Elacytarabine: Lipid vector technology under investigation in acute myeloid leukemia

Expert Review of Hematology

Volumn 6, Issue 1, 2013, Pages 9-24

  Keane, Niamh ^a   Freeman, Ciara ^b   Swords, Ronan ^c   Giles, Francis J ^a  

^a NATIONAL UNIVERSITY OF IRELAND   (Ireland)

^b UNIVERSITY COLLEGE LONDON   (United Kingdom)

^c UNIVERSITY OF MIAMI   (United States)

Author keywords

acute myeloid leukemia; CP 4055; elacytarabine; human equilibrative nucleoside receptor; lipid vector technology; resistance

Indexed keywords

BEVACIZUMAB; CETUXIMAB; CYTARABINE; DNA; DOCETAXEL; DRUG CARRIER; ELACYTARABINE; ELAIDIC ACID; GEMCITABINE; GEMCITABINE ELAIDATE; IDARUBICIN; IRINOTECAN; LAROMUSTINE; LIPID; LIPID VECTOR; OXALIPLATIN; RNA; TOPOTECAN; TRASTUZUMAB; UNCLASSIFIED DRUG;

ACUTE GRANULOCYTIC LEUKEMIA; ANTINEOPLASTIC ACTIVITY; ARTICLE; BONE MARROW SUPPRESSION; CANCER CELL CULTURE; CANCER CHEMOTHERAPY; CANCER COMBINATION CHEMOTHERAPY; CANCER PATIENT; CANCER REGRESSION; CANCER RESISTANCE; CANCER SURVIVAL; CELL LEVEL; CHEMICAL COMPOSITION; CONTINUOUS INFUSION; COUGHING; DIARRHEA; DNA SYNTHESIS INHIBITION; DOSE RESPONSE; DRUG BLOOD LEVEL; DRUG CYTOTOXICITY; DRUG DELIVERY SYSTEM; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG ELIMINATION; DRUG HALF LIFE; DRUG INTERMITTENT THERAPY; DRUG MECHANISM; DRUG MEGADOSE; DRUG POTENTIATION; DRUG SAFETY; DRUG UPTAKE; ESTERIFICATION; FEBRILE NEUTROPENIA; HAND FOOT SYNDROME; HUMAN; HYPOKALEMIA; HYPOMAGNESEMIA; INTRACELLULAR TRANSPORT; LEUKEMIA CELL; LIVER FUNCTION TEST; MAXIMUM PLASMA CONCENTRATION; NAUSEA; NONHUMAN; OVERALL SURVIVAL; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROMYELOCYTIC LEUKEMIA; RNA SYNTHESIS; SEPSIS; SIDE EFFECT;

ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; CYTARABINE; DRUG DELIVERY SYSTEMS; DRUG DISCOVERY; HUMANS; LEUKEMIA, MYELOID, ACUTE; MOLECULAR TARGETED THERAPY;

EID: 84873390139     PISSN: 17474086     EISSN: 17474094     Source Type: Journal    
DOI: 10.1586/ehm.12.68     Document Type: Article

References (78)

1. Galmarini CM, Mackey JR, Dumontet C. Nucleoside analogues: mechanisms of drug resistance and reversal strategies. Leukemia 15(6), 875-890 (2001). (Pubitemid 32529886)
2. Brueckner B, Rius M, Markelova MR et al. Delivery of 5-azacytidine to human cancer cells by elaidic acid esterification increases therapeutic drug efficacy. Mol. Cancer Ther. 9(5), 1256-1264 (2010).
3. Galmarini CM, Myhren F, Sandvold ML. CP-4055 and CP-4126 are active in ara-C and gemcitabine-resistant lymphoma cell lines. Br. J. Haematol. 144(2), 273-275 (2009).
4. Bergman AM, Kuiper CM, Myhren F, Sandvold ML, Hendriks HR, Peters GJ. Antiproliferative activity and mechanism of action of fatty acid derivatives of arabinosylcytosine (ara-C) in leukemia and solid tumor cell lines. Nucleosides Nucleotides Nucleic Acids 23(8-9), 1523-1526 (2004). (Pubitemid 39625956)
5. Brueckner B, Rius M, Markelova MR et al. Modulation of cellular uptake and increased therapeutic efficacy of the azacytidine-elaidic acid ester CP-4200 in vitro and in vivo. Cancer Res. 71(8 Suppl.), Abstract 2013 (2011).
6. Bergman AM, Adema AD, Balzarini J et al. Antiproliferative activity, mechanism of action and oral antitumor activity of CP-4126, a fatty acid derivative of gemcitabine, in in vitro and in vivo tumor models. Invest. New Drugs 29(3), 456-466 (2011).
7. Breistøl K, Balzarini J, Sandvold ML et al. Antitumor activity of P-4055 (elaidic acid-cytarabine) compared to cytarabine in metastatic and s.c. human tumor xenograft models. Cancer Res. 59(12), 2944-2949 (1999). (Pubitemid 29283136)
8. Adema A, Smid K, Losekoot N, Myhren F, Sandvold M, Peters G. Fatty acid derivatives of cytarabine and gemcitabine, CP-4055 and CP-4126, show a prolonged cellular retention compared to the parent drug. AACR Annual Meeting. San Diego, CA, USA, 12-16 April 2008 (Abstract 5740).
9. Nilsson B, Hendlisz A, Castella M et al. First-in-human study of a novel nucleoside analogue, CP-4126, in patients with advanced solid tumors. ASCO Meeting Abstracts 27(15S), Abstract 2577 (2009).
10. Adema AD, Smid K, Losekoot N et al. Metabolism and accumulation of the lipophilic deoxynucleoside analogs elacytarabine and CP-4126. Invest. New Drugs 30(5), 1908-1916 (2012).
11. Sandvold ML, Galmarini C, Myhren F, Peters G. The activity of the lipophilic nucleoside derivatives elacytarabine and CP-4126 in a panel of tumor cell lines resistant to nucleoside analogues. Nucleosides Nucleotides Nucleic Acids 29(4-6), 386-393 (2010).
12. Estey EH. General approach to, and perspectives on clinical research in, older patients with newly diagnosed acute myeloid leukemia. Semin. Hematol. 43(2), 89-95 (2006).
13. Thomas X, Dombret H. Timed-sequential chemotherapy as induction and/or consolidation regimen for younger adults with acute myelogenous leukemia. Hematology 12(1), 15-28 (2007). (Pubitemid 46394865)
14. Tsurumi H, Kanemura N, Hara T et al. Therapeutic strategy of untreated de novo acute myeloid leukemia in the elderly: The efficacy of continuous drip infusion with low dose cytarabine and etoposide. J. Cancer Res. Clin. Oncol. 133(8), 547-553 (2007). (Pubitemid 46955683)
15. Cros E, Jordheim L, Dumontet C, Galmarini CM. Problems related to resistance to cytarabine in acute myeloid leukemia. Leuk. Lymphoma 45(6), 1123-1132 (2004). (Pubitemid 38584893)
16. Kufe D, Spriggs D, Egan EM, Munroe D. Relationships among Ara-CTP pools, formation of (Ara-C)DNA, and cytotoxicity of human leukemic cells. Blood 64(1), 54-58 (1984). (Pubitemid 14085726)
17. Estey E, Plunkett W, Dixon D, Keating M, McCredie K, Freireich EJ. Variables predicting response to high dose cytosine arabinoside therapy in patients with refractory acute leukemia. Leukemia 1(8), 580-583 (1987). (Pubitemid 18005688)
18. Cai J, Damaraju VL, Groulx N et al. Two distinct molecular mechanisms underlying cytarabine resistance in human leukemic cells. Cancer Res. 68(7), 2349-2357 (2008). (Pubitemid 351521809)
19. Pastor-Anglada M, Cano-Soldado P, Molina-Arcas M et al. Cell entry and export of nucleoside analogues. Virus Res. 107(2), 151-164 (2005). (Pubitemid 40093088)
20. Weinstein HJ, Griffin TW, Feeney J, Cohen HJ, Propper RD, Sallan SE. Pharmacokinetics of continuous intravenous and subcutaneous infusions of cytosine arabinoside. Blood 59(6), 1351-1353 (1982). (Pubitemid 12074870)
21. Ho DH, Frei E 3rd. Clinical pharmacology of 1-beta-d-arabinofuranosyl cytosine. Clin. Pharmacol. Ther. 12(6), 944-954 (1971).
22. Capizzi RL, Yang JL, Cheng E et al. Alteration of the pharmacokinetics of high-dose ara-C by its metabolite, high ara-U in patients with acute leukemia. J. Clin. Oncol. 1(12), 763-771 (1983). (Pubitemid 14167250)
23. Löwenberg B, Pabst T, Vellenga E et al.; Dutch-Belgian Cooperative Trial Group for HematoYOncology (HOVON) and Swiss Group for Clinical Cancer Research (SAKK) Collaborative Group. Cytarabine dose for acute myeloid leukemia. N. Engl. J. Med. 364(11), 1027-1036 (2011).
24. Mayer RJ, Davis RB, Schiffer CA et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N. Engl. J. Med. 331(14), 896-903 (1994). (Pubitemid 24299870)
25. Bishop JF, Matthews JP, Young GA et al. A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood 87(5), 1710-1717 (1996). (Pubitemid 26068888)
26. Hubeek I, Peters GJ, Broekhuizen R et al. In vitro sensitivity and cross-resistance to deoxynucleoside analogs in childhood acute leukemia. Haematologica 91(1), 17-23 (2006). (Pubitemid 43235381)
27. Lamba JK. Genetic factors influencing cytarabine therapy. Pharmacogenomics 10(10), 1657-1674 (2009).
28. Kufe DW, Major PP, Egan EM, Beardsley GP. Correlation of cytotoxicity with incorporation of ara-C into DNA. J. Biol. Chem. 255(19), 8997-8900 (1980).
29. Grant S. Ara-C: cellular and molecular pharmacology. Adv. Cancer Res. 72, 197-233 (1998). (Pubitemid 27435556)
30. Baker WJ, Royer GL Jr, Weiss RB. Cytarabine and neurologic toxicity. J. Clin. Oncol. 9 4), 679 693 (1991).
31. Mitra AK, Crews KR, Pounds S et al. Genetic variants in cytosolic 5′-nucleotidase II are associated with its expression and cytarabine sensitivity in HapMap cell lines and in patients with acute myeloid leukemia. J. Pharmacol. Exp. Ther. 339(1), 9-23 (2011).
32. Clarke ML, Mackey JR, Baldwin SA, Young JD, Cass CE. The role of membrane transporters in cellular resistance to anticancer nucleoside drugs. Cancer Treat. Res. 112, 27-47 (2002).
33. Takagaki K, Katsuma S, Kaminishi Y et al. Gene-expression profiling reveals down-regulation of equilibrative nucleoside transporter 1 (ENT1) in Ara-C-resistant CCRF-CEM-derived cells. J. Biochem. 136(5), 733-740 (2004). (Pubitemid 40364197)
34. Hubeek I, Stam RW, Peters GJ et al. The human equilibrative nucleoside transporter 1 mediates in vitro cytarabine sensitivity in childhood acute myeloid leukaemia. Br. J. Cancer 93(12), 1388-1394 (2005). (Pubitemid 41752866)
35. Galmarini CM, Thomas X, Calvo F et al. In vivo mechanisms of resistance to cytarabine in acute myeloid leukaemia. Br. J. Haematol. 117(4), 860-868 (2002). (Pubitemid 34639247)
36. Galmarini CM, Thomas X, Calvo F et al. Potential mechanisms of resistance to cytarabine in AML patients. Leuk. Res. 26(7), 621-629 (2002). (Pubitemid 34465699)
37. Gati WP, Paterson AR, Belch AR et al. Es nucleoside transporter content of acute leukemia cells: role in cell sensitivity to cytarabine (araC). Leuk. Lymphoma 32(1-2), 45-54 (1998). (Pubitemid 29086382)
38. Jin G, Matsushita H, Asai S et al. FLT3-ITD induces ara-C resistance in myeloid leukemic cells through the repression of the ENT1 expression. Biochem. Biophys. Res. Commun. 390(3), 1001-1006 (2009).
39. Verhoef V, Sarup J, Fridland A. Identification of the mechanism of activation of 9-β-d-arabinofuranosyladenine in human lymphoid cells using mutants deficient in nucleoside kinases. Cancer Res. 41(11 Pt 1), 4478-4483 (1981). (Pubitemid 12201361)
40. Bhalla K, Nayak R, Grant S. Isolation and characterization of a deoxycytidine kinase-deficient human promyelocytic leukemic cell line highly resistant to 1-β-d-arabinofuranosylcytosine. Cancer Res. 44(11), 5029-5037 (1984). (Pubitemid 15204459)
41. Stegmann AP, Honders WH, Willemze R, Ruiz van Haperen VW, Landegent JE. Transfection of wild-type deoxycytidine kinase (dck) cDNA into an AraC- and DAC-resistant rat leukemic cell line of clonal origin fully restores drug sensitivity. Blood 85(5), 1188-1194 (1995).
42. Abraham A, Varatharajan S, Jayavelu AK et al. Expression of Ara-C metabolizing enzymes mediates in vitro sensitivity to Ara-C in primary AML cells from patients with denovo AML. ASH Annual Meeting Abstracts 118(21), Abstract 3481 (2011).
43. Dumontet C, Fabianowska-Majewska K, Mantincic D et al. Common resistance mechanisms to deoxynucleoside analogues in variants of the human erythroleukaemic line K562. Br. J. Haematol. 106(1), 78-85 (1999). (Pubitemid 29343530)
44. Yamauchi T, Negoro E, Kishi S et al. Intracellular cytarabine triphosphate production correlates to deoxycytidine kinase/cytosolic 5′-nucleotidase II expression ratio in primary acute myeloid leukemia cells. Biochem. Pharmacol. 77(12), 1780-1786 (2009).
45. Galmarini CM. What does over-expression of cN-II enzyme signify in haematological malignancies? Leuk. Res. 31(10), 1325-1326 (2007). (Pubitemid 47212429)
46. Galmarini CM, Cros E, Thomas X, Jordheim L, Dumontet C. The prognostic value of cN-II and cN-III enzymes in adult acute myeloid leukemia. Haematologica 90(12), 1699-1701 (2005). (Pubitemid 41814998)
47. Abraham A, Varatharajan S, Abbas S et al. Cytidine deaminase genetic variants influence RNA expression and cytarabine cytotoxicity in acute myeloid leukemia. Pharmacogenomics 13(3), 269-282 (2012).
48. Tang J, Xie X, Zhang X et al. Long term cultured HL-60 cells are intrinsically resistant to Ara-C through high CDA activity. Front. Biosci. 17, 569-574 (2012).
49. Schröder JK, Kirch C, Seeber S, Schütte J. Structural and functional analysis of the cytidine deaminase gene in patients with acute myeloid leukaemia. Br. J. Haematol. 103(4), 1096-1103 (1998). (Pubitemid 29012650)
50. Peters GJ, Voorn DA, Kuiper CM et al. Cell specific cytotoxicity and structureactivity relationship (SAR) of lipophilic 1-B-d- arabinofuranosylcytosine (ARA-C) derivatives. Nucleosides Nucleotides 18(4-5), 877-878 (1998). (Pubitemid 29320619)
51. Wiley JS, Jones SP, Sawyer WH, Paterson AR. Cytosine arabinoside influx and nucleoside transport sites in acute leukemia. J. Clin. Invest. 69(2), 479-489 (1982). (Pubitemid 12177627)
52. Rizzieri D, Vey N, Gobbi M et al. A randomized Phase III study of elacytarabine versus limited investigator's choice in patients with refractory acute myeloid leukemia (AML). ASCO Meeting Abstracts 29(15 Suppl.), Abstract TPS206 (2011).
53. Rizzieri DA, Vey N, Schlenk RF et al. A Phase II study of elacytarabine/idarubicin as second course remission-induction in patients with acute myeloid leukemia who failed cytarabine/anthracycline, and evaluation of the impact of the nucleoside transporter hENT1 on response. ASH Annual Meeting Abstracts 118(21), Abstract 1533 (2011).
54. Bergman AM, Kuiper CM, Voorn DA et al. Antiproliferative activity and mechanism of action of fatty acid derivatives of arabinofuranosylcytosine in leukemia and solid tumor cell lines. Biochem. Pharmacol. 67(3), 503-511 (2004). (Pubitemid 38232890)
55. Adema AD, Losekoot N, Smid K et al. Induction of resistance to the lipophilic cytarabine prodrug elacytarabine (CP-4055) in CEM leukemic cells. Nucleosides Nucleotides Nucleic Acids 29(4-6), 394-399 (2010).
56. Noordhuis P, Kazemier KM, Kasperrs GJ, Peters GJ. Modulation of metabolism and cytotoxicity of cytosine arabinoside with N-(phosphon)-acetyl-l- aspartate in human leukemic blast cells and cell lines. Leuk. Res. 20(2), 127-134 (1996). (Pubitemid 26107311)
57. Braess J, Voss S, Jahns-Streubel G et al. The pharmacodynamic basis for the increased antileukaemic efficacy of cytosine arabinoside-based treatment regimens in acute myeloid leukaemia with a high proliferative activity. Br. J. Haematol. 110(1), 170-179 (2000). (Pubitemid 30625604)
58. Braess J, Wegendt C, Jahns-Streubel G et al. Successful modulation of high-dose cytosine arabinoside metabolism in acute myeloid leukaemia by haematopoietic growth factors: no effect of ribonucleotide reductase inhibitors fludarabine and gemcitabine. Br. J. Haematol. 109(2), 388-395 (2000). (Pubitemid 30350723)
59. Plunkett W, Gandhi V. Cellular pharmacodynamics of anticancer drugs. Semin. Oncol. 20(1), 50-63 (1993). (Pubitemid 23082218)
60. Adema AD, Laan AC, Myhren F et al. Cell cycle effects of fatty acid derivatives of cytarabine, CP-4055, and of gemcitabine, CP-4126, as basis for the interaction with oxaliplatin and docetaxel. Int. J. Oncol. 36(1), 285-294 (2010).
61. Giles F, Rizzieri D, Ravandi F, Swords R, Jacobsen TF, O'Brien S. Elacytarabine, a novel 5-elaidic acid derivative of cytarabine, and idarubicin combination is active in refractory acute myeloid leukemia. Leuk. Res. 36(4), e71-e73 (2012).
62. Giles FJ, Vey N, Rizzieri D et al. Phase I and pharmacokinetic study of elacytarabine, a novel 5′-elaidic acid derivative of cytarabine, in adults with refractory hematological malignancies. Leukemia 26(7), 1686-1689 (2012).
63. O'Brien S, Kantarjian H, Ravandi F et al. A Phase I dose finding study with CP-4055 (ELACYT) plus idarubicin in patients with relapsed/refractory AML. AACR Meeting Abstracts. Abstract 4589 (2009).
64. Raymond E, Dueland S, Lind MJ et al. Pharmacokinetics of a nucleoside analogue CP-4055 in two Phase I trials using a daily for 5 days schedule and three intermittent weekly or biweekly schedules. AACR Meeting Abstracts 1, Abstract 936 (2005).
65. O'Brien SM, Vey N, Rizzieri DA et al. A Phase I study with CP-4055 in patients with hematologic malignancies. ASCO Meeting Abstracts 26(15 Suppl.), Abstract 2532 (2008).
66. Adams DJ, Sandvold ML, Myhren F, Jacobsen TF, Giles F, Rizzieri DA. Anti proliferative activity of ELACY (CP-4055) in combination with cloretazine (VNP40101M), idarubicin, gemcitabine, irinotecan and topotecan in human leukemia and lymphoma cells. Leuk. Lymphoma 49(4), 786-797 (2008). (Pubitemid 351517226)
67. Bruheim S, Malandsmo GM, Sandvold ML, Myhren F, Fodstad O. Antitumor activity of CP-4055 is enhanced in combination with bevacizumab, cetuximab, and trastuzumab in human NSCLC xenografts. AACR Meeting Abstracts 3, Abstract B287 (2007).
68. O'Brien S, Rizzieri DA, Vey N et al. Elacytarabine has single-agent activity in patients with advanced acute myeloid leukaemia. Br. J. Haematol. 158(5), 581-588 (2012).
69. Rizzieri D, Krug U, Schlenk RF et al. A Phase II study of elacytarabine plus idarubicin as second course remissioninduction therapy in patients with acute myeloid leukemia. ASCO Meeting Abstracts 29(15 Suppl.), Abstract TPS207 (2011).
70. Döhner H, Estey EH, Amadori S et al.; European LeukemiaNet. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 115(3), 453-474 (2010).
71. Roboz GJ. Novel approaches to the treatment of acute myeloid leukemia. Hematology Am. Soc. Hematol. Educ. Program 2011, 43-50 (2011).
72. Yee KW, Keating A. Older patients with acute myeloid leukemia. Expert Rev. Hematol. 3(6), 755-774 (2010).
73. Juliusson G, Antunovic P, Derolf A et al. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood 113(18), 4179-4187 (2009).
74. Baz R, Rodriguez C, Fu AZ et al. Impact of remission induction chemotherapy on survival in older adults with acute myeloid leukemia. Cancer 110(8), 1752-1759 (2007). (Pubitemid 47557300)
75. Odenike O, Thirman MJ, Artz AS, Godley LA, Larson RA, Stock W. Gene mutations, epigenetic dysregulation, and personalized therapy in myeloid neoplasia: Are we there yet? Semin. Oncol. 38(2), 196-214 (2011).
76. LoRusso PM, Schnipper LE, Stewart DJ, Boerner SA, Averbuch SD, Wolf W. Translating clinical trials into meaningful outcomes. Clin. Cancer Res. 16(24), 5951-5955 (2010).
77. Fojo T, Parkinson DR. Biologically targeted cancer therapy and marginal benefits: Are we making too much of too little or are we achieving too little by giving too much? Clin. Cancer Res. 16(24), 5972-5980 (2010).
78. Adema AD, Bijnsdorp IV, Sandvold ML, Verheul HM, Peters GJ. Innovations and opportunities to improve conventional (deoxy)nucleoside and fluoropyrimidine analogs in cancer. Curr. Med. Chem. 16(35), 4632-4643 (2009).