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).
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