Skip to main content
SpringerLink
Log in

Gemcitabine

Mechanism of Action and Resistance

  • Chapter
Deoxynucleoside Analogs In Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Gemcitabine (2′,2′-difluorodeoxycytidine, Gemzar®) is a deoxycytidine analog with pronounced antitumor activity against a variety of solid tumors, such as non-small cell lung carcinoma and pancreatic and bladder cancer. In this chapter, we summarize the role of the key enzymes in its metabolic activation and deactivation pathways, the role of the various targets, the associated mechanisms of acquired and inherent resistance, and the changes in DNA caused by exposure to this drug. Extensive research has revealed a complex mechanism of action of this relatively new drug. Gemcitabine requires phosphorylation to mono-, di-, and triphosphates (dFdCTP) to be active; this mechanism results in a unique pattern of self-potentiation of the drug, ultimately resulting (when incorporated into the DNA) in a masked chain termination. Similar to the structurally and functionally related deoxycytidine analog 1-β-D-arabinofuranosylcytosine (ara-C), the first, crucial step in phosphorylation is catalyzed by deoxycytidine kinase (dCK). However, unlike ara-C, gemcitabine has multiple intracellular targets; up- or downregulation of these targets may confer resistance to this drug. Resistance is associated with altered activities of enzymes (e.g., dCK) involved in the metabolism of the drug, of target enzymes (e.g., ribo-nucleotide reductase), and of enzymes involved in programmed cell death. Strong correlations with gemcitabine sensitivity have been observed for dCK activity and dFdCTP pools; microarray analyses have suggested a potentially important role for ribonucleotide reductase.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Grindey GB, Boder GB, Hertel LW, et al. Antitumor activity of 2′,2′-difluorodeoxycytidine (LY188011). Proc Am Assoc Cancer Res 1986;27. Abstract 1175.

    Google Scholar 

  2. Hertel LW, Kroin JS, Misner JW, Tustin JM. Synthesis of 2′-deoxy-2′,2′-difluoro-D-ribose and 2′-deoxy-2′,2′-difluoro-D-ribofuranosyl nucleosides. J Org Chem 1988;53:2406–2409.

    Article  CAS  Google Scholar 

  3. Heinemann V, Hertel LW, Grindey GB, Plunkett W. Comparison of the cellular pharmacokinetics and toxicity of 2′,2′-difluorodeoxycytidine and 1-β-D-arabino-furanosylcytosine. Cancer Res 1988;48:4024–4031.

    PubMed  CAS  Google Scholar 

  4. Abratt RP, Rezwoda W, Falkson G, Goedhals L, Hacking D. Efficacy and safety profile of gemcitabine in non-small cell lung cancer. Phase II study. J Clin Oncol 1994;12:1535–1540.

    PubMed  CAS  Google Scholar 

  5. Van Moorsel CJA, Peters GJ, Pinedo HM. Gemcitabine: future prospects of single-agent combination studies. Oncologist 1997;2:127–134.

    PubMed  Google Scholar 

  6. Kaye SB. Gemcitabine: current status of phase I and II trials. J Clin Oncol 1994;12:1527–1531.

    PubMed  CAS  Google Scholar 

  7. Heinemann V. Gemcitabine: progress in the treatment of pancreatic cancer. Oncology 2001;60:8–18.

    Article  PubMed  CAS  Google Scholar 

  8. Ramalingam S, Belani CP. State of the art chemotherapy for advanced non-small cell lung cancer. Semin Oncol 2004;(31(1 suppl 1)):68–74.

    Article  PubMed  CAS  Google Scholar 

  9. Hussain SA, James ND. The systemic treatment of advanced and metastatic bladder cancer. Lancet Oncol 2003;8:489–497.

    Article  Google Scholar 

  10. Heinemann V. Gemcitabine in the treatment of advanced pancreatic cancer: a comparative analysis of randomized trials. Semin Oncol 2002;(29(6 suppl 20)):9–16.

    PubMed  CAS  Google Scholar 

  11. Carmichael J. The role of gemcitabine in the treatment of other tumors. Br J Cancer 1998;(78(suppl. 3)):21–25.

    PubMed  CAS  Google Scholar 

  12. Cass CE. Nucleoside transport. In: Georgopapadakou NH, ed. Drug transport in antimicrobial and anticancer chemotherapy. New York: Marcel Dekker:1995:403.

    Google Scholar 

  13. Griffith DA, Jarvis SM. Nucleoside and nucleobase transport systems of mammalian cells. Biochim Biophys Acta 1996;1286:153–181.

    PubMed  CAS  Google Scholar 

  14. Hammond JR, Lee S, Ferguson J. [3H]Gemcitabine uptake by nucleoside transporters in a human head and neck squamous carcinoma cell line. Pharm Exp Ther 1999;288:1185–1191.

    CAS  Google Scholar 

  15. Fang X, Parkinson FE, Mowles DA, Young JD, Cass CE. Functional characterization of a recombinant sodium-dependent nucleoside transporter with selectivity for pyrimidine nucleosides (cNT1rat) by transient expression in cultured mammalian cells. Biochem J 1996;317:457–465.

    PubMed  CAS  Google Scholar 

  16. Burke T, Lee S, Ferguson PJ, Hammond JR. Interaction of 2′,2′-difluorodeoxycytidine (gemcitabine) and formycin B with Na+-dependent and-independent nucleoside transporters of Ehrlich ascites tumor cells. J Pharm Exp Ther 1998;286:1333–1340.

    CAS  Google Scholar 

  17. Mackey JR, Yao SY, Smith KM, et al. Gemcitabine transport in Xenopus oocytes expressing recombinant plasma membrane mammalian nucleoside transporters. J Natl Cancer Inst 1999;91:1876–1881.

    Article  PubMed  CAS  Google Scholar 

  18. Ritzel MW, Ng AM, Yao SY, et al. Molecular identification and characterization of novel human and mouse concentrative Na+-nucleoside cotransporter proteins (hCNT3 and mCNT3) broadly selective for purine and pyrimidine nucleosides (system cib). J Biol Chem 2001;276:2914–2927.

    Article  PubMed  CAS  Google Scholar 

  19. Borst P, Evers R, Kool M, Wijnholds J. A family of drug transporters: the multidrug resistance-associated proteins. J Natl Cancer Inst 2000;92:1295–1302.

    Article  PubMed  CAS  Google Scholar 

  20. Reid G, Wielinga P, Zelcer N, et al. Characterization of transport of nucleoside analog drugs by the human multidrug resistance proteins MRP4 and MRP5. Mol Pharmacol 2003;63:1094–1103.

    Article  PubMed  CAS  Google Scholar 

  21. Jansen WJ, Pinedo HM, Van der Wilt CL, Feller N, Bamberger U, Boven E. The influence of BIBW22BS, a dipyridamole derivative, on the antiproliferative effects of 5-fluorouracil, methotrexate and gemcitabine in vitro and in human tumour xenografts. Eur J Cancer 1995;31:2313–2319.

    Article  Google Scholar 

  22. Mackey JR, Mani RS, Selner M, et al. Functional nucleoside transporters are required for gemcitabine influx and manifestations of toxicity in cancer cell lines. Cancer Res 1998;58:4349–4357.

    PubMed  CAS  Google Scholar 

  23. Gourdeau H, Clarke ML, Ouellet F, et al. Mechanisms of uptake and resistanceto troxacitabine, a novel deoxycytidine nucleoside analogue, in human leukemicand solid tumor cell lines. Cancer Res 2001;61:7217–7224.

    PubMed  CAS  Google Scholar 

  24. Dumontet C, Fabianowska-Majewska K, Matincic D, et al. Common resistancemechanisms to deoxynucleoside analogues in variants of the human erythroleukaemicline K562. Br J Haematol 1999;106:78–85.

    Article  PubMed  CAS  Google Scholar 

  25. Rauchwerger DR, Firby PS, Hedley DW, Moore MJ. Equilibrative-sensitivenucleoside transporter and its role in gemcitabine sensitivity. Cancer Res 2000;60:6075–6079.

    PubMed  CAS  Google Scholar 

  26. Bouffard DY, Laliberte J, Momparler RL. Kinetic studies on 2′,2′-difluorodeoxy-cytidine(gemcitabine) with purified human deoxycytidine kinase and cytidinedeaminase. Biochem Pharmacol 1993;45:1857–1861.

    Article  PubMed  CAS  Google Scholar 

  27. Wang L, Munch-Petersen B, Herrstrom Sjoberg A, et al. Human thymidinekinase 2: molecular cloning and characterisation of the enzyme activity withantiviral and cytostatic nucleoside substrates. FEBS Lett 1999;443:170–174.

    Article  PubMed  CAS  Google Scholar 

  28. Heinemann V, Xu Y-Z, Chubb S, et al. Cellular elimination of 2′,2′-difluorodeoxycytidine5′-triphosphate: a mechanism of self potentiation. Cancer Res1992;52:533–539.

    PubMed  CAS  Google Scholar 

  29. Xu YZ, Plunkett W. Modulation of deoxycytidylate deaminase in intact humanleukemia cells. Action of 2′,2′-difluorodeoxycytidine. Biochem Pharmacol1992;44:1819–1827.

    Article  PubMed  CAS  Google Scholar 

  30. Beausejour CM, Cagnon J, Primeau M, Momparler RL. Cytotoxic activity of2′,2′-difluorodeoxycytidine, 5-aza-2′-deoxycytidine and cytosine arabinoside incells transduced with deoxycytidine kinase gene. Biochem Biophys ResCommun 2002;293:1478–1484.

    Article  CAS  Google Scholar 

  31. Kroep JR, Loves WJ, van der Wilt CL, et al. Pretreatment deoxycytidinekinase levels predict in vivo gemcitabine sensitivity. Mol Cancer Ther 2002;6:371–376.

    Google Scholar 

  32. Ruiz van Haperen VWT, Veerman G, Eriksson S, et al. Development and molecularcharacterization of a 2′,2′-difluorodeoxycytidine-resistant variant of the human ovariancarcinoma cell line A2780. Cancer Res 1994;54:4138–4143.

    Google Scholar 

  33. Ruiz van Haperen VWT, Veerman G, Vermorken JB, Pinedo HM, Peters GJ. Regulation of phosphorylation of deoxycytidine and 2′,2′-difluorodeoxycytidine(gemcitabine);effects of cytidine 5′-triphosphate and uridine 5′-triphosphate in relationto chemosensitivity for 2′,2′-difluorodeoxycytidine. Biochem Pharm 1996;51:911–918.

    Article  Google Scholar 

  34. Davidson JD, Ma L, Flagella M, Geeganage S, Gelbert LM, Slapak CA. Anincrease in the expression of ribonucleotide reductase large subunit 1 is associatedwith gemcitabine resistance in non-small cell lung cancer cell lines. CancerRes 2004;64:3761–3766.

    Article  CAS  Google Scholar 

  35. Bergman AM, Pinedo HM, Jongsma APM, et al. Decreased resistance to gemcitabineof cytosine arabinoside resistant myeloblastic murine and rat leukemiacell lines: role of altered activity and substrate specificity of deoxycytidinekinase. Biochem Pharmacol 1999;57:397–406.

    Article  PubMed  CAS  Google Scholar 

  36. Shewach DS, Reynolds KK, Hertel LW. Nucleotide specificity of human deoxycytidinekinase. Mol Pharmacol 1992;42:518–524.

    PubMed  CAS  Google Scholar 

  37. Goan YG, Zhou B, Hu E, Mi S, Yen Y. Overexpression of ribonucleotide reductaseas a mechanism of resistance to 2′, 2′-difluorodeoxycytidine in the human KBcancer cell line. Cancer Res 1999;59:4204–4207.

    PubMed  CAS  Google Scholar 

  38. Bergman AM, Munch-Petersen B, Jensen P-B, et al. Collateral sensitivity to gemcitabine(2′,2′-difluorodeoxycytidine) and cytosine arabinoside of daunorubicineand VM-26 resistant variants of human small cell lung cancer cells. BiochemPharmacol 2001;61:1401–1408.

    CAS  Google Scholar 

  39. Nielsen SE, Munch-Petersen B, Mejer J. Increased ratio between deoxycytidinekinase and thymidine kinase 2 in CLL lymphocytes compared to normal lymphocytes. LeukRes 1995;19:443–447.

    CAS  Google Scholar 

  40. Oka J, Matsumoto A, Hosokawa Y, Inoue S. Molecular cloning of human cytosolicpurine 5′-nucleotidase. Biochem Biophys Res Commun 1994;205:917–922.

    Article  PubMed  CAS  Google Scholar 

  41. Hunsucker SA, Spychala J, Mitchell BS. Human cytosolic 5′-nucleotidase Int JBiol Chem 2001;276:10,498–10,504.

    CAS  Google Scholar 

  42. Neff T, Blau CA. Forced expression of cytidine deaminase confers resistance tocytosine arabinoside and gemcitabine. Exp Haematol 1996;24:1340–1346.

    CAS  Google Scholar 

  43. Eliopoulos N, Cournoyer D, Momparler RL. Drug resistance to 5-aza-2′-deoxy-cytidine, 2′,2′-difluorodeoxycytidine, and cytosine arabinoside conferred byretroviral-mediated transfer of human cytidine deaminase cDNA into murinecells. Cancer Chemother Pharmacol 1998;42:373–378.

    Article  PubMed  CAS  Google Scholar 

  44. Eda H, Ura M, Ouchi KF, Tanaka Y, Miwa M, Ishitsuka H. The antiproliferativeactivity of DMDC is modulated by inhibition of cytidine deaminase. Cancer Res1998;58:1165–1169.

    PubMed  CAS  Google Scholar 

  45. Bergman AM, Pinedo HM, Talianidis I, et al. Increased sensitivity to gemcitabineof P-glycoprotein and multidrug resistance-associated protein-overexpressinghuman cancer cell lines. Br J Cancer 2003;88:1963–1970.

    Article  PubMed  CAS  Google Scholar 

  46. Ruiz van Haperen VWT, Veerman G, Braakhuis BJM, et al. Deoxycytidine kinaseand deoxycytidine deaminase activities, in human tumour xenografts. Eur J Cancer1993;29:132–137.

    Article  Google Scholar 

  47. Huang P, Chubb S, Hertel LW, Grindey GB, Plunkett W. Action of 2′,2′-difluorodeoxycytidineon DNA synthesis. Cancer Res 1991;51:6110–6117.

    PubMed  CAS  Google Scholar 

  48. Achanta G, Pelicano H, Feng L, Plunkett W, Huang P. Interaction of p53 andDNA-PK in response to nucleoside analogues: potential role as a sensor complexfor DNA damage. Cancer Res 2001;61:8723–8729.

    PubMed  CAS  Google Scholar 

  49. Ruiz van Haperen VWT, Veerman G, Vermorken JB, Peters GJ. 2′,2′-Difluorodeoxycytidine(gemcitabine) incorporation into RNA and DNA from tumour celllines. Biochem Pharmacol 1993;46:762–766.

    Article  Google Scholar 

  50. Ruiz van Haperen VWT, Veerman G, Boven E, Noordhuis P, Vermorken JB, Peters GJ. Schedule dependence of sensitivity to 2′, 2′-difluorodeoxycytidine(gemcitabine) in relation to accumulation and retention of its triphosphatein solid tumour cell lines and solid tumours. Biochem Pharmacol 1994;48:1327–1339.

    Article  Google Scholar 

  51. Van Moorsel CJA, Bergman AM, Veerman G, et al. Differential effects of gemcitabineon ribonucleotide pools of 21 solid tumour and leukaemia cell lines. Biochim Biophys Acta 2000;1474:5–12.

    PubMed  Google Scholar 

  52. Plunkett W, Huang P, Gandhi V. Gemcitabine: actions and interactions. Nucleosides Nucleotides 1997;16:1261–1270.

    Article  CAS  Google Scholar 

  53. Ruiz van Haperen VWT, Veerman G, Van Moorsel CJA, Peters GJ. Induction ofin vivo resistance against gemcitabine (dFdC, 2′,2′-difluorodeoxycytidine). AdvExp Med Biol 1998;431:637–640.

    Google Scholar 

  54. Heinemann V, Xu Y-Z, Chubb S, et al. Inhibition of ribonucleotide reduction inCCRF-CEM cells by 2′,2′-difluorodeoxycytidine. Mol Pharmacol 1990;38:567–572.

    PubMed  CAS  Google Scholar 

  55. Datta NS, Shewach DS, Hurley MC, Mitchell BS, Fox IH. Human T-lymphoblastdeoxycytidine kinase: purification and properties. Biochemistry 1989;28:114–123.

    Article  PubMed  CAS  Google Scholar 

  56. Abbruzzese JL, Grunewald R, Weeks EA, et al. A phase I clinical, plasma, andcellular pharmacology study of gemcitabine. J Clin Oncol 1991;9:491–498.

    PubMed  CAS  Google Scholar 

  57. Edzes HT, Peters GJ, Noordhuis P, Vermorken JB. Determination of theantimetabolite gemcitabine (2′,2′-difluoro-2′-deoxycytidine) and 2′,2′-difluoro-2′-deoxyuridineby 19F nuclear magnetic resonance spectroscopy. Anal Biochem1993;214:25–30.

    Article  PubMed  CAS  Google Scholar 

  58. Kroep JR, Giaccone G, Voorn DA, et al. Gemcitabine and paclitaxel: pharmacokineticand pharmacodynamic interactions in patients with non-small-cell lungcancer. J Clin Oncol 1999;17:2190–2197.

    PubMed  CAS  Google Scholar 

  59. Peters GJ, Van der Wilt CL, Van Triest B, et al. Thymidylate synthase and drugresistance. Eur J Cancer 1995;31:1299–1305.

    Article  Google Scholar 

  60. Ruiz van Haperen VWT, Veerman G, Smid K, Pinedo HM, Peters GJ. Gemcitabineinhibits thymidylate synthase (TS) activity in solid tumour cell lines. Proc AmAssoc Cancer Res 1995;36:354. Abstract 2107.

    Google Scholar 

  61. Heinemann V, Schulz L, Issels RD, Plunkett W. Gemcitabine: a modulator ofintracellular nucleotide and deoxynucleotide metabolism. Semin Oncol 1995;22:11–18.

    PubMed  CAS  Google Scholar 

  62. Duxbury MS Ito H Zinner MJ Ashley SW Whang EE. RNA interference targetingthe M2 subunit of ribonucleotide reductase enhances pancreatic adenocarcinomachemosensitivity to gemcitabine. Oncogene 2004;23:1539–1548

    Google Scholar 

  63. Bergman AM, Eijk PP, Ruiz van Haperen VWT, et al. In vivo induction of resistance to gemcitabine results in increased expression of ribonucleotide reductase subunit M1 as the major determinant. Cancer Res 2005;65:9510–9516.

    Article  PubMed  CAS  Google Scholar 

  64. Rosell R, Danenberg KD, Alberola V, et al. Ribonucleotide reductase messengerRNA expression and survival in gemcitabine/cisplatin treated advanced non-smallcell lung cancer patients. Clin Cancer Res 2004;10:1318–1325.

    Article  PubMed  CAS  Google Scholar 

  65. Cory AH, Hertel LW, Kroin JS, Cory JG. Effects of 2′,2′-difluorodeoxycytidine(gemcitabine) on wild type and variant mouse leukemia L1210 cells. Oncol Res 1993;5:59–63.

    PubMed  CAS  Google Scholar 

  66. Wong SJ, Myette MS, Wereley JP, Chitambar CR. Increased sensitivity ofhydroxyurea-resistant leukemic cells to gemcitabine. Clin Cancer Res 1999;5:439–443.

    PubMed  CAS  Google Scholar 

  67. Smitskamp-Wilms E, Pinedo HM, Veerman G, Ruiz van Haperen VWT, Peters GJ. Postconfluent multilayered cell line cultures for selective screening of gemcitabine. Eur J Cancer 1998;34:921–926.

    Article  PubMed  CAS  Google Scholar 

  68. Ross DD, Cuddy DP. Molecular effects of 2′,2′-difluorodeoxycytidine (gemcitabine)on DNA replication in intact HL-60 cells. Biochem Pharmacol 1994;48:1619–1630.

    Article  PubMed  CAS  Google Scholar 

  69. Kroep JR, Giaccone G, Tolis C, et al. Sequence dependent effect of paclitaxel ongemcitabine metabolism in relation to cell cycle and cytotoxicity in non-smallcelllung cancer cell lines. Br J Cancer 2000;83:1069–1076.

    Article  PubMed  CAS  Google Scholar 

  70. Van Moorsel CJA, Pinedo HM, Veerman G, et al. Mechanisms of synergismbetween cisplatin and gemcitabine in ovarian and non-small cell lung cancer celllines. Br J Cancer 1999;80:981–990.

    Article  PubMed  Google Scholar 

  71. Ostruszka LJ, Shewach DS. The role of DNA synthesis inhibition in the cytotoxicityof 2′,2′-difluoro-2′-deoxycytidine. Cancer Chemother Pharmacol 2003;52:325–332.

    Article  PubMed  CAS  Google Scholar 

  72. Miura S, Izuta S. DNA polymerases as targets of anticancer nucleosides. CurrDrug Targets 2004;5:191–195.

    Article  CAS  Google Scholar 

  73. Bergman AM, Ciaccone G, Van Moorsel CJA, et al. Cross-resistance in the 2′,2′-difluorodeoxycytidine(gemcitabine) resistant human ovarian cancer cell lineAG6000 to standard and investigational drugs. Eur J Cancer 2000;36:1974–1983.

    Article  PubMed  CAS  Google Scholar 

  74. Gandhi V, Legha J, Chen F, Hertel LW, Plunkett W. Excision of 2′,2′-difluorodeoxycytidine(gemcitabine) monophosphate residues from DNA. Cancer Res1996;56:4453–4459.

    PubMed  CAS  Google Scholar 

  75. Feng L, Achanta G, Pelicano H, Zhang W, Plunkett W, Huang P. Role of p53 incellular response to anticancer nucleoside analog induced DNA damage. Int JMol Med 2000;5:597–604.

    CAS  Google Scholar 

  76. Parsons R, Li GM, Longley MJ, et al. Hypermutability and mismatch repair deficiencyin RER+ tumor cells. Cell 1993;75:1227–1236.

    Article  PubMed  CAS  Google Scholar 

  77. Lin X, Howell SB. Effect of loss of DNA mismatch repair on development oftopotecan-, gemcitabine-, and paclitaxel-resistant variants after exposure to cisplatin. Mol Pharm 1999;56:390–395.

    CAS  Google Scholar 

  78. Fisher DE. Apoptosis in cancer therapy: crossing the threshold. Cell 1994;78:539–542.

    Article  PubMed  CAS  Google Scholar 

  79. Huang P, Plunkett W. Induction of apoptosis by gemcitabine. Semin Oncol 1995;22:19–25.

    PubMed  Google Scholar 

  80. Kucera GL, Capizzi RL. 1-β-D-Arabinofuranosylcytosine-diphosphate-choline isformed by the reversal of choline phosphotransferase and not via cytidyltransferase. Cancer Res 1992;52:3886.

    PubMed  CAS  Google Scholar 

  81. Tolis C, Peters GJ, Ferreira CG, Pinedo HM, Giaccone G. Cell cycle disturbancesand apoptosis induced by topotecan and gemcitabine on human lung cancer celllines. Eur J Cancer 1999;35:796–807.

    Article  PubMed  CAS  Google Scholar 

  82. Chen M, Hough AM, Lawrence TS. The role of p53 in gemcitabine-mediatedcytotoxicity and radiosensitization. Cancer Chemother Pharmacol 45:369–374.

    Google Scholar 

  83. Pace E, Melis M, Siena L, et al. Effects of gemcitabine on cell proliferation andapoptosis in non small cell lung cancer (NSCLC) cell lines. Cancer ChemotherPharmacol 2000;46:467–476.

    Article  CAS  Google Scholar 

  84. Sun XM, MacFarlane M, Zhuang J, Wolf BB, Bgeen DR, Cohen GM. Distinctcaspase cascades are initiated in receptor-mediated and chemical-induced apoptosis. J Biol Chem 1999;274:5053–5060.

    Article  PubMed  CAS  Google Scholar 

  85. Ferreira CG, Span SW, Peters GJ, Kruyt FAE, Giaccone G. Chemotherapytriggers apoptosis in a caspase-8 dependent and mitochondria controlled mannerin the non-small cell lung cancer cell line NCI-H460. Cancer Res 2000;60:7133–7141.

    PubMed  CAS  Google Scholar 

  86. Nabhan C, Gajria D, Krett NL, Gandhi V, Ghias K, Rosen ST. Caspase activationis required for gemcitabine activity in multiple myeloma cell lines. Mol CancerTher2002;13:1221–1227.

    Google Scholar 

  87. Arlt A, Gehrz A, Muerkoster S, et al. Role of NF-kappaB and Akt/PI3K in theresistance of pancreatic carcinoma cell lines against gemcitabine-induced celldeath. Oncogene 2003;22:3243–3251.

    Article  PubMed  CAS  Google Scholar 

  88. Habiro A, Tanno S, Koizumi K, et al. Involvement of p38 mitogen-activated proteinkinase in gemcitabine-induced apoptosis in human pancreatic cancer cells. Biochem Biophys Res Commun 2004;316:71–77.

    Article  PubMed  CAS  Google Scholar 

  89. Galmarini CM, Clarke ML, Falette N, Puisieux A, Mackey JR, Dumontet C. Expression of a non-functional p53 affects the sensitivity of cancer cells to gemcitabine. Int J Cancer 2002;97:439–445.

    Article  PubMed  CAS  Google Scholar 

  90. Cascallo M, Calbo J, Gelpi JL, Mazo A. Modulation of drug cytotoxicity by reintroductionof wild-type p53 gene (Ad5CMV-p53) in human pancreatic cancer. Cancer Gene Ther 2000;7:545–556.

    Article  PubMed  CAS  Google Scholar 

  91. Shi X, Liu S, Kleeff J, Friess H, Buchler MW. Acquired resistance of pancreaticcancer cells towards 5-fluorouracil and gemcitabine is associated with alteredexpression of apoptosis-regulating genes. Oncology 2002;62:354–362.

    Article  PubMed  CAS  Google Scholar 

  92. Orlandi L, Bearzatto A, Abolafio G, De Marco C, Daidone MG, Zaffaroni N. Involvement of bcl-2 and p21waf1 proteins in response of human breast cancercell clones to Tomudex. Br J Cancer 1999;81:252–260.

    Article  PubMed  CAS  Google Scholar 

  93. Xu ZW, Friess H, Solioz M, et al. Bcl-x(L) antisense oligonucleotides induceapoptosis and increase sensitivity of pancreatic cancer cells to gemcitabine. Int JCancer 2001;94:268–274.

    Article  CAS  Google Scholar 

  94. Xu ZW, Friess H, Buchler MW, Solioz M. Overexpression of Bax sensitizeshuman pancreatic cancer cells to apoptosis induced by chemotherapeutic agents. Cancer Chemother Pharmacol 2002;49:504–510.

    Article  PubMed  CAS  Google Scholar 

  95. Auer H, Oehler R, Lindner R, et al. Characterization of genotoxic properties of2′,2′-difluorodeoxycytidine. Mutat Res 1997;393:165–173.

    PubMed  CAS  Google Scholar 

  96. Al-Madhoun AS, Van der Wilt CL, Loves WJP, et al. Detection of an alternativelyspliced form of deoxycytidine kinase mRNA in the 2′-2′-difluorodeoxycytidine(gemcitabine)-resistant human ovarian cancer cell line AG6000. BiochemPharmacol 2004;68:601–609.

    CAS  Google Scholar 

  97. Schwab M, Amler LC. Amplification of cellular oncogenes. A predictor of clinicaloutcome of cancer. Genes Chromosomes Cancer 1990;1:181–193.

    Article  PubMed  CAS  Google Scholar 

  98. Brennan J, O’Connor T, Makuch RW, et al. Myc family DNA amplification in 107tumours and tumour cell lines from patients with small cell lung cancer treated withdifferent combination chemotherapy regimens. Cancer Res 1991;51:1708–1712.

    PubMed  CAS  Google Scholar 

  99. Stark GR, Wahl GM. Gene amplification. Annu Rev Biochem 1984;53:447–491.

    Article  PubMed  CAS  Google Scholar 

  100. Sun J, Blaskovich MA, Knowles D, et al. Antitumor efficacy of a novel class of non-thiol-containing peptidomimetic inhibitors of farnesyltransferase and geranylgeranyltransferaseI: combination therapy with the cytotoxic agents cisplatin,taxol and gemcitabine. Cancer Res 1999;59:4919–4926.

    PubMed  CAS  Google Scholar 

  101. Ng SW, Tsao MS, Chow S, Hedley DW. Inhibition of phosphatidylinositide 3-kinaseenhances gemcitabine-induced apoptosis in human pancreatic cancer cells. CancerRes 2000;60:5451–5455.

    CAS  Google Scholar 

  102. Abratt RP, Bezwoda WR, Falkson G, Goedhals L, Hacking D, Rugg TA. Efficacyand safety profile of gemcitabine in non-small-cell lung cancer: a phase II study. J Clin Oncol 1994;12:1535–1540.

    PubMed  CAS  Google Scholar 

  103. Von Hoff DD, Schilsky R, Reichert CM, et al. Toxic effects of cis-dichlorodiammineplatinum(II)in man. Cancer Treat Rep 1979;63:1527–1531.

    Google Scholar 

  104. Bergman AM, Ruiz van Haperen VW, Veerman G, Kuiper CM, Peters GJ. Synergistic interaction between cisplatin and gemcitabine in vitro. Clin CancerRes 1996;2:521–530.

    CAS  Google Scholar 

  105. van Moorsel CJ, Pinedo HM, Smid K, et al. Schedule-dependent pharmacodynamiceffects of gemcitabine and cisplatin in mice bearing Lewis lung murinenon-small cell lung tumours. Eur J Cancer 2000;36:2420–2429.

    Article  PubMed  Google Scholar 

  106. Edelman MJ, Quam H, Mullins B. Interactions of gemcitabine, carboplatin andpaclitaxel in molecularly defined non-small-cell lung cancer cell lines. CancerChemother Pharmacol 2001;48:141–144.

    Article  CAS  Google Scholar 

  107. Chow KC, Macdonald TL, Ross WE. DNA binding by epipodophyllotoxins andN-acyl anthracyclines: implications for mechanism of topoisomerase II inhibition. Mol Pharmacol 1988;34:467–473.

    PubMed  CAS  Google Scholar 

  108. van Moorsel CJ, Pinedo HM, Veerman G, et al. Combination chemotherapy studieswith gemcitabine and etoposide in non-small cell lung and ovarian cancer celllines. Biochem Pharmacol 1999;57:407–415.

    Article  PubMed  Google Scholar 

  109. Kroep JR, Giaccone G, Tolis C, et al. Sequence dependent effect of paclitaxel ongemcitabine metabolism in relation to cell cycle and cytotoxicity in non-small-celllung cancer cell lines. Br J Cancer 2000;83:1069–1076.

    Article  PubMed  CAS  Google Scholar 

  110. Perabo FG, Lindner H, Schmidt D, et al. Preclinical evaluation of gemcitabine/paclitaxel-interactionsin human bladder cancer lines. Anticancer Res 2003;23:4805–4814.

    PubMed  CAS  Google Scholar 

  111. Zoli W, Ricotti L, Dal Susino M, et al. Docetaxel and gemcitabine activity inNSCLC cell lines and in primary cultures from human lung cancer. Br J Cancer1999;81:609–615.

    Article  PubMed  CAS  Google Scholar 

  112. Ricotti L, Tesei A, De Paola F, et al. In vitro schedule-dependent interactionbetween docetaxel and gemcitabine in human gastric cancer cell lines. ClinCancer Res 2003;9:900–905.

    CAS  Google Scholar 

  113. Bergman AM, Pinedo HM, Peters GJ. Determinants of resistance to 2′,2′-difluorodeoxycytidine(gemcitabine). Drug Resist Updat 2002;5:19–33.

    Article  PubMed  CAS  Google Scholar 

  114. Bohman C, Eriksson S. Deoxycytidine kinase from human leukemic spleen:preparation and characteristics of homogenous enzyme. Biochemistry1988;27:4258–4265.

    Article  PubMed  CAS  Google Scholar 

  115. Munch-Petersen B, Cloos L, Tyrsted G, Eriksson S. Diverging substrate specificityof pure human thymidine kinases 1 and 2 against antiviral dideoxynucleosides. J Biol Chem 1991;266:9032–9038.

    PubMed  CAS  Google Scholar 

  116. Fanuchi MP, Watanabe KA, Fox JJ, Chou T-C. Kinetics and substrate specificityof human and canine cytidine deaminase. Biochem Pharmacol 1986;35:1199–1201.

    Article  Google Scholar 

  117. Jordheim LP, Cros E, Gouy MH, et al. Characteristics of a gemcitabine resistantmurine leukemic cell line: reversion of in vitro resistance by a mononucleotideprodrug. Clin Cancer Res 2004;10:5614–5621.

    Article  PubMed  CAS  Google Scholar 

  118. Calmarini CM, Clarke ML, Jordheim L, et al. Resistance to gemcitabine in ahuman follicular lymphoma cell line is to partial deletion of the deoxycytidinekinase gene. BMC Pharmacol 2004;4:8.

    Article  Google Scholar 

  119. Dong M, Feng FY, Lin C, et al. Mechanisms of the drug resistance of a 2′, 2′-difluoro-deoxycytidine(gemcitabine)-resistant variant of a human adenocarcinomacell line. Zhonhua Yi Xue Za Zhi 2004;84:323–328.

    CAS  Google Scholar 

  120. Van Bree C, Castro Kreder N, Loves WJ, Franken NA, Peters GJ, Haveman J. Sensitivity to ionizing radiation and chemotherapeutic agents in gemcitabineresistanthuman tumor cell lines. Int J Radiat Oncol Biol Phys 2002;54:237–244.

    Article  PubMed  Google Scholar 

  121. Blackstock AW, Lightfoot H, Case LD, et al. Tumor uptake and elimination of2′,2′-difluoro-2′-deoxycytidine (gemcitabine) after deoxycytidine gene transfer:correlation with in vivo tumor response. Clin Cancer Res 2001;7:3263–3268.

    PubMed  CAS  Google Scholar 

  122. Giovannetti E, Mey V, Danesi R, Mosca I, Del Tacca M. Synergistic cytotoxicityand pharmacogenetics of gemcitabine and pemetrexed combination in pancreaticcancer cell lines. Clin Cancer Res 2004;10:2936–2943.

    Article  PubMed  CAS  Google Scholar 

  123. Sigmond J, Kroep JR, Loves W, Codacci-Pisanelli G, Peters GJ. Quantitative realtime PCR of deoxycytidine kinase mRNA by Light Cycler PCR in relation toenzyme activity and gemcitabine sensitivity. Cancer Lett 2004;213:173–179.

    Article  PubMed  CAS  Google Scholar 

  124. Gregoire V, Rosier JF, De Bast M, et al. Role of deoxycytidine kinase (dCK)activity in gemcitabine’s radioenhancement in mice and human cell lines in vitro. Radiother Oncol 2002;63:329–338.

    Article  PubMed  CAS  Google Scholar 

  125. Schirmer M, Stegmann AP, Geisen F, Konwalinka G. Lack of cross-resistancewith gemcitabine and cytarabine in cladribine-resistant HL60 cells with elevated5′-nucleotidase activity. Exp Hematol 1998;26:1223–1228.

    PubMed  CAS  Google Scholar 

  126. Duxbury MS, Ito H, Benoit E, Zinner MJ, Ashley SW, Whang EE. Retrovirallymediated RNA interference targeting the M2 subunit of ribonucleotide reductase:a novel therapeutic strategy in pancreatic cancer. Surgery 2004;136:261–269.

    Article  PubMed  Google Scholar 

  127. Liu X, Zhou B, Xue L, et al. Nuclear factor Y regulation and promoter transactivationof human ribonucleotide reductase subunit M2 gene in a gemcitabineresistant KB clone. Biochem Pharmacol 2004;67:1499–1511.

    Article  PubMed  CAS  Google Scholar 

  128. Zhou B, Mo X, Liu X, Qiu W, Yen Y. Human ribonucleotide reductase M2 subunitgene amplification and transcriptional regulation in a homogenous stainingchromosome region responsible for the mechanism of drug resistance. CytogenetCell Genet 2001;95:34–42.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands

    Andries M. Bergman MD, PhD & Godefridus J. Peters PhD (Professor)

Authors
  1. Andries M. Bergman MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Godefridus J. Peters PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. VU University Medical Center Amsterdam, The Netherlands

    Godefridus J. Peters PhD (Professor of Medical Oncology) (Professor of Medical Oncology)

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Humana Press Inc., Totowa, NJ

About this chapter

Cite this chapter

Bergman, A.M., Peters, G.J. (2006). Gemcitabine. In: Peters, G.J. (eds) Deoxynucleoside Analogs In Cancer Therapy. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-148-2_11

Download citation

Publish with us

Policies and ethics

Search

Navigation