{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T08:39:05Z","timestamp":1770971945594,"version":"3.50.1"},"reference-count":44,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCO"],"published-print":{"date-parts":[[2001,4,15]]},"abstract":"<jats:p> PURPOSE: A pilot protocol was designed to evaluate the efficacy of fludarabine with nelarabine (the prodrug of arabinosylguanine [ara-G]) in patients with hematologic malignancies. The cellular pharmacokinetics was investigated to seek a relationship between response and accumulation of ara-G triphosphate (ara-GTP) in circulating leukemia cells and to evaluate biochemical modulation of cellular ara-GTP metabolism by fludarabine triphosphate. <\/jats:p><jats:p> PATIENTS AND METHODS: Nine of the 13 total patients had indolent leukemias, including six whose disease failed prior fludarabine therapy. Two patients had T-acute lymphoblastic leukemia, one had chronic myelogenous leukemia, and one had mycosis fungoides. Nelarabine (1.2 g\/m<jats:sup>2<\/jats:sup>) was infused on days 1, 3, and 5. On days 3 and 5, fludarabine (30 mg\/m<jats:sup>2<\/jats:sup>) was administered 4 hours before the nelarabine infusion. Plasma and cellular pharmacokinetic measurements were conducted during the first 5 days. <\/jats:p><jats:p> RESULTS: Seven patients had a partial or complete response, six of whom had indolent leukemias. The disease in four responders had failed prior fludarabine therapy. The median peak intracellular concentrations of ara-GTP were significantly different (P = .001) in responders (890 \u03bcmol\/L, n = 6) and nonresponders (30 \u03bcmol\/L, n = 6). Also, there was a direct relationship between the peak fludarabine triphosphate and ara-GTP in each patient (r = 0.85). The cellular elimination of ara-GTP was slow (median, 35 hours; range, 18 to &gt; 48 hours). The ratio of ara-GTP to its normal counterpart, deoxyguanosine triphosphate, was higher in each patient (median, 42; range, 14 to 1,092) than that of fludarabine triphosphate to its normal counterpart, deoxyadenosine triphosphate (median, 2.2; range, 0.2 to 27). <\/jats:p><jats:p> CONCLUSION: Fludarabine plus nelarabine is an effective, well-tolerated regimen against leukemias. Clinical responses suggest the need for further exploration of nelarabine against fludarabine-refractory diseases. Determination of ara-GTP levels in the target tumor population may provide a prognostic test for the activity of nelarabine. <\/jats:p>","DOI":"10.1200\/jco.2001.19.8.2142","type":"journal-article","created":{"date-parts":[[2017,2,24]],"date-time":"2017-02-24T06:37:31Z","timestamp":1487918251000},"page":"2142-2152","source":"Crossref","is-referenced-by-count":49,"title":["Evaluation of the Combination of Nelarabine and Fludarabine in Leukemias: Clinical Response, Pharmacokinetics, and Pharmacodynamics in Leukemia Cells"],"prefix":"10.1200","volume":"19","author":[{"given":"Varsha","family":"Gandhi","sequence":"first","affiliation":[{"name":"From the Departments of Experimental Therapeutics, Biostatistics, and Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and GlaxoWellcome Inc, Research Triangle Park, NC."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"Plunkett","sequence":"additional","affiliation":[{"name":"From the Departments of Experimental Therapeutics, Biostatistics, and Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and GlaxoWellcome Inc, Research Triangle Park, NC."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steve","family":"Weller","sequence":"additional","affiliation":[{"name":"From the Departments of Experimental Therapeutics, Biostatistics, and Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and GlaxoWellcome Inc, Research Triangle Park, NC."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Du","sequence":"additional","affiliation":[{"name":"From the Departments of Experimental Therapeutics, Biostatistics, and Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and GlaxoWellcome Inc, Research Triangle Park, NC."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary","family":"Ayres","sequence":"additional","affiliation":[{"name":"From the Departments of Experimental Therapeutics, Biostatistics, and Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and GlaxoWellcome Inc, Research Triangle Park, NC."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"Jr","given":"Carlos O.","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"From the Departments of Experimental Therapeutics, Biostatistics, and Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and GlaxoWellcome Inc, Research Triangle Park, NC."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Prameen","family":"Ramakrishna","sequence":"additional","affiliation":[{"name":"From the Departments of Experimental Therapeutics, Biostatistics, and Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and GlaxoWellcome Inc, Research Triangle Park, NC."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gary L.","family":"Rosner","sequence":"additional","affiliation":[{"name":"From the Departments of Experimental Therapeutics, Biostatistics, and Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and GlaxoWellcome Inc, Research Triangle Park, NC."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeff P.","family":"Hodge","sequence":"additional","affiliation":[{"name":"From the Departments of Experimental Therapeutics, Biostatistics, and Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and GlaxoWellcome Inc, Research Triangle Park, NC."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan","family":"O\u2019Brien","sequence":"additional","affiliation":[{"name":"From the Departments of Experimental Therapeutics, Biostatistics, and Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and GlaxoWellcome Inc, Research Triangle Park, NC."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael J.","family":"Keating","sequence":"additional","affiliation":[{"name":"From the Departments of Experimental Therapeutics, Biostatistics, and Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and GlaxoWellcome Inc, Research Triangle Park, NC."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"233","reference":[{"key":"R1-087632","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V72.3.1069.1069"},{"key":"R2-087632","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1993.11.4.679"},{"key":"R3-087632","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/82.17.1416"},{"key":"R4-087632","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1989.7.2.168"},{"key":"R5-087632","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V74.1.19.19"},{"key":"R6-087632","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V92.4.1165"},{"key":"R7-087632","doi-asserted-by":"publisher","DOI":"10.1021\/bi00889a004"},{"key":"R8-087632","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6215(00)80531-5"},{"key":"R9-087632","unstructured":"Lambe  CU,   Averett  DR,   Paff  MT,  et al:  2-Amino-6-methoxypurine arabinoside:   An agent for T-cell malignancies.   Cancer Res 55:  3352,1995-3356,"},{"key":"R10-087632","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2000.18.5.995"},{"key":"R11-087632","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(89)90500-5"},{"key":"R12-087632","doi-asserted-by":"crossref","unstructured":"Wang  L,   Karlsson  A,   Arn\u00e9r  ESJ,  et al:  Substrate specificity of mitochondrial 2\u2032-deoxyguanosine kinase:   Efficient phosphorylation of 2-chlorodeoxyadenosine.   J Biol Chem 268:  22847,1993-22852,","DOI":"10.1016\/S0021-9258(18)41605-5"},{"key":"R13-087632","doi-asserted-by":"crossref","unstructured":"Krenitsky  TA,   Tuttle  JV,   Koszalka  GW,  et al:  Deoxycytidine kinase from calf thymus:   Substrate and inhibitor specificity.   J Biol Chem 251:  4055,1976-4061,","DOI":"10.1016\/S0021-9258(17)33354-9"},{"key":"R14-087632","unstructured":"Kurtzberg  J,   Ernst  TJ,   Keating  MJ,  et al:  A phase I study of 2-amino-9-\u03b2-D-arabinosyl-6-methoxy-9H-purine (nelarabine) administered on a consecutive five day schedule in children and adults with refractory hematologic malignancies.   Blood 94:  629a,1999  (abstr 2794)"},{"key":"R15-087632","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1998.16.11.3607"},{"key":"R16-087632","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V61.4.660.bloodjournal614660"},{"key":"R17-087632","doi-asserted-by":"publisher","DOI":"10.1172\/JCI111514"},{"key":"R18-087632","unstructured":"Shewach  DS,   Daddona  PE,   Ashcraft  E,  et al:  Metabolism and selective cytotoxicity of 9-\u03b2-D-arabinofuranosylguanine in human lymphoblasts.   Cancer Res 45:  1008,1985-1014,"},{"key":"R19-087632","unstructured":"Verhoef  V,   Fridland  A:   Metabolic basis of arabinonucleoside selectivity for human leukemic T- and B-lymphoblasts.   Cancer Res 45:  3646,1985-3650,"},{"key":"R20-087632","unstructured":"Shewach  DS,   Mitchell  BS:   Differential metabolism of 9-\u03b2-arabinofuranosylguanine in human leukemic cells.   Cancer Res 49:  6498,1989-6502,"},{"key":"R21-087632","unstructured":"Rodriguez  CO Jr,   Legha  JK,   Estey  E,  et al:  Pharmacological and biochemical strategies to increase the accumulation of arabinofuranosylguanine triphosphate in primary human leukemia cells.   Clin Cancer Res 3:  2107,1997-2113,"},{"key":"R22-087632","doi-asserted-by":"publisher","DOI":"10.3109\/10428199309147356"},{"key":"R23-087632","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(89)90127-5"},{"key":"R24-087632","unstructured":"Gandhi  V,   Plunkett  W:   Modulation of arabinosylnucleoside metabolism by arabinosylnucleotides in human leukemia cells.   Cancer Res 48:  329,1988-334,"},{"key":"R25-087632","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1993.11.1.116"},{"key":"R26-087632","unstructured":"Gandhi  V,   Keating  MJ,   Estey  E,  et al:  Fludarabine infusion potentiates arabinosylcytosine metabolism in lymphocytes of patients with chronic lymphocytic leukemia.   Cancer Res 52:  897,1992-903,"},{"key":"R27-087632","unstructured":"Plunkett  W,   Hug  V,   Keating  M,  et al:  Quantitation of 1-\u03b2-D-arabinofuranosylcytosine 5\u2032-triphosphate in the leukemic cells from bone marrow and peripheral blood of patients receiving 1-\u03b2-D- arabinofuranosylcytosine therapy.   Cancer Res 40:  588,1980-591,"},{"key":"R28-087632","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-4347(00)00303-0"},{"key":"R29-087632","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(89)90420-X"},{"key":"R30-087632","unstructured":"O\u2019Brien  S,   Thomas  D,   Kantarjian  H,  et al:  Compound 506 has activity in mature lymphoid leukemia.   Blood 92:  490a,1998-491a,"},{"key":"R31-087632","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(77)90275-1"},{"key":"R32-087632","unstructured":"Hepke  DM,   Stegmann  APA,   Mitchell  BS:   Retroviral transfer of deoxycytidine kinase into tumor cell lines enhances nucleoside toxicity.   Cancer Res 56:  2343,1996-2347,"},{"key":"R33-087632","unstructured":"Rodriguez  CO Jr,   Mitchell  BS,   Eriksson  S,  et al:  Arabinosylguanine is phosphorylated by both deoxycytidine kinase and deoxyguanosine kinase.   Proc Am Assoc Cancer Res 41:  864,2000  (abstr 5491)"},{"key":"R34-087632","unstructured":"Gandhi  V,   Huang  P,   Chapman  A,  et al:  Incorporation of fludarabine and arabinosylcytosine 5\u2032-triphosphates by DNA polymerase \u03b1:   Affinity, interaction, and consequences.   Clin Cancer Res 3:  1347,1997-1355,"},{"key":"R35-087632","doi-asserted-by":"crossref","unstructured":"Kufe  DW,   Major  PP,   Egan  EM,  et al:  Correlation of cytotoxicity with incorporation of ara-C into DNA.   J Biol Chem 255:  8997,1980-9000,","DOI":"10.1016\/S0021-9258(19)70512-2"},{"key":"R36-087632","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V64.1.54.bloodjournal64154"},{"key":"R37-087632","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(86)90521-6"},{"key":"R38-087632","doi-asserted-by":"crossref","unstructured":"Huang  P,   Chubb  S,   Plunkett  W:   Termination of DNA synthesis by 9-\u03b2-D-arabinofuranosyl-2-fluoroadenine 5\u2032-triphosphate:   A mechanism of toxicity.   J Biol Chem 265:  16617,1990-16625,","DOI":"10.1016\/S0021-9258(17)46267-3"},{"key":"R39-087632","unstructured":"Huang  P,   Chubb  S,   Hertel  LW,  et al:  Actions of 2\u2032,2\u2032-difluorodeoxycytidine on DNA synthesis.   Cancer Res 51:  6110,1991-6117,"},{"key":"R40-087632","unstructured":"Rodriguez  CO Jr,   Gandhi  V:   Arabinosylguanine-induced apoptosis of T-lymphoblastic cells:   Incorporation into DNA is a necessary step.   Cancer Res 59:  4937,1999-4943,"},{"key":"R41-087632","unstructured":"Ono  K,   Ohashi  A,   Yamamoto  A,  et al:  Inhibitory effects of 9-\u03b2-D-arabinofuranosylguanine 5\u2032-triphosphate and 9-\u03b2-D-arabinofuranosyladenine 5\u2032-triphosphate on DNA polymerases from murine cells and oncornavirus.   Cancer Res 39:  4673,1979-4680,"},{"key":"R42-087632","unstructured":"Gandhi  V,   Mineishi  S,   Huang  P,  et al:  Cytotoxicity, metabolism, and mechanisms of action of 2\u2032,2\u2032-difluorodeoxyguanosine in Chinese hamster ovary cells.   Cancer Res 55:  1517,1995-1524,"},{"key":"R43-087632","unstructured":"Gandhi  V,   Mineishi  S,   Huang  P,  et al:  Difluorodeoxyguanosine:   Cytotoxicity, metabolism, and actions on DNA synthesis in human leukemia cells.   Semin Oncol 22:  61,1995-67,"},{"key":"R44-087632","unstructured":"Plunkett  W,   Huang  P,   Gandhi  V:   Metabolism and action of fludarabine.   Semin Oncol 17:  3,1990-17,     (suppl 5)"}],"container-title":["Journal of Clinical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascopubs.org\/doi\/pdfdirect\/10.1200\/JCO.2001.19.8.2142","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,25]],"date-time":"2022-05-25T21:31:32Z","timestamp":1653514292000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascopubs.org\/doi\/10.1200\/JCO.2001.19.8.2142"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2001,4,15]]},"references-count":44,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2001,4,15]]}},"alternative-id":["10.1200\/JCO.2001.19.8.2142"],"URL":"https:\/\/doi.org\/10.1200\/jco.2001.19.8.2142","relation":{},"ISSN":["0732-183X","1527-7755"],"issn-type":[{"value":"0732-183X","type":"print"},{"value":"1527-7755","type":"electronic"}],"subject":[],"published":{"date-parts":[[2001,4,15]]}}}