Cytotoxic effect of R-etodolac (SDX-101) in combination with purine analogs or monoclonal antibodies on ex vivo B-cell chronic lymphocytic leukemia cells.
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.
Robak
Paweł
P
Department of Hematology, Medical University of Lodz, Lodz, Poland.
Linke
Anna
A
Cebula
Barbara
B
Robak
Tadeusz
T
Smolewski
Piotr
P
D000074323:Alemtuzumab; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D000912:Antibodies, Neoplasm / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D017338:Cladribine / Q000008:administration & dosage; D017308:Etodolac / Q000008:administration & dosage*; D006801:Humans; D015448:Leukemia, B-Cell / Q000188:drug therapy*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D011687:Purines / Q000737:chemistry*; D000069283:Rituximab; D013050:Spectrometry, Fluorescence / Q000379:methods; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D000912:Antibodies, Neoplasm; D011687:Purines; D017308:Etodolac; D000074323:Alemtuzumab; D017338:Cladribine; D000069283:Rituximab; D014740:Vidarabine; C024352:fludarabine