Diminished Sensitivity of Chronic Lymphocytic Leukemia cells to ABT-737 and ABT-263 Due to Albumin Binding in Blood.
Clinical cancer research : an official journal of the American Association for Cancer Research 2010 Jul 2; In press
Vogler M, Furdas S, Jung M, Kuwana T, Dyer M MJ, Cohen G GM
Toxicology Unit, Medical Research Council.
PURPOSE: Inhibition of the anti-apoptotic BCL2 family is one of the most promising areas of anti-cancer drug development. However, ABT-737, a specific BCL2 inhibitor, is neither orally bioavailable nor metabolically stable. To overcome these problems, the structurally related molecule, ABT-263, was synthesized and recently entered clinical trials in hematological malignancies, including chronic lymphocytic leukemia (CLL). Almost all laboratory studies have been carried out with ABT-737 rather than ABT-263, the drug being used in clinical trials. Currently there are no published data on the comparative effects of these inhibitors. To gain insight into the potential value or limitations of ABT-263 in the clinic, we assess its ability to induce apoptosis in clinically relevant cellular models of CLL. EXPERIMENTAL DESIGN: The susceptibility of freshly isolated primary CLL cells to these inhibitors was compared in standard culture conditions and to more closely mimic in vivo conditions in a whole blood assay system. RESULTS: ABT-737 was more potent than ABT-263 at inducing apoptosis in CLL cells. In whole blood, ~100-fold higher concentrations of both drugs were required to induce apoptosis. We found that ABT-263 was highly bound by albumin and that an increased albumin binding of ABT-263 as compared to ABT-737 accounted for the differential sensitivity of CLL cells. CONCLUSIONS: Our data indicate that the exquisite in vitro sensitivity of CLL cells to BCL2-inhibitors may be lost in vivo due to high cell densities and the albumin binding of ABT-263. Modification of ABT-263 may yield a BCL2-inhibitor with greater bioavailability and more favorable pharmacokinetics.