责人: IRWIN D BERNSTEIN
• 金额: $ 37.32万
• 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/6798723
• 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; cyclosporines; cytotoxicity; drug screening /evaluation; gene expression; human subject; immunoconjugates; laboratory mouse; membrane transport proteins; multidrug resistance; neoplasm /cancer immunotherapy; neoplasm /cancer relapse /recurrence; 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）：吉妥珠单抗奥佐米星 (GO)，一种 由高效加利车霉素衍生物组成的免疫缀合物 含有人源化抗 CD33 抗体，已被证明安全有效地治疗 复发的急性髓性白血病（AML）患者。然而，大多数 的患者未能做出反应，我们的初步数据暗示了 由多药耐药（MDR）基因编码的蛋白质，特别是 P-糖蛋白（Pgp）。体外研究进一步表明 GO 诱导 环孢菌素 A (CSA) 可增强 AML 细胞的凋亡，环孢素 A 是一种已知的药物 调节Pgp功能。 我们假设 MDR 逆转剂在以下情况下将是有益的： 抗体定向化疗，其中逆转剂的作用将是 预计仅限于靶组织。因此，我们建议确定 MDR基因在抑制GO细胞毒性作用中的作用；和效果 逆转耐药性的药物，例如 CSA，可增强 GO 介导的耐药性 细胞毒努力。这些研究将评估转导的细胞系（目标 I） 和原发性 AML 母细胞（目标 II）。在I期和II期临床试验中，我们将 确定 CSA 是否可以增强 GO 的治疗效果 复发性 AML 患者（目标 III）。