Cytotoxic effect of R-etodolac (SDX-101) in combination with purine analogs or monoclonal antibodies on ex vivo B-cell chronic lymphocytic leukemia cells

Abstract

R-etodolac (SDX-101) is an isoform of the non-steroidal anti-inflammatory drug, etodolac, and is currently being tested in phase II clinical trials for the treatment of refractory B-cell chronic lymphocytic leukemia (B-CLL). The aim of this study was to evaluate the cytotoxicity of SDX-101 combined with agents proven to be effective as first-line treatment of B-CLL: the purine nucleoside analogs, fludarabine (FA) and cladribine (2-CdA), and the monoclonal antibodies, anti-CD52 (alemtuzumab; ALT) and anti-CD20 (rituximab; RIT). The cytotoxicity and specific pro-apoptotic effects of the study drugs on B-CLL cells were assessed in vitro in samples from overall 37 untreated patients. The combinations of SDX-101 with 2-CdA, FA or RIT exerted additive effects in B-CLL cells, with the following combination indices (CI): 0.89 for SDX-101 + 2-CdA, 0.95 for SDX-101 + RIT, and 1.17 for SDX-101 + FA. The main mechanism of these interactions was caspase-mediated apoptosis. The SDX-101 plus ALT combination resulted in only sub-additive cytotoxicity (CI = 1.25). In conclusion, these data obtained in vitro indicate that addition of 2-CdA, FA or RIT to SDX-101 significantly enhance cytotoxicity in B-CLL cells.