The deoxynucleoside analogs cytarabine (Ara-C) and gemcitabine (dFdC) are widely used in the treatment of cancer. Due to their hydrophilic nature they need the equilibrative (hENT) and concentrative (hCNT) nucleoside transporters to enter the cell. To bypass drug resistance due to decreased uptake, lipophilic 5'elaidic acid esters were synthesized, elacytarabine (CP-4055, from ara-C) and CP-4126 (from gemcitabine), which are currently in clinical development for solid and hematological tumors. We investigated whether resistance can be induced in vitro, and treated the CEM leukemic cell line with weekly increasing elacytarabine concentrations, up to 0.28 microM (10 times IC(50)). The IC(50) of the resistant CEM/CP-4055 was 35 microM, about 1,000 times that of the wildtype CEM, and comparable to that of CEM/dCK- (deoxycytidine kinase deficient) (22 microM). CEM/CP-4055 was also cross-resistant to Ara-C, gemcitabine and CP-4126 (28 and 33 microM, respectively). A low level of mRNA dCK was observed, and similar to CEM/dCK-, CEM/CP-4055 did not accumulate Ara-CTP after exposure to Ara-C or elacytarabine, which is consistent with a deficiency in dCK. In conclusion, elacytarabine induced resistance similar to Ara-C. This resistance was caused by downregulation of dCK.
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Discontinued in 2013: oncology drugs.
Expert Opin Investig Drugs
January 2015
Drug Development Office, Cancer Research UK , Angel Building, 407 St John Street, London EC1V 4AD , UK +44 203 469 6900 ;
Introduction: Attrition in clinical development is widely recognised as a key factor negatively impacting overall R&D efficiency. Gaining an understanding of the reasons for candidate failure may lead to improvements in success rates and return on R&D investment. Areas covered: This report provides an analysis of reasons for discontinuation of development of 40 drugs dropped from the global oncology pipeline in 2013 - the largest number of terminations reported since this annual analysis began in 2005.
View Article and Find Full Text PDFInternational randomized phase III study of elacytarabine versus investigator choice in patients with relapsed/refractory acute myeloid leukemia.
J Clin Oncol
June 2014
Gail J. Roboz, Weill Cornell Medical College and the New York Presbyterian Hospital; Todd Rosenblat, Columbia University Medical Center, New York, NY; Martha Arellano, Winship Cancer Institute at Emory University; Scott R. Solomon, The Blood and Marrow Transplant Group of Georgia, Atlanta, GA; Jessica K. Altman, Francis J. Giles, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Casey O'Connell, University of Southern California Norris Comprehensive Cancer Center and Hospital, Los Angeles, CA; Marco Gobbi, Azienda Ospedaliera Universitaria San Martino, University of Genoa, Genoa, Italy; Pau Montesinos, Hospital Universitario y Politécnico La Fé, Valencia, Spain; Arnaud Pigneux, Centre Hospitalier Universitaire de Bordeaux Hôpital Haut-Lévêque, Pessac; Norbert Vey, L'Institut Paoli-Calmettes, Marseilles, France; Robert Hills, Cardiff University School of Medicine, Cardiff, United Kingdom; Tove Flem Jacobsen, Athos Gianella-Borradori, Øivind Foss, and Sylvia Vetrhus, Clavis Pharma ASA, Oslo, Norway.
Purpose: Most patients with acute myeloid leukemia (AML) eventually experience relapse. Relapsed/refractory AML has a dismal prognosis and currently available treatment options are generally ineffective. The objective of this large, international, randomized clinical trial was to investigate the efficacy of elacytarabine, a novel elaidic acid ester of cytarabine, versus the investigator's choice of one of seven commonly used AML salvage regimens, including high-dose cytarabine, multiagent chemotherapy, hypomethylating agents, hydroxyurea, and supportive care.
View Article and Find Full Text PDFElacytarabine is the elaidic acid ester derivative of cytarabine, designed to enter cells independently of nucleoside transporters. Effects of elacytarabine on QT interval, serum lipid profile and clinical activity were investigated in 43 relapsed/refractory AML patients. Mean maximum increase in corrected QT interval of 24( ± 29)ms occurred 48 h after elacytarabine infusion without associated arrhythmias or clinical symptoms.
View Article and Find Full Text PDFA phase II study of elacytarabine in combination with idarubicin and of human equilibrative nucleoside transporter 1 expression in patients with acute myeloid leukemia and persistent blasts after the first induction course.
Leuk Lymphoma
September 2014
Duke University Medical Center, Durham, NC , USA.
Unlike cytarabine, cellular entry of Elacytarabine, the elaidic acid ester derivative of cytarabine, is independent of the human equilibrative nucleoside transporter 1 (hENT1). This phase II study tested whether the hENT1 blast expression level can be used as a predictive marker for cytarabine response and if the efficacy of elacytarabine is independent of hENT1 expression. A total of 51 patients with acute myeloid leukemia (AML) induction failure were given elacytarabine-idarubicin as a second induction course.
View Article and Find Full Text PDFAntitumor activity of elacytarabine combined with bevacizumab, cetuximab and trastuzumab in human NSCLC xenografts.
Anticancer Res
September 2013
Deparment of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Montebello, N-0310 Oslo, Norway.
Aim: The objective of the present study was to determine the in vivo antitumor activity of elacytarabine, the 5'-elaidic acid ester of arabinofuranosyl cytidine, alone and in combination with bevacizumab, cetuximab and trastuzumab in Vascular endothelial growth factor (VEGF), Epidermal growth factor receptor (EGFR)- and Human epidermal growth factor receptor 2 (HER2)-expressing non-small cell lung cancer xenografts.
Materials And Methods: The antitumor activity of elacytarabine, was tested at the maximal tolerable dose (MTD; 50 mg/kg) and half MTD (25 mg/kg), alone and in combination with the antibodies bevacizumab (5 mg/kg), cetuximab (20 mg/kg) and trastuzumab (4 mg/kg) in two human non-small cell lung cancer xenografts.
Results: Elacytarabine exhibited very high activity in the EKVX xenograft at both dose levels, but was inactive in MAKSAX.
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