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The Role of Membrane Transporters in Cellular Resistance to Anticancer Nucleoside Drugs

  • Marilyn L. Clarke
  • John R. Mackey
  • Stephen A. Baldwin
  • James D. Young
  • Carol E. Cass
Part of the Cancer Treatment and Research book series (CTAR, volume 112)

Abstract

Physiologic nucleosides and most therapeutic nucleoside analogs do not readily cross plasma membranes by passive diffusion due to their low solubility in lipid bilayers, and their cellular uptake is mediated by integral membrane proteins. Nucleoside transporters serve as the cellular entry point for nucleoside salvage pathways. Some cell types use these pathways exclusively because they lack the ability to synthesize purine and pyrimidine nucleotides. Other cell types use salvage pathways in addition to their de novo synthesis pathways. Nucleotides are key activated intermediates for many essential cellular biosynthetic pathways, including the synthesis of DNA and RNA

Keywords

Nucleoside Analog Purine Nucleoside Nucleoside Transporter Pyrimidine Nucleoside Deoxycytidine Kinase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Saier MH. A functional-phylogenetic classification system for transmembrane solute transporters. Microbiol Mol Biol Rev, 64:354–411, 2000.PubMedCrossRefGoogle Scholar
  2. 2.
    Ritzel MWL, Ng AML, Yao SYM, et al. Molecular identification and characterization of novel human and mouse concentrative Natnucleoside cotransporter proteins (hCNT3 and mCNT3) broadly selective for purine and pyrimidine nucleosides (System cib). J Biol Chem, 276:2914–2927, 2001.PubMedCrossRefGoogle Scholar
  3. 3.
    Vickers MF, Young JD, Baldwin SA, et al. Nucleoside transporter proteins: emerging targets for drug discovery. Emerging Therapeutic Targets, 4:515–539, 2000.CrossRefGoogle Scholar
  4. 4.
    Griffiths M, Beaumont N, Yao SY, et al. Cloning of a human nucleoside transporter implicated in the cellular uptake of adenosine and chemotherapeutic drugs. Nature Med, 3:89–93, 1997.PubMedCrossRefGoogle Scholar
  5. 5.
    Ritzel MWL, Yao SYM, Huang MY, et al. Molecular cloning and functional expression of cDNAs encoding a human Na+-nucleoside cotransporter (hCNT1). Amer J Physiol, 272:C707–C714, 1997.PubMedGoogle Scholar
  6. 6.
    Crawford CR, Patel DH, Naeve C, Belt JA. Cloning of the human equilibrative, nitrobenzylmercaptopurine riboside (NBMPR)-insensitive nucleoside transporter ei by functional expression in a transport-deficient cell line. J Biol Chem, 273:5288–5293, 1998.PubMedCrossRefGoogle Scholar
  7. 7.
    Griffiths M, Yao SYM, Abidi F, et al. Molecular cloning and characterization of a nitrobenzylthioinosine-insensitive (ei) equilibrative nucleoside transporter from human placenta. Biochem J, 328:739–743, 1997.PubMedGoogle Scholar
  8. 8.
    Wang J, Su S-F, Dresser MJ, et al. Na+-dependent purine nucleoside transporter from human kidney: cloning and functional characterization. Amer J Physiol, 273:F1058–F1065, 1997.PubMedGoogle Scholar
  9. 9.
    Ritzel MW, Yao SY, Ng AM, et al. Molecular cloning, functional expression and chromosomal localization of a cDNA encoding a human Na+/nucleoside cotransporter (hCNT2) selective for purine nucleosides and uridine. Mol Membr Biol, 15:203–211, 1998.PubMedCrossRefGoogle Scholar
  10. 10.
    Cass CE. Nucleoside transport. In: Drug Transport in Antimicrobial Therapy and Anticancer Therapy. NH Georgopapadakou (ed.), Marcel Dekker, New York, NY, 1995.Google Scholar
  11. 11.
    Griffith DA, Jarvis SM. Nucleoside and nucleobase transport systems of mammalian cells. Biochim Biophys Acta, 1286:153–181, 1996.PubMedCrossRefGoogle Scholar
  12. 12.
    Buolamwini JK. Nucleoside transport inhibitors: Structure-activity relationships and potential therapeutic applications. Curr Med Chem, 4:35–66, 1997.Google Scholar
  13. 13.
    Wang J, Schaner ME, Thomassen S, et al. Functional and molecular characteristics of Na(+)-dependent nucleoside transporters. Pharm Res, 14:1524–1532, 1997.PubMedCrossRefGoogle Scholar
  14. 14.
    Che M, Gatmaitan Z, Arias IM. Ectonucleotidases, purine nucleoside transporter, and function of the bile canalicular plasma membrane of the hepatocyte. FASEB J, 11:101–108, 1997.PubMedGoogle Scholar
  15. 15.
    Thorn JA, Jarvis SM. Adenosine transporters. Gen Pharmacol, 27:613–620, 1996.PubMedCrossRefGoogle Scholar
  16. 16.
    Sundaram M, Yao SY, Ng AM, et al. Chimeric constructs between human and rat equilibrative nucleoside transporters (hENTI and rENT1) reveal hENTI structural domains interacting with coronary vasoactive drugs. J Biol Chem, 273:21519–21525, 1998.PubMedCrossRefGoogle Scholar
  17. 17.
    Baldwin SA, Mackey JR, Cass CE, Young JD. Nucleoside transporters: molecular biology and implications for therapeutic development. Mol Med Today, 5:216–224, 1999.PubMedCrossRefGoogle Scholar
  18. 18.
    Osses N, Pearson JD, Yudilevich DL, Jarvis SM. Hypoxanthine enters human vascular endothelial cells (ECV 304) via the nitrobenzylthioinosine-insensitive equilibrative nucleoside transporter. Biochem J, 317:843–848, 1996.PubMedGoogle Scholar
  19. 19.
    Tattersall MH, Slowiaczek P, De Fazio A. Regional variation in human extracellular purine levels. J Lab Clin Med, 102:411–420, 1983.PubMedGoogle Scholar
  20. 20.
    Vickers MF, Mani RS, Sundaram M, et al. Functional production and reconstitution of the human equilibrative nucleoside transporter (hENTI) in Saccharomyces cerevisiae. Interaction of inhibitors of nucleoside transport with recombinant hENTI and a glycosylation-defective derivative (hENT I/N48Q). Biochem J, 339:21–32, 1999.PubMedCrossRefGoogle Scholar
  21. 21.
    Kwong FY, Wu JS, Shi MM, et al. Enzymic cleavage as a probe of the molecular structures of mammalian equilibrative nucleoside transporters. J Biol Chem, 268:22127–22134, 1993.PubMedGoogle Scholar
  22. 22.
    Coe IR, Griffiths M, Young JD, et al. Assignment of the human equilibrative nucleoside transporter (hENT1) to 6p21.1-p21.2. Genomics, 45:459–460, 1997.PubMedCrossRefGoogle Scholar
  23. 23.
    Yao SY, Ng AM, Muzyka WR, et al. Molecular cloning and functional characterization of nitrobenzylthioinosine (NBMPR)-sensitive (es) and NBMPR-insensitive (ei) equilibrative nucleoside transporter proteins (rENT1 and rENT2) from rat tissues. J Biol Chem, 272:28423–28430, 1997.PubMedCrossRefGoogle Scholar
  24. 24.
    Boleti H, Coe IR, Baldwin SA, et al. Molecular identification of the equilibrative NBMPR-sensitive (es) nucleoside transporter and demonstration of an equilibrative NBMPR-insensitive (ei) transport activity in human erythroleukemia (K562) cells. Neuropharmacol, 36:1167–1179, 1997.CrossRefGoogle Scholar
  25. 25.
    Ward JL, Sherali A, Mo ZP, Tse CM. Kinetic and pharmacological properties of cloned human equilibrative nucleoside transporters, ENT1 and ENT2, stably expressed in nucleoside transporter-deficient PK15 cells. ENT2 exhibits a low affinity for guanosine and cytidine but a high affinity for inosine. J Biol Chem, 275:8375–8381, 2000.PubMedCrossRefGoogle Scholar
  26. 26.
    Hyde RJ, Cass CE, Young JD, Baldwin SA. The ENT family of eukaryote nucleoside transporters: recent advances in the investigation of structure/function relationships and the identification of novel isoforms. Mol Membr Biol, 18:53–63, 2001.PubMedCrossRefGoogle Scholar
  27. 27.
    Hamilton SR, Yao SYM, Ingram JC, et al. Sub-cellular distribution and membrane topology of the rat concentrative Natnucleoside co-transporter rCNT1. J Biol Chem, 276:27981–27988, 2001.PubMedCrossRefGoogle Scholar
  28. 28.
    Loewen SK, Ng AM, Yao SY, et al. Identification of amino acid residues responsible for the pyrimidine and purine nucleoside specificities of human concentrative Na(+) nucleoside cotransporters hCNTI and hCNT2. J Biol Chem, 274:24475–24484, 1999.PubMedCrossRefGoogle Scholar
  29. 29.
    Soler C, Felipe A, Mata JF, et al. Regulation of nucleoside transport by lipopolysaccharide, phorbol esters, and tumour necrosis factor-a in human Blymphocytes. J Biol Chem, 273:26939–26945, 1998.PubMedCrossRefGoogle Scholar
  30. 30.
    Kichenin K, Pignede G, Fudelej F, Seman M. CD3 activation induces concentrative nucleoside transport in human T lymphocytes. Eur J Immunol, 30:366–370, 2000.PubMedCrossRefGoogle Scholar
  31. 31.
    Vijayalakshmi D, Belt JA. Sodium-dependent nucleoside transport in mouse intestinal epithelial cells. Two transport systems with differing substrate specificities. J Biol Chem, 263:19419–19423, 1988.PubMedGoogle Scholar
  32. 32.
    Huang QQ, Yao SY, Ritzel MW, et al. Cloning and functional expression of a complementary DNA encoding a mammalian nucleoside transport protein. J Biol Chem, 269:17757–17760, 1994.PubMedGoogle Scholar
  33. 33.
    Huang QQ, Harvey CM, Paterson AR, et al. Functional expression of Na(+)-dependent nucleoside transport systems of rat intestine in isolated oocytes of Xenopus laevis. Demonstration that rat jejunum expresses the purine-selective system NI (cif) and a second, novel system N3 having broad specificity for purine and pyrimidine nucleosides. J Biol Chem, 268:20613–20619, 1993.PubMedGoogle Scholar
  34. 34.
    Yao SY, Cass CE, Young JD. Transport of the antiviral nucleoside analogs 3’-azido-3’- deoxythymidine and 2’,3’-dideoxycytidine by a recombinant nucleoside transporter (rCNT) expressed in Xenopus laevis oocytes. Mol Pharmacol, 50:388–393, 1996.PubMedGoogle Scholar
  35. 35.
    Fang X, Parkinson FE, Mowles DA, et al. Functional characterization of a recombinant sodium-dependent nucleoside transporter with selectivity for pyrimidine nucleosides (cNTlrat) by transient expression in cultured mammalian cells. Biochem J, 317:457–465, 1996.PubMedGoogle Scholar
  36. 36.
    Crawford CR, Cass CE, Young JD, Belt JA. Stable expression of a recombinant sodium-dependent, pyrimidine-selective nucleoside transporter (CNT1) in a transport-deficient mouse leukemia cell line. Biochem Cell Biol, 76:843–851, 1998.PubMedCrossRefGoogle Scholar
  37. 37.
    Mackey JR, Mani RS, Selner M, et al. Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. Cancer Res, 58:4349–4357, 1998.PubMedGoogle Scholar
  38. 38.
    Mackey JR, Yao SY, Smith KM, et al. Gemcitabine transport in xenopus oocytes expressing recombinant plasma membrane mammalian nucleoside transporters. J Natl Cancer Inst, 91:1876–1881, 1999.PubMedCrossRefGoogle Scholar
  39. 39.
    Graham KA, Leithoff J, Coe IR, et al. Differential transport of cytosine-containing nucleosides by recombinant human concentrative nucleoside transporter protein hCNT1. Nucleosides Nucleotides Nucleic Acids, 19:415–434, 2000.PubMedCrossRefGoogle Scholar
  40. 40.
    Dresser MJ, Gerstin KM, Gray AT, et al. Electrophysiological analysis of the substrate selectivity of a sodium-coupled nucleoside transporter (rCNT1) expressed in Xenopus laevis oocytes. Drug Metabolism and Disposition, 28:1135–1140, 2000.PubMedGoogle Scholar
  41. 41.
    Che M, Ortiz DF, Arias IM. Primary structure and functional expression of a cDNA encoding the bile canalicular, purine-specific Na+-nucleoside cotransporter. J Biol Chem, 270:13596–13599, 1995.PubMedCrossRefGoogle Scholar
  42. 42.
    Yao SY, Ng AM, Ritzel MW, et al. Transport of adenosine by recombinant purine-and pyrimidine-selective sodium/nucleoside cotransporters from rat jejunum expressed in Xenopus laevis oocytes. Mol Pharmacol, 50:1529–1535, 1996.PubMedGoogle Scholar
  43. 43.
    Roovers KI, Meckling-Gill KA. Characterization of equilibrative and concentrative Na+- dependent (cif) nucleoside transport in acute promyelocytic leukemia NB4 cells. J Cell Physiol, 166:593–600, 1996.PubMedCrossRefGoogle Scholar
  44. 44.
    Belt JA, Harper EH, Byl JA, Noel LD. Sodium-dependent nucleoside transport in human myeloid leukemic cell lines and freshly isolated myeloblasts. Proc Amer Assoc Cancer Res, 33:20, 1992.Google Scholar
  45. 45.
    Belt JA, Marina NM, Phelps DA, Crawford CR. Nucleoside transport in normal and neoplastic cells. Adv Enzyme Regul, 33:235–252, 1993.PubMedCrossRefGoogle Scholar
  46. 46.
    Flanagan SA, Mecklinggill KA. Characterization of a novel Na+ dependent, guanosine specific, nitrobenzylthioinosine sensitive transporter in acute promyelocytic leukemia cells. J Biol Chem, 272:18026–18032, 1997.PubMedCrossRefGoogle Scholar
  47. 47.
    Paterson AR, Gati WP, Vijayalakshmi D, et al. Inhibitor-sensitive, Na(+)-linked transport of nucleoside analogs in leukemia cells from patients. Proc Amer Assoc Cancer Res, 34:A84, 1993.Google Scholar
  48. 48.
    Wiley JS, Cebon JS, Jamieson GP, et al. Assessment of proliferative responses to granulocyte-macrophage colony-stimulating factor (GM-CSF) in acute myeloid leukaemia using a fluorescent ligand for the nucleoside transporter. Leukemia, 8:181–185, 1994.PubMedGoogle Scholar
  49. 49.
    Smith CL, Pilarski LM, Egerton ML, Wiley JS. Nucleoside transport and proliferative rate in human thymocytes and lymphocytes. Blood, 74:2038–2042, 1989.PubMedGoogle Scholar
  50. 50.
    Wiley JS, Snook MB, Jamieson GP. Nucleoside transport in acute leukaemia and lymphoma: close relation to proliferative rate. Br J Haematol, 71:203–207, 1989.PubMedCrossRefGoogle Scholar
  51. 51.
    Mackey JR, Jennings LL, Clarke ML, et al. Immunohistochemical variation of human equilibrative nucleoside transporter 1 (hENT1) protein in primary breast cancers. Clin Cancer Res, 1:110–116, 2002.Google Scholar
  52. 52.
    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, 32:45–54, 1998.PubMedGoogle Scholar
  53. 53.
    Wright AM, Gati WP, Paterson AR. Enhancement of retention and cytotoxicity of 2- chlorodeoxyadenosine in cultured human leukemic lymphoblasts by nitrobenzylthioinosine, an inhibitor of equilibrative nucleoside transport. Leukemia, 14:52–60, 2000.PubMedCrossRefGoogle Scholar
  54. 54.
    Chen R, Nelson JA. Role of organic cation transporters in the renal secretion of nucleosides. Biochem Pharmacol, 60:215–219, 2000.PubMedCrossRefGoogle Scholar
  55. 55.
    Cohen A, Ullman B, Martin DW, Jr. Characterization of a mutant mouse lymphoma cell with deficient transport of purine and pyrimidine nucleosides. J Biol Chem, 254:112–116, 1979.PubMedGoogle Scholar
  56. 56.
    Cass CE, Kolassa N, Uehara Y, et al. Absence of binding sites for the transport inhibitor nitrobenzylthioinosine on nucleoside transport-deficient mouse lymphoma cells. Biochim Biophys Acta, 649:769–777, 1981.PubMedCrossRefGoogle Scholar
  57. 57.
    Ullman B, Coons T, Rockwell S, McCartan K. Genetic analysis of 2’,3’-dideoxycytidine incorporation into cultured human T lymphoblasts. J Biol Chem, 263:12391–12396, 1988.PubMedGoogle Scholar
  58. 58.
    Ullman B. Dideoxycytidine metabolism in wild type and mutant CEM cells deficient in nucleoside transport or deoxycytidine kinase. Adv Exp Med Biol, 253B:415–420, 1989.PubMedCrossRefGoogle Scholar
  59. 59.
    Hoffman J. Murine erythroleukemia cells resistant to periodate-oxidized adenosine have lowered levels of nucleoside transporter. Adv Exp Med Biol, 309A:443–446, 1991.PubMedGoogle Scholar
  60. 60.
    Sobrero AF, Handschumacher RE, Bertino JR. Highly selective drug combinations for human colon cancer cells resistant in vitro to 5-fluoro-2’-deoxyuridine. Cancer Res, 45:3161–3163, 1985.PubMedGoogle Scholar
  61. 61.
    Ellison RR, Holland JF, Weil M, et al. Arabinosyl cytosine: a useful agent in the treatment of acute leukemia in adults. Blood, 32:507–523, 1968.PubMedGoogle Scholar
  62. 62.
    Solimando DA, Bressler LR, Kintzel PE, Geraci M. Drug Information Handbook for Oncology. Lexi-Comp Inc., Hudson (Cleveland), Ohio, 1999.Google Scholar
  63. 63.
    Allegra CJ, Grem JL. Antimetabolites. In: Cancer: Principles and Practice of Oncology. 5th edition, VT DeVita Jr (ed.), Lippincott-Raven, Philadelphia, PA, 1997.Google Scholar
  64. 64.
    Skeel RT. Handbook of Cancer Chemotherapy, 5th edition, Lippincott Williams and Wilkins, New York, NY, 1999.Google Scholar
  65. 65.
    Wiley JS, Jones SP, Sawyer WH. Cytosine arabinoside transport by human leukaemic cells. Eur J Cancer Clin Oncol, 19:1067–1074, 1983.PubMedCrossRefGoogle Scholar
  66. 66.
    Yoshida S, Yamada M, Masaki S. Inhibition of DNA polymerase a and r3 of calf thymus by 1–13-D-arabinofuranosylcytosine 5’ triphosphate. Biochim Biophys Acta, 477:144–150, 1977.PubMedCrossRefGoogle Scholar
  67. 67.
    Dijkwel PA, Wanka F. Enhanced release of nascent single strands from DNA synthesized in the presence of arabinosylcytosine. Biochim Biophys Acta, 520:461–471, 1978.PubMedCrossRefGoogle Scholar
  68. 68.
    Gunji H, Kharbanda S, Kufe D. Induction of internucleosomal DNA fragmentation in human myeloid leukemia cells by 1–0-D-arabinofuranosylcytosine. Cancer Res, 51:741–743, 1991.PubMedGoogle Scholar
  69. 69.
    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, 64:54–58, 1984.PubMedGoogle Scholar
  70. 70.
    Rustum YM, Preisler HD. Correlation between leukemic cell retention of l-ß-Darabinofuranosylcytosine 5’-triphosphate and response to therapy. Cancer Res, 39:42–49, 1979.PubMedGoogle Scholar
  71. 71.
    Ho DHW, Frei E. Clinical pharmacology of 1–13-D-arabinofuranosyl cytosine. Clin Pharmacol Ther, 12:944–954, 1971.PubMedGoogle Scholar
  72. 72.
    Wiley JS, Jones SP, Sawyer WH, Paterson AR. Cytosine arabinoside influx and nucleoside transport sites in acute leukemia. J Clin Invest, 69:479–489, 1982.PubMedCrossRefGoogle Scholar
  73. 73.
    Wiley JS, Woodruff RK, Jamieson GP, et al. Cytosine arabinoside in the treatment of Tcell acute lymphoblastic leukemia. Aust N Z J Med, 7;17:379–386, 1987.Google Scholar
  74. 74.
    Wiley JS, Taupin J, Jamieson GP, et al. Cytosine arabinoside transport and metabolism in acute leukemias and T cell lymphoblastic lymphoma. J Clin Invest, 75:632–642, 1985.PubMedCrossRefGoogle Scholar
  75. 75.
    Gati WP, Paterson AR, Larratt LM, et al. Sensitivity of acute leukemia cells to cytarabine is a correlate of cellular es nucleoside transporter site content measured by flow cytometry with SAENTA-fluorescein. Blood, 90:346–353, 1997.PubMedGoogle Scholar
  76. 76.
    White JC, Rathmell JP, Capizzi RL. Membrane transport influences the rate of accumulation of cytosine arabinoside in human leukemia cells. J Clin Invest, 79:380–387, 1987.PubMedCrossRefGoogle Scholar
  77. 77.
    Jamieson GP, Snook MB, Wiley JS. Saturation of intracellular cytosine arabinoside triphosphate accumulation in human leukemic blast cells. Leuk Res, 14:475–479, 1990.PubMedCrossRefGoogle Scholar
  78. 78.
    Capizzi RL, Yang JL, Cheng E, et al. Alteration of the pharmacokinetics of high-dose araC by its metabolite, high ara-U in patients with acute leukemia. J Clin Oncol, 1:763–771, 1983.PubMedGoogle Scholar
  79. 79.
    Bishop JF, Matthews JP, Young GA, et al. A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood, 87:1710–1717, 1996.PubMedGoogle Scholar
  80. 80.
    Weick JK, Kopecky KJ, Appelbaum FR, et al. A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood, 88:2841–2851, 1996.PubMedGoogle Scholar
  81. 81.
    Greyer MR, Kopecky KJ, Coltman CA, et al. Fludarabine monophosphate: a potentially useful agent in chronic lymphocytic leukemia. Nouv Rev Fr Hematol, 30:457–459, 1988.Google Scholar
  82. 82.
    Cheson BD. New prospects in the treatment of indolent lymphomas with purine analogues. Cancer J, 4:S27–S36, 1998.Google Scholar
  83. 83.
    Leiby JM, Snider KM, Kraut EH, et al. Phase II trial of 9–13-D-arabinofuranosy1–2- fluoroadenine 5’-monophosphate in non-Hodgkin’s lymphoma: prospective comparison of response with deoxvcvtidine kinase activity. Cancer Res, 47:2719–2722. 1987.PubMedGoogle Scholar
  84. 84.
    Plunkett W, Saunders PP. Metabolism and action of purine nucleoside analogs. Pharmacol Ther, 49:239–268, 1991.PubMedCrossRefGoogle Scholar
  85. 85.
    Cheson BD. Miscellaneous chemotherapeutic agents. In: Cancer: Principles and Practice of Oncology, 5th edition, VT DeVita Jr (ed.), Lippincott-Raven, Philadelphia, PA, 1997.Google Scholar
  86. 86.
    Ross SR, McTavish D, Faulds D. Fludarabine. A review of its pharmacological properties and therapeutic potential in malignancy. Drugs, 45:737–759, 1993.PubMedCrossRefGoogle Scholar
  87. 87.
    Plunkett W, Chubb S, Alexander L, Montgomery JA. Comparison of the toxicity and metabolism of 9-I3-D-arabinofuranosy1–2-fluoroadenine and 9-ft-D- arabinofuranosyladenine in human lymphoblastoid cells. Cancer Res, 40:2349–2355, 1980.PubMedGoogle Scholar
  88. 88.
    Huang P, Plunkett W. Fludarabine-and gemcitabine-induced apoptosis: incorporation of analogs into DNA is a critical event. Cancer Chemother Pharmacol, 36:181–188, 1995.PubMedCrossRefGoogle Scholar
  89. 89.
    Huang P, Plunkett W. Action of 9-ft-D-arabinofuranosy1–2-fluoroadenine on RNA metabolism. Mol Pharmacol, 39:449–455, 1991.PubMedGoogle Scholar
  90. 90.
    King KM, Cass CE. Membrane transport of 2-chloro-2’-deoxyadenosine and 2-chloro-2’- arabinofluoro-2’-deoxyadenosine is required for cytotoxicity. Proc Amer Assoc Cancer Res, 35:A3436, 1994.Google Scholar
  91. 91.
    Avery TL, Rehg JE, Lumm WC, et al. Biochemical pharmacology of 2chlorodeoxyadenosine in malignant human hematopoietic cell lines and therapeutic effects of 2-bromodeoxyadenosine in drug combinations in mice. Cancer Res, 49:4972–4978, 1989.PubMedGoogle Scholar
  92. 92.
    Heinemann V, Xu YZ, Chubb S, et al. Cellular elimination of 2’,2’-difluorodeoxycytidine 5’-triphosphate: a mechanism of self-potentiation. Cancer Res, 52:533–539, 1992.PubMedGoogle Scholar
  93. 93.
    Baker CH, Banzon J, Bollinger JM, et al. 2’-Deoxy-2’-methylenecytidine and 2’-deoxy2’,2’-difluorocytidine 5’- diphosphates: potent mechanism-based inhibitors of ribonucleotide reductase. J Med Chem, 34:1879–1884, 1991.PubMedCrossRefGoogle Scholar
  94. 94.
    Heinemann V, Hertel LW, Grindey GB, Plunkett W. Comparison of the cellular pharmacokinetics and toxicity of 2’,2’-difluorodeoxycytidine and 1-beta-Darabinofuranosylcytosine. Cancer Res, 48:4024–4031, 1988.PubMedGoogle Scholar
  95. 95.
    Blum JL, Jones SE, Buzdar AU, et al. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol, 17:485–493, 1999.PubMedGoogle Scholar
  96. 96.
    Ishikawa T, Utoh M, Sawada N, et al. Tumor selective delivery of 5-fluorouracil by capecitabine, a new oral fluoropyrimidine carbamate, in human cancer xenografts. Biochem Pharmacol, 55:1091–1097, 1998.PubMedCrossRefGoogle Scholar
  97. 97.
    Schmoll H-J, Buchele T, Grothey A, Dempke W. Where do we stand with 5-fluorouracil? Semin Oncol, 26:589–605, 1999.PubMedGoogle Scholar
  98. 98.
    Jennings LL, Hao C, Cabrita MA, et al. Distinct regional distribution of human equilibrative nucleoside transporter proteins 1 and 2 (hENTI and hENT2) in the central nervous system. Neuropharmacol, 40:722–731, 2001.CrossRefGoogle Scholar
  99. 99.
    Ahmad I, Al-Katib AM, Beck FW, Mohammad RM. Sequential treatment of a resistant chronic lymphocytic leukemia patient with bryostatin 1 followed by 2chlorodeoxyadenosine: case report. Clin Cancer Res, 6:1328–1332, 2000.PubMedGoogle Scholar
  100. 100.
    Beck FW, Al-Katib AM, Ahmad I, et al. Bryostatin 1-induced modulation of nucleoside transporters and 2-chlorodeoxyadenosine influx in WSU-CLL cells. Int J Mol Med, 5:341–347, 2000.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Marilyn L. Clarke
    • 1
  • John R. Mackey
    • 1
    • 2
    • 6
  • Stephen A. Baldwin
    • 3
  • James D. Young
    • 4
  • Carol E. Cass
    • 1
    • 5
    • 6
  1. 1.Departments of Experimental OncologyCanada
  2. 2.Department of MedicineCross Cancer InstituteEdmontonCanada
  3. 3.School of Biochemistry and Molecular BiologyUniversity of LeedsLeedsUK
  4. 4.Department of PhysiologyUniversity of AlbertaEdmontonCanada
  5. 5.Department of BiochemistryUniversity of AlbertaEdmontonCanada
  6. 6.Department of OncologyUniversity of AlbertaEdmontonCanada

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