袁田 1,2 , 廖泉 2 , 趙玉沛 2
  • 1.中國醫(yī)學(xué)科學(xué)院北京協(xié)和醫(yī)學(xué)院（北京 100730）;;
  • 2.中國醫(yī)學(xué)科學(xué)院北京協(xié)和醫(yī)院基本外科（北京 100730）;

目的  介紹吉西他濱代謝酶對胰腺癌化療耐藥影響的研究進展。
方法  復(fù)習(xí)和總結(jié)了近年來的相關(guān)文獻，對吉西他濱代謝酶與胰腺癌化療耐藥關(guān)系的研究進展加以綜述。
結(jié)果  hENT1、dCK、RRM1、CDA等代謝酶與胰腺癌對吉西他濱化療的耐藥具有密切關(guān)系； 代謝酶的單核苷酸多態(tài)性與胰腺癌對吉西他濱耐藥的關(guān)系仍有待研究。
結(jié)論  胰腺癌對吉西他濱化療耐藥是多因素、多因子共同作用的結(jié)果，對于代謝酶影響胰腺癌化療耐藥的機理有待進一步研究。

引用本文： 袁田,廖泉,趙玉沛. 吉西他濱代謝酶與胰腺癌化療耐藥關(guān)系的研究進展. 中國普外基礎(chǔ)與臨床雜志, 2009, 16(8): 613-616. doi: 復(fù)制

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2. Abbruzzese JL. New applications of gemcitabine and future directions in the management of pancreatic cancer [Ｊ]. Cancer, 2002; 95 (4 Suppl): 941-945.
3. Burris HA 3rd, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial [Ｊ]. J Clin Oncol, 1997; 15(6): 2403-2413.
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5. Galmarini CM, Mackey JR, Dumontet C. Nucleoside analogues: mechanisms of drug resistance and reversal strategies [Ｊ]. Leukemia, 2001; 15(6): 875-890.
6. Shi JY, Shi ZZ, Zhang SJ, et al. Association between single nucleotide polymorphisms in deoxycytidine kinase and treatment response among acute myeloid leukaemia patients [Ｊ]. Pharmacogenetics, 2004; 14(11): 759-768.
7. Ward JL, Leung GP, Toan SV, et al. Functional analysis of site-directed glycosylation mutants of the human equilibrative nucleoside transporter-2 [Ｊ]. Arch Biochem Biophys, 2003; 411(1): 19-26.
8. García-Manteiga J, Molina-Arcas M, Casado FJ, et al. Nucleoside transporter profiles in human pancreatic cancer cells: role of hCNT1 in 2’, 2’-difluorodeoxycytidine-induced cytotoxicity [Ｊ]. Clin Cancer Res, 2003; 9(13): 5000-5008.
9. Mori R, Ishikawa T, Ichikawa Y, et al. Human equilibrative nucleoside transporter 1 is associated with the chemosensitivity of gemcitabine in human pancreatic adenocarcinoma and biliary tract carcinoma cells [Ｊ]. Oncol Rep, 2007; 17(5): 1201-1205.
10. Rauchwerger DR, Firby PS, Hedley DW, et al. Equilibrative-sensitive nucleoside transporter and its role in gemcitabine sensitivity [Ｊ]. Cancer Res, 2000; 60(21): 6075-6079.
11. Giovannetti E, Del Tacca M, Mey V, et al. Transcription analysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemcitabine [Ｊ]. Cancer Res, 2006; 66(7): 3928-3935.
12. Farrell JJ, Elsaleh H, Garcia M, et al. Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer [Ｊ]. Gastroenterology, 2009; 136(1): 187-195.
13. Spratlin J, Sangha R, Darry Glubrecht D, et al. The absence of human equilibrative nucleoside transporter 1 is associated with reduced survival in patients with gemcitabine-treated pancreas adenocarcinoma [Ｊ]. Clin Cancer Res, 2004; 10(20): 6956-6961.
14. Giovannetti E, Mey V, Nannizzi S, et al. Pharmacogenetics of anticancer drug sensitivity in pancreatic cancer [Ｊ]. Mol Cancer Ther, 2006; 5(6): 1387-1395.
15. Kroep JR, Loves WJ, van der Wilt CL, et al. Pretreatment deoxycytidine kinase levels predict in vivo gemcitabine sensitivity [Ｊ]. Mol Cancer Ther, 2002; 1(6): 371-376.
16. Blackstock AW, Lightfoot H, Case LD, et al. Tumor uptake and elimination of 2’, 2’-difluoro-2’-deoxycytidine (gemcitabine) after deoxycytidine kinase gene transfer: correlation with in vivo tumor response [Ｊ]. Clin Cancer Res, 2001; 7(10): 3263-3268.
17. Veuger MJ, Heemskerk MH, Honders MW, et al. Functional role of alternatively spliced deoxycytidine kinase in sensitivity to cytarabine of acute myeloid leukemic cells [Ｊ]. Blood, 2002; 99(4): 1373-1380.
18. Veuger MJ, Honders MW, Landegent JE, et al. High incidence of alternatively spliced forms of deoxycytidine kinase in patients with resistant acute myeloid leukemia [Ｊ]. Blood, 2000; 96(4): 1517-1524.
19. Galmarini CM, Clarke ML, Jordheim L, et al. Resistance to gemcitabine in a human follicular lymphoma cell line is due to partial deletion of the deoxycytidine kinase gene [Ｊ]. BMC Pharmacol, 2004; 4: 8-20.
20. Ohhashi S, Ohuchida K, Mizumoto K, et al. Down-regulation of deoxycytidine kinase enhances acquired resistance to gemcitabine in pancreatic cancer [Ｊ]. Anticancer Res, 2008; 28(4B): 2205-2212.
21. Szantai E, Ronai Z, Sasvari-Szekely M, et al. Multicapillary electrophoresis analysis of single-nucleotide sequence variations in the deoxycytidine kinase gene [Ｊ]. Clin Chem, 2006; 52(9): 1756-1762.
22. Sebastiani V, Ricci F, Rubio-Viqueira B, et al. Immunohistochemical and genetic evaluation of deoxycytidine kinase in pancreatic cancer: relationship to molecular mechanisms of gemcitabine resistance and survival [Ｊ]. Clin Cancer Res, 2006; 12(8): 2492-2497.
23. Davidson JD, Ma L, Flagella M, et al. An increase in the expression of ribonucleotide reductase large subunit 1 is associated with gemcitabine resistance in non-small cell lung cancer cell lines [Ｊ]. Cancer Res, 2004; 64(11): 3761-3766.
24. Bergman AM, Eijk PP, Ruiz van Haperen VW, et al. In vivo induction of resistance to gemcitabine resultsin increased expression of ribonucleotide reductase subunit M1 as the major determinant [Ｊ]. Cancer Res, 2005; 65(20): 9510-9516.
25. Guex N, Peitsch MC. SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling [Ｊ]. Electrophoresis, 1997; 18(15): 2714-2723.
26. Yonemori K, Ueno H, Okusaka T, et al. Severe drug toxicity associated with a single-nucleotide polymorphism of the cytidine deaminase gene in a Japanese cancer patient treated with gemcitabine plus cisplatin [Ｊ]. Clin Cancer Res, 2005; 11(7): 2620-2624.
27. Sugiyama E, Kaniwa N, Kim SR, et al. Pharmacokinetics of gemcitabine in Japanese cancer patients: the impact of a cytidine deaminase polymorphism [Ｊ]. J Clin Oncol, 2007; 25(1): 32-42.
28. Nakano Y, Tanno S, Koizumi K, et al. Gemcitabine chemoresistance and molecular markers associated with gemcitabine transport and metabolism in human pancreatic cancer cells [Ｊ]. Br J Cancer, 2007; 96(3): 457-463.
29. 張立陽， 趙玉沛， 吳元德， 等. 胰腺癌阿霉素耐藥細胞株SW1990/ADM的建立及其耐藥機理研究 [Ｊ]. 中國普外基礎(chǔ)與臨床雜志， 2005； 12（1）： 46-50.
30. 潘博， 郭俊超， 廖泉， 等. 吉西他濱與胰腺癌化療耐藥 [Ｊ]. 中國普外基礎(chǔ)與臨床雜志， 2005； 12（5）： 530-532.
  1. 1. Alexakis N, Halloran C, Raraty M, et al. Current standards of surgery for pancreatic cancer [Ｊ]. Br J Surg, 2004; 91(11): 1410-1427.
  2. 2. Abbruzzese JL. New applications of gemcitabine and future directions in the management of pancreatic cancer [Ｊ]. Cancer, 2002; 95 (4 Suppl): 941-945.
  3. 3. Burris HA 3rd, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial [Ｊ]. J Clin Oncol, 1997; 15(6): 2403-2413.
  4. 4. Mini E, Nobili S, Caciagli B, et al. Cellular pharmacology of gemcitabine [Ｊ]. Ann Oncol, 2006; 17 (Suppl 5): v7-v12.
  5. 5. Galmarini CM, Mackey JR, Dumontet C. Nucleoside analogues: mechanisms of drug resistance and reversal strategies [Ｊ]. Leukemia, 2001; 15(6): 875-890.
  6. 6. Shi JY, Shi ZZ, Zhang SJ, et al. Association between single nucleotide polymorphisms in deoxycytidine kinase and treatment response among acute myeloid leukaemia patients [Ｊ]. Pharmacogenetics, 2004; 14(11): 759-768.
  7. 7. Ward JL, Leung GP, Toan SV, et al. Functional analysis of site-directed glycosylation mutants of the human equilibrative nucleoside transporter-2 [Ｊ]. Arch Biochem Biophys, 2003; 411(1): 19-26.
  8. 8. García-Manteiga J, Molina-Arcas M, Casado FJ, et al. Nucleoside transporter profiles in human pancreatic cancer cells: role of hCNT1 in 2’, 2’-difluorodeoxycytidine-induced cytotoxicity [Ｊ]. Clin Cancer Res, 2003; 9(13): 5000-5008.
  9. 9. Mori R, Ishikawa T, Ichikawa Y, et al. Human equilibrative nucleoside transporter 1 is associated with the chemosensitivity of gemcitabine in human pancreatic adenocarcinoma and biliary tract carcinoma cells [Ｊ]. Oncol Rep, 2007; 17(5): 1201-1205.
  10. 10. Rauchwerger DR, Firby PS, Hedley DW, et al. Equilibrative-sensitive nucleoside transporter and its role in gemcitabine sensitivity [Ｊ]. Cancer Res, 2000; 60(21): 6075-6079.
  11. 11. Giovannetti E, Del Tacca M, Mey V, et al. Transcription analysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemcitabine [Ｊ]. Cancer Res, 2006; 66(7): 3928-3935.
  12. 12. Farrell JJ, Elsaleh H, Garcia M, et al. Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer [Ｊ]. Gastroenterology, 2009; 136(1): 187-195.
  13. 13. Spratlin J, Sangha R, Darry Glubrecht D, et al. The absence of human equilibrative nucleoside transporter 1 is associated with reduced survival in patients with gemcitabine-treated pancreas adenocarcinoma [Ｊ]. Clin Cancer Res, 2004; 10(20): 6956-6961.
  14. 14. Giovannetti E, Mey V, Nannizzi S, et al. Pharmacogenetics of anticancer drug sensitivity in pancreatic cancer [Ｊ]. Mol Cancer Ther, 2006; 5(6): 1387-1395.
  15. 15. Kroep JR, Loves WJ, van der Wilt CL, et al. Pretreatment deoxycytidine kinase levels predict in vivo gemcitabine sensitivity [Ｊ]. Mol Cancer Ther, 2002; 1(6): 371-376.
  16. 16. Blackstock AW, Lightfoot H, Case LD, et al. Tumor uptake and elimination of 2’, 2’-difluoro-2’-deoxycytidine (gemcitabine) after deoxycytidine kinase gene transfer: correlation with in vivo tumor response [Ｊ]. Clin Cancer Res, 2001; 7(10): 3263-3268.
  17. 17. Veuger MJ, Heemskerk MH, Honders MW, et al. Functional role of alternatively spliced deoxycytidine kinase in sensitivity to cytarabine of acute myeloid leukemic cells [Ｊ]. Blood, 2002; 99(4): 1373-1380.
  18. 18. Veuger MJ, Honders MW, Landegent JE, et al. High incidence of alternatively spliced forms of deoxycytidine kinase in patients with resistant acute myeloid leukemia [Ｊ]. Blood, 2000; 96(4): 1517-1524.
  19. 19. Galmarini CM, Clarke ML, Jordheim L, et al. Resistance to gemcitabine in a human follicular lymphoma cell line is due to partial deletion of the deoxycytidine kinase gene [Ｊ]. BMC Pharmacol, 2004; 4: 8-20.
  20. 20. Ohhashi S, Ohuchida K, Mizumoto K, et al. Down-regulation of deoxycytidine kinase enhances acquired resistance to gemcitabine in pancreatic cancer [Ｊ]. Anticancer Res, 2008; 28(4B): 2205-2212.
  21. 21. Szantai E, Ronai Z, Sasvari-Szekely M, et al. Multicapillary electrophoresis analysis of single-nucleotide sequence variations in the deoxycytidine kinase gene [Ｊ]. Clin Chem, 2006; 52(9): 1756-1762.
  22. 22. Sebastiani V, Ricci F, Rubio-Viqueira B, et al. Immunohistochemical and genetic evaluation of deoxycytidine kinase in pancreatic cancer: relationship to molecular mechanisms of gemcitabine resistance and survival [Ｊ]. Clin Cancer Res, 2006; 12(8): 2492-2497.
  23. 23. Davidson JD, Ma L, Flagella M, et al. An increase in the expression of ribonucleotide reductase large subunit 1 is associated with gemcitabine resistance in non-small cell lung cancer cell lines [Ｊ]. Cancer Res, 2004; 64(11): 3761-3766.
  24. 24. Bergman AM, Eijk PP, Ruiz van Haperen VW, et al. In vivo induction of resistance to gemcitabine resultsin increased expression of ribonucleotide reductase subunit M1 as the major determinant [Ｊ]. Cancer Res, 2005; 65(20): 9510-9516.
  25. 25. Guex N, Peitsch MC. SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling [Ｊ]. Electrophoresis, 1997; 18(15): 2714-2723.
  26. 26. Yonemori K, Ueno H, Okusaka T, et al. Severe drug toxicity associated with a single-nucleotide polymorphism of the cytidine deaminase gene in a Japanese cancer patient treated with gemcitabine plus cisplatin [Ｊ]. Clin Cancer Res, 2005; 11(7): 2620-2624.
  27. 27. Sugiyama E, Kaniwa N, Kim SR, et al. Pharmacokinetics of gemcitabine in Japanese cancer patients: the impact of a cytidine deaminase polymorphism [Ｊ]. J Clin Oncol, 2007; 25(1): 32-42.
  28. 28. Nakano Y, Tanno S, Koizumi K, et al. Gemcitabine chemoresistance and molecular markers associated with gemcitabine transport and metabolism in human pancreatic cancer cells [Ｊ]. Br J Cancer, 2007; 96(3): 457-463.
  29. 29. 張立陽， 趙玉沛， 吳元德， 等. 胰腺癌阿霉素耐藥細胞株SW1990/ADM的建立及其耐藥機理研究 [Ｊ]. 中國普外基礎(chǔ)與臨床雜志， 2005； 12（1）： 46-50.
  30. 30. 潘博， 郭俊超， 廖泉， 等. 吉西他濱與胰腺癌化療耐藥 [Ｊ]. 中國普外基礎(chǔ)與臨床雜志， 2005； 12（5）： 530-532.