John F Marcelletti1, Branimir I Sikic2,3, Larry D Cripe4, Elisabeth Paietta5. 1. Department of Clinical Development, Kanisa Pharmaceuticals, San Diego, California. 2. Department of Medicine, Stanford University, Stanford, California. 3. Oncology Division, Stanford University, Stanford, California. 4. Department of Hematology/Oncology, Indiana University Simon Cancer Center, Indianapolis, Indiana. 5. Oncology Department, Albert Einstein College of Medicine, Bronx, New York.
Abstract
BACKGROUND: Multidrug resistance (MDR) transporter proteins such as P-glycoprotein (P-gp) efflux a variety of chemotherapeutic drugs from acute myeloid leukemia (AML) blasts leading to clinical drug resistance. METHODS: This study examined heterogeneity of MDR functional efflux by AML blasts using two flow cytometry bioassays. Bone marrow specimens (N = 50) from elderly patients with newly diagnosed AML were analyzed for CD34+ blasts with MDR efflux function. Efflux was measured with a fluorescent dye (DiOC2 ) as a surrogate for oncology drugs that are substrates for MDR efflux. P-gp-mediated efflux was differentiated from non-P-gp MDR activities using zosuquidar, a highly selective P-gp modulator. The bioassays included a zosuquidar-dependent DiOC2 accumulation bioassay that measured only P-gp. The second method, termed the efflux bioassay, could detect P-gp and other non-P-gp efflux depending on bioassay culture conditions. RESULTS: Sixty-two percent of the specimens were considered positive for blasts with P-gp function, and 26% of such P-gp-positive specimens also exhibited zosuquidar-resistant (i.e., non-P-gp) MDR efflux activity; 37% of P-gp-negative AML blast specimens displayed zosuquidar-resistant MDR function in the efflux bioassay. CONCLUSIONS: These results confirm the heterogeneous nature of MDR efflux pumps in AML blasts, and provide support for the hypothesis that non-P-gp MDR contributed to negative results with zosuquidar in AML trials like ECOG-ACRIN E3999.
BACKGROUND: Multidrug resistance (MDR) transporter proteins such as P-glycoprotein (P-gp) efflux a variety of chemotherapeutic drugs from acute myeloid leukemia (AML) blasts leading to clinical drug resistance. METHODS: This study examined heterogeneity of MDR functional efflux by AML blasts using two flow cytometry bioassays. Bone marrow specimens (N = 50) from elderly patients with newly diagnosed AML were analyzed for CD34+ blasts with MDR efflux function. Efflux was measured with a fluorescent dye (DiOC2 ) as a surrogate for oncology drugs that are substrates for MDR efflux. P-gp-mediated efflux was differentiated from non-P-gp MDR activities using zosuquidar, a highly selective P-gp modulator. The bioassays included a zosuquidar-dependent DiOC2 accumulation bioassay that measured only P-gp. The second method, termed the efflux bioassay, could detect P-gp and other non-P-gp efflux depending on bioassay culture conditions. RESULTS: Sixty-two percent of the specimens were considered positive for blasts with P-gp function, and 26% of such P-gp-positive specimens also exhibited zosuquidar-resistant (i.e., non-P-gp) MDR efflux activity; 37% of P-gp-negative AML blast specimens displayed zosuquidar-resistant MDR function in the efflux bioassay. CONCLUSIONS: These results confirm the heterogeneous nature of MDR efflux pumps in AML blasts, and provide support for the hypothesis that non-P-gp MDR contributed to negative results with zosuquidar in AML trials like ECOG-ACRIN E3999.
Authors: Brian C Shaffer; Jean-Pierre Gillet; Chirayu Patel; Maria R Baer; Susan E Bates; Michael M Gottesman Journal: Drug Resist Updat Date: 2012-03-11 Impact factor: 18.500
Authors: Larry D Cripe; Hajime Uno; Elisabeth M Paietta; Mark R Litzow; Rhett P Ketterling; John M Bennett; Jacob M Rowe; Hillard M Lazarus; Selina Luger; Martin S Tallman Journal: Blood Date: 2010-08-17 Impact factor: 22.113
Authors: Jeffrey E Lancet; Maria R Baer; George E Duran; Alan F List; Robert Fielding; John F Marcelletti; Pratik S Multani; Branimir I Sikic Journal: Leuk Res Date: 2008-12-23 Impact factor: 3.156
Authors: Kevin G Chen; George E Duran; Mark J Mogul; Yan C Wang; Kevin L Ross; Jean-Pierre Jaffrézou; Lyn M Huff; Kory R Johnson; Tito Fojo; Norman J Lacayo; Branimir I Sikic Journal: Cancer Drug Resist Date: 2020-11-03