Genomes and Genes
Summary: Nucleosides containing arabinose as their sugar moiety.
- Hanaoka K, Suzuki M, Kobayashi T, Tanzawa F, Tanaka K, Shibayama T, et al. Antitumor activity and novel DNA-self-strand-breaking mechanism of CNDAC (1-(2-C-cyano-2-deoxy-beta-D-arabino-pentofuranosyl) cytosine) and its N4-palmitoyl derivative (CS-682). Int J Cancer. 1999;82:226-36 pubmed..This novel DNA-self-strand-breaking mechanism may contribute to the potent antitumor activity of CS-682. ..
- Faderl S, Ravandi F, Huang X, Garcia Manero G, Ferrajoli A, Estrov Z, et al. A randomized study of clofarabine versus clofarabine plus low-dose cytarabine as front-line therapy for patients aged 60 years and older with acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood. 2008;112:1638-45 pubmed publisher..4 months vs 5.8 months; P = .1). Clofarabine plus low-dose cytarabine has a higher response rate than clofarabine alone with comparable toxicity. This trial is registered at www.clinicaltrials.gov as no. NCT00088218. ..
- Advani A, Gundacker H, Sala Torra O, Radich J, Lai R, Slovak M, et al. Southwest Oncology Group Study S0530: a phase 2 trial of clofarabine and cytarabine for relapsed or refractory acute lymphocytic leukaemia. Br J Haematol. 2010;151:430-4 pubmed..Nucleoside transporter expression did not predict outcome. This regimen lacked sufficient activity to warrant further testing. ..
- Faderl S, Ferrajoli A, Wierda W, Huang X, Verstovsek S, Ravandi F, et al. Clofarabine combinations as acute myeloid leukemia salvage therapy. Cancer. 2008;113:2090-6 pubmed publisher..MTD for CIA was clofarabine 22.5 mg/m(2) intravenously x 5, idarubicin 6 mg/m(2) intravenously x 3, and cytarabine 0.75 g/m(2) intravenously x 5 days. A phase 2 randomized trial is in process to compare activity between treatment arms. ..
- Sampat K, Kantarjian H, Borthakur G. Clofarabine: emerging role in leukemias. Expert Opin Investig Drugs. 2009;18:1559-64 pubmed publisher..An oral formulation of clofarabine is also currently under development. ..
- Kantarjian H, Garcia Manero G, O Brien S, Faderl S, Ravandi F, Westwood R, et al. Phase I clinical and pharmacokinetic study of oral sapacitabine in patients with acute leukemia and myelodysplastic syndrome. J Clin Oncol. 2010;28:285-91 pubmed publisher..Sapacitabine is a new, safely administered, oral deoxycytidine analog that has encouraging activity in leukemia and MDS. Phase II studies are ongoing. ..
- Hijiya N, Barry E, Arceci R. Clofarabine in pediatric acute leukemia: current findings and issues. Pediatr Blood Cancer. 2012;59:417-22 pubmed publisher..In this article, we review the development of clofarabine, rationale and history of combination regimens, and their potential roles and toxicities in the treatment of pediatric ALL that are important to treating clinicians. ..
- Kantarjian H, Erba H, Claxton D, Arellano M, Lyons R, Kovascovics T, et al. Phase II study of clofarabine monotherapy in previously untreated older adults with acute myeloid leukemia and unfavorable prognostic factors. J Clin Oncol. 2010;28:549-55 pubmed publisher..ORR did not seem affected by the presence of multiple unfavorable prognostic factors. ..
- Jeha S, Gaynon P, Razzouk B, Franklin J, Kadota R, Shen V, et al. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol. 2006;24:1917-23 pubmed..The toxicity profile is as expected in this heavily pretreated patient population. Studies exploring rational combinations of clofarabine with other agents are ongoing in an effort to maximize clinical benefit. ..
- Burnett A, Russell N, Kell J, Dennis M, Milligan D, Paolini S, et al. European development of clofarabine as treatment for older patients with acute myeloid leukemia considered unsuitable for intensive chemotherapy. J Clin Oncol. 2010;28:2389-95 pubmed publisher..Clofarabine is active and generally well tolerated in this patient group. It is worthy of further evaluation in comparative trials and might be of particular use in patients with adverse cytogenetics. ..
- King K, Damaraju V, Vickers M, Yao S, Lang T, Tackaberry T, et al. A comparison of the transportability, and its role in cytotoxicity, of clofarabine, cladribine, and fludarabine by recombinant human nucleoside transporters produced in three model expression systems. Mol Pharmacol. 2006;69:346-53 pubmed..These results suggest that the nature and activity of the plasma membrane proteins capable of inward transport of nucleosides are important determinants of Cl-F-ara-A activity in human cells. ..
- Gökbuget N, Basara N, Baurmann H, Beck J, Bruggemann M, Diedrich H, et al. High single-drug activity of nelarabine in relapsed T-lymphoblastic leukemia/lymphoma offers curative option with subsequent stem cell transplantation. Blood. 2011;118:3504-11 pubmed publisher..Exploration of nelarabine in earlier stages of relapse (eg, increasing minimal residual disease), in front-line therapy, and in combination is warranted. ..
- Faderl S, Gandhi V, O Brien S, Bonate P, Cortes J, Estey E, et al. Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias. Blood. 2005;105:940-7 pubmed..The combination of clofarabine with ara-C is safe and active. Cellular pharmacology data support the biochemical modulation strategy. ..
- Jeha S, Gandhi V, Chan K, McDonald L, Ramirez I, Madden R, et al. Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia. Blood. 2004;103:784-9 pubmed..Clofarabine is well tolerated and shows significant antileukemic activity in heavily pretreated children. Multicenter phase 2 trials in pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are ongoing. ..
- Takahashi T, Shimizu M, Akinaga S. Mechanisms of the apoptotic activity of Cl-F-araA in a human T-ALL cell line, CCRF-CEM. Cancer Chemother Pharmacol. 2002;50:193-201 pubmed..We further found that in combination with caffeine, Cl-F-araA potentiated apoptosis induction. Taken together, our findings suggest that Cl-F-araA may be an effective drug in vivo. ..
- Kurtzberg J, Ernst T, Keating M, Gandhi V, Hodge J, Kisor D, et al. Phase I study of 506U78 administered on a consecutive 5-day schedule in children and adults with refractory hematologic malignancies. J Clin Oncol. 2005;23:3396-403 pubmed..Nelarabine is a novel nucleoside with significant cytotoxic activity against malignant T cells. DLT is neurologic. Phase II and III trials in patients with T-cell malignancies are encouraged. ..
- Ghanem H, Jabbour E, Faderl S, Ghandhi V, Plunkett W, Kantarjian H. Clofarabine in leukemia. Expert Rev Hematol. 2010;3:15-22 pubmed publisher..This article describes the development, pharmacology and clinical activity of clofarabine, as well as its emerging role in the treatment of acute leukemia, myelodysplastic syndrome and solid tumors. ..
- Kantarjian H, Gandhi V, Cortes J, Verstovsek S, Du M, Garcia Manero G, et al. Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood. 2003;102:2379-86 pubmed..03). This increased only in responders (median, 1.8-fold; P =.008) after the second clofarabine infusion. In summary, clofarabine is active in acute leukemias and MDS; cellular pharmacokinetics may have prognostic significance. ..
- Aleem A, Anjum F, Algahtani F, Iqbal Z, Alsaleh K, Almomen A. Clofarabine in the treatment of elderly patients with acute myeloid leukemia. Asian Pac J Cancer Prev. 2013;14:1089-92 pubmed..2 months (Range 3-10). Clofarabine (alone or in combination) is active in elderly AML patients with an acceptable safety profile and should be considered a potential option in this group. ..
- Green S, Choudhary A, Fleming I. Combination of sapacitabine and HDAC inhibitors stimulates cell death in AML and other tumour types. Br J Cancer. 2010;103:1391-9 pubmed publisher..Sapacitabine and HDAC inhibitors are an effective drug combination that is worthy of clinical exploration. ..
- Baytan B, Ozdemir O, Gunes A, Donmez O. Clofarabine-induced capillary leak syndrome in a child with refractory acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2010;32:144-6 pubmed publisher..In previous pediatric trials, various adverse effects have been described. In this case, we report a child with refractory acute lymphoblastic leukemia who developed fatal capillary leak syndrome during clofarabine therapy. ..
- Parker W, Shaddix S, Rose L, Waud W, Shewach D, Tiwari K, et al. Metabolism of 4'-thio-beta-D-arabinofuranosylcytosine in CEM cells. Biochem Pharmacol. 2000;60:1925-32 pubmed..The data in this study represent another example of how relatively small structural changes in nucleoside analogs can profoundly affect the biochemical activity. ..
- Chan T, Gill H, Hwang Y, Sim J, Tse A, Loong F, et al. Breakthrough invasive fungal diseases during echinocandin treatment in high-risk hospitalized hematologic patients. Ann Hematol. 2014;93:493-8 pubmed publisher..Breakthrough IFD during echinocandin treatment occurred infrequently (1.5 %), caused predominantly by Candida species. Clofarabine usage was an important risk factor. ..
- Jeha S. Recent progress in the treatment of acute lymphoblastic leukemia: clofarabine. Hematol Oncol Clin North Am. 2009;23:1137-44, viii pubmed publisher..Ongoing trials are studying the benefits of clofarabine combinations in less heavily pretreated patients, and the use of different dose schedules in a variety of hematologic malignancies. ..
- Lee J, Campbell D, Satyamurthy N, Czernin J, Radu C. Stratification of nucleoside analog chemotherapy using 1-(2'-deoxy-2'-18F-fluoro-?-D-arabinofuranosyl)cytosine and 1-(2'-deoxy-2'-18F-fluoro-?-L-arabinofuranosyl)-5-methylcytosine PET. J Nucl Med. 2012;53:275-80 pubmed publisher..These findings support the utility of PET-based phenotyping of tumor nucleoside metabolism for guiding the selection of NA prodrugs. ..
- Chiao N, Bumgardner A, Duvic M. Clofarabine-induced acral erythema during the treatment of patients with myelodysplasia and acute leukemia: report of two cases. Leuk Lymphoma. 2003;44:1405-7 pubmed..We describe two patients who developed acral erythema after receiving clofarabine. One patient had myelodysplastic syndrome while the other had acute lymphoblastic leukemia. ..
- Kurtzberg J. The long and winding road of the clinical development of Nelarabine. Leuk Lymphoma. 2007;48:1-2 pubmed
- Thudium K, Ghoshal S, Fetterly G, Haese J, Karpf A, Wetzler M. Synergism between clofarabine and decitabine through p53R2: a pharmacodynamic drug-drug interaction modeling. Leuk Res. 2012;36:1410-6 pubmed publisher..These results confirm a role for p53R2 in both CLO and DEC mechanism of action, demonstrate synergism between these two drugs in this AML model and support the use of this combination in a future clinical trial. ..
- Hussar D. New drugs: abatacept, sorafenib, and nelarabine. J Am Pharm Assoc (2003). 2006;46:300-3 pubmed
- Nazha A, Kantarjian H, Ravandi F, Huang X, Choi S, Garcia Manero G, et al. Clofarabine, idarubicin, and cytarabine (CIA) as frontline therapy for patients ?60 years with newly diagnosed acute myeloid leukemia. Am J Hematol. 2013;88:961-6 pubmed publisher..In multivariate analysis, CIA retained its favorable impact on OS compared to IA. Thus, CIA is an effective and safe therapy for patients ?60 years with newly diagnosed AML. ..
- Tischer J, Stemmler H, Engel N, Hubmann M, Fritsch S, Prevalsek D, et al. Feasibility of clofarabine cytoreduction followed by haploidentical hematopoietic stem cell transplantation in patients with relapsed or refractory advanced acute leukemia. Ann Hematol. 2013;92:1379-88 pubmed publisher..NRM and rate of GvHD were comparable to results after HSCT from HLA-matched donors. ..
- Mathisen M, Kantarjian H, Jabbour E, Garcia Manero G, Ravandi F, Faderl S, et al. Clofarabine does not negatively impact the outcomes of patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation. Clin Lymphoma Myeloma Leuk. 2013;13:139-43 pubmed publisher..We conclude that clofarabine-containing chemotherapy does not adversely impact the outcome of allo-SCT. Specifically, it does not predispose patients to an increased risk of hepatotoxicity, VOD, GVHD, or relapse. ..
- Lee Y, Im J, Lee D, Park J, Won S, Cho M, et al. Synergistic inhibition of mesothelioma cell growth by the combination of clofarabine and resveratrol involves Nrf2 downregulation. BMB Rep. 2012;45:647-52 pubmed..Altogether, these results suggest that the synergistic cytotoxic effect of clofarabine and resveratrol was mediated, at least in part, through suppression of Nrf2 signaling. ..
- Takahashi K, Kantarjian H, Garcia Manero G, Borthakur G, Kadia T, Dinardo C, et al. Clofarabine Plus Low-Dose Cytarabine Is as Effective as and Less Toxic Than Intensive Chemotherapy in Elderly AML Patients. Clin Lymphoma Myeloma Leuk. 2016;16:163-8.e1-2 pubmed publisher..033). Compared with intensive induction, CLDA offers equivalent responses and survival but less toxicity in clinically well-matched cohorts of elderly AML patients. Prospective randomized trials to confirm these findings are warranted. ..
- Kim W, Le T, Wei L, Poddar S, Bazzy J, Wang X, et al. [18F]CFA as a clinically translatable probe for PET imaging of deoxycytidine kinase activity. Proc Natl Acad Sci U S A. 2016;113:4027-32 pubmed publisher..The selectivity of [(18)F]CFA for dCK and its favorable biodistribution in humans justify further studies to validate [(18)F]CFA PET as a new cancer biomarker for treatment stratification and monitoring. ..
- Stackhouse M, Gilbert K, Scoggins J, Waud W. Preclinical combination therapy of clofarabine plus radiation. Nucleosides Nucleotides Nucleic Acids. 2012;31:692-705 pubmed..The radiomodifying capacity of clofarabine was superior to that for gemcitabine in two models (PANC-1 and HCT-116) and was comparable in the other four models. ..
- Serova M, Galmarini C, Ghoul A, Benhadji K, Green S, Chiao J, et al. Antiproliferative effects of sapacitabine (CYC682), a novel 2'-deoxycytidine-derivative, in human cancer cells. Br J Cancer. 2007;97:628-36 pubmed..Sapacitabine is therefore a good candidate for further evaluation in combination with currently used anticancer agents in tumour types with unmet needs. ..
- Farag S, Wood L, Schwartz J, Srivastava S, Nelson R, Robertson M, et al. Phase I trial and pharmacokinetic study of high-dose clofarabine and busulfan and allogeneic stem cell transplantation in adults with high-risk and refractory acute leukemia. Leukemia. 2011;25:599-605 pubmed publisher..8?mg per kg total dose) for further study as a myeloablative regimen for allogeneic SCT for high-risk acute leukemia. ..
- Buie L, Epstein S, Lindley C. Nelarabine: a novel purine antimetabolite antineoplastic agent. Clin Ther. 2007;29:1887-99 pubmed..Objective response rates in Phase II clinical trials of nelarabine have ranged from 11% to 60%. Use of nelarabine is limited by potentially severe neurotoxicity. ..
- Lewis R, Link L. Phosphorylation of arabinosyl guanine by a mitochondrial enzyme of bovine liver. Biochem Pharmacol. 1989;38:2001-6 pubmed
- Hernández A, Familiar O, Negri A, Rodríguez Barrios F, Gago F, Karlsson A, et al. N1-substituted thymine derivatives as mitochondrial thymidine kinase (TK-2) inhibitors. J Med Chem. 2006;49:7766-73 pubmed
- Peng X, Seela F. Halogenated 7-deazapurine nucleosides: stereoselective synthesis and conformation of 2'-deoxy-2'-fluoro-beta-D-arabinonucleosides. Org Biomol Chem. 2004;2:2838-46 pubmed..The fluorine atom in the sugar moiety shifts the sugar conformation from S towards N by about 10%, while the halogen substituents in the base moiety increase the hydrophobicity and polarizability of the nucleobases. ..
- Zheng X, Lundberg M, Karlsson A, Johansson M. Lipid-mediated protein delivery of suicide nucleoside kinases. Cancer Res. 2003;63:6909-13 pubmed..Our results show that direct delivery of suicide gene proteins to cells may be an alternative approach to conventional suicide gene therapy strategies. ..
- Lindemalm S, Liliemark J, Gruber A, Eriksson S, Karlsson M, Wang Y, et al. Comparison of cytotoxicity of 2-chloro- 2'-arabino-fluoro-2'-deoxyadenosine (clofarabine) with cladribine in mononuclear cells from patients with acute myeloid and chronic lymphocytic leukemia. Haematologica. 2003;88:324-32 pubmed..The greater in vitro cytotoxicity and cell metabolism of CAFdA compared to CdA confirm the high activity of CAFdA and encourage clinical trials with CAFdA in leukemic patients. ..
- Yin H, D Souza F, Lowary T. Arabinofuranosides from mycobacteria: synthesis of a highly branched hexasaccharide and related fragments containing beta-arabinofuranosyl residues. J Org Chem. 2002;67:892-903 pubmed..In the preparation of the targets, the key step was a low-temperature glycosylation reaction that installed the beta-arabinofuranosyl residues with good to excellent stereocontrol. ..
- Balzarinia J, Degreve B, Zhu C, Durini E, Porcu L, De Clercq E, et al. 2'-O-Acyl/alkyl-substituted arabinosyl nucleosides as inhibitors of human mitochondrial thymidine kinase. Biochem Pharmacol. 2001;61:727-32 pubmed..This is the first report on such a highly selective arabinosyl nucleoside inhibitor of mitochondrial TK-2, and opens perspectives for the rational design of selective mitochondrial TK-2 inhibitors. ..
- Larson R. Recent clinical trials in acute lymphocytic leukemia by the Cancer and Leukemia Group B. Hematol Oncol Clin North Am. 2000;14:1367-79, x pubmed..These protocols have enrolled all adult patients older than 15 years with ALL, without an upper age restriction, and did not exclude Philadelphia (Ph) chromosome-positive patients...
- Gandhi V, Plunkett W, Rodriguez C, Nowak B, Du M, Ayres M, et al. Compound GW506U78 in refractory hematologic malignancies: relationship between cellular pharmacokinetics and clinical response. J Clin Oncol. 1998;16:3607-15 pubmed..GW506U78 is an effective prodrug and a potent agent for hematologic malignancies with major efficacy in T-cell diseases. The pharmacokinetics of ara-GTP in leukemia cells are strongly correlated with clinical responses to GW506U78. ..
- Shewach D, Mitchell B. Differential metabolism of 9-beta-D-arabinofuranosylguanine in human leukemic cells. Cancer Res. 1989;49:6498-502 pubmed..Furthermore, degradation of araG did not limit the accumulation of araGTP in the leukemic cells. These results indicate that araG may be valuable as a selectively acting chemotherapeutic agent in T-lymphoblastic malignancies. ..
- Valdez B, Li Y, Murray D, Champlin R, Andersson B. The synergistic cytotoxicity of clofarabine, fludarabine and busulfan in AML cells involves ATM pathway activation and chromatin remodeling. Biochem Pharmacol. 2011;81:222-32 pubmed publisher..Our results provide a conceptual mechanistic basis for exploring this triple-drug combination in pretransplant conditioning therapy for allo-HSCT. ..
- Beesley A, Palmer M, Ford J, Weller R, Cummings A, Freitas J, et al. In vitro cytotoxicity of nelarabine, clofarabine and flavopiridol in paediatric acute lymphoblastic leukaemia. Br J Haematol. 2007;137:109-16 pubmed..FP should be widely effective in ALL if sufficient plasma levels can be achieved clinically. ..
- Scappini B, Gianfaldoni G, Caracciolo F, Mannelli F, Biagiotti C, Romani C, et al. Cytarabine and clofarabine after high-dose cytarabine in relapsed or refractory AML patients. Am J Hematol. 2012;87:1047-51 pubmed publisher..Safety data were consistent with previously reported salvage therapies. Further studies and a longer follow up are warranted. ..
- Cociorva O, Lowary T. Synthesis of oligosaccharides as potential inhibitors of mycobacterial arabinosyltransferases. Di- and trisaccharides containing C-5 modified arabinofuranosyl residues. Carbohydr Res. 2004;339:853-65 pubmed..Deprotection of the glycosylation products afforded the azido, fluoro, or methoxy analogs directly. The amino derivatives were obtained in one additional step by reduction of the azido compounds. ..