REFERENCES
1. Bonjouklian R, Phillips ML, Kuhler KM, Grindey GB, Poore GA, et al. Studies of the antitumor activity of (2-alkoxyalkyl)- and (2-alkoxyalkenyl)phosphocholines. J Med Chem 1986;29:2472-7.
2. Heinemann V, Hertel LW, Grindey GB, Plunkett W. Comparison of the cellular pharmacokinetics and toxicity of 2’,2’-difluorodeoxycytidine and 1-beta-D-arabinofuranosylcytosine. Cancer Res 1988;48:4024-31.
3. Boswell-Casteel RC, Hays FA. Equilibrative nucleoside transporters-a review. Nucleosides Nucleotides Nucleic Acids 2017;36:7-30.
4. Shimada T, Nakanishi T, Tajima H, Yamazaki M, Yokono R, et al. Saturable hepatic extraction of gemcitabine involves biphasic uptake mediated by nucleoside transporters Equilibrative Nucleoside Transporter 1 and 2. J Pharm Sci 2015;104:3162-9.
5. Mini E, Nobili S, Caciagli B, Landini I, Mazzei T. Cellular pharmacology of gemcitabine. Ann Oncol 2006;17 Suppl 5:v7-12.
6. Ruiz van Haperen VW, Veerman G, Vermorken JB, Peters GJ. 2’,2’-Difluoro-deoxycytidine (gemcitabine) incorporation into RNA and DNA of tumour cell lines. Biochem Pharmacol 1993;46:762-6.
7. Bergman AM, Pinedo HM, Peters GJ. Determinants of resistance to 2’,2’-difluorodeoxycytidine (gemcitabine). Drug Resist Updat 2002;5:19-33.
8. Kroep JR, Giaccone G, Tolis C, Voorn DA, Loves WJ, et al. Sequence dependent effect of paclitaxel on gemcitabine metabolism in relation to cell cycle and cytotoxicity in non-small-cell lung cancer cell lines. Br J Cancer 2000;83:1069-76.
9. Honeywell RJ, Ruiz van Haperen VW, Veerman G, Smid K, Peters GJ. Inhibition of thymidylate synthase by 2’,2’-difluoro-2’-deoxycytidine (Gemcitabine) and its metabolite 2’,2’-difluoro-2’-deoxyuridine. Int J Biochem Cell Biol 2015;60:73-81.
10. Motoi F, Unno M. Neoadjuvant treatment for resectable pancreatic adenocarcinoma: What is the best protocol? Ann Gastroenterol Surg 2020;4:100-8.
11. Gesto DS, Cerqueira NM, Fernandes PA, Ramos MJ. Gemcitabine: a critical nucleoside for cancer therapy. Curr Med Chem 2012;19:1076-87.
12. Kelderman S, Schumacher TN, Haanen JB. Acquired and intrinsic resistance in cancer immunotherapy. Mol Oncol 2014;8:1132-9.
13. Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 2015;527:525-30.
14. Arumugam T, Ramachandran V, Fournier KF, Wang H, Marquis L, et al. Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res 2009;69:5820-8.
15. Fang Y, Zhou W, Rong Y, Kuang T, Xu X, et al. Exosomal miRNA-106b from cancer-associated fibroblast promotes gemcitabine resistance in pancreatic cancer. Exp Cell Res 2019;383:111543.
16. Yang Z, Zhao N, Cui J, Wu H, Xiong J, et al. Exosomes derived from cancer stem cells of gemcitabine-resistant pancreatic cancer cells enhance drug resistance by delivering miR-210. Cell Oncol (Dordr) 2020;43:123-36.
17. Ritzel MW, Ng AM, Yao SY, Graham K, Loewen SK, et al. Recent molecular advances in studies of the concentrative Na+-dependent nucleoside transporter (CNT) family: identification and characterization of novel human and mouse proteins (hCNT3 and mCNT3) broadly selective for purine and pyrimidine nucleosides (system cib). Mol Membr Biol 2001;18:65-72.
18. Lostao MP, Mata JF, Larrayoz IM, Inzillo SM, Casado FJ, et al. Electrogenic uptake of nucleosides and nucleoside-derived drugs by the human nucleoside transporter 1 (hCNT1) expressed in
19. Mackey JR, Mani RS, Selner M, Mowles D, Young JD, et al. Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. Cancer Res 1998;58:4349-57.
20. Garcia-Manteiga J, Molina-Arcas M, Casado FJ, Mazo A, Pastor-Anglada M. Nucleoside transporter profiles in human pancreatic cancer cells: Role of hCNT1 in 2’,2’-difluorodeoxycytidine- induced cytotoxicity. Clin Cancer Res 2003;9:5000-5008.
21. Rauchwerger DR, Firby PS, Hedley DW, Moore MJ. Equilibrative-sensitive nucleoside transporter and its role in gemcitabine sensitivity. Cancer Res 2000;60:6075-9.
22. Mohelnikova-Duchonova B, Melichar B. Human equilibrative nucleoside transporter 1 (hENT1): do we really have a new predictive biomarker of chemotherapy outcome in pancreatic cancer patients? Pancreatology 2013;13:558-63.
23. Orlandi A, Calegari MA, Martini M, Cocomazzi A, Bagala C, et al. Gemcitabine versus FOLFIRINOX in patients with advanced pancreatic adenocarcinoma hENT1-positive: everything was not too bad back when everything seemed worse. Clin Transl Oncol 2016;18:988-95.
24. Bird NT, Elmasry M, Jones R, Psarelli E, Dodd J, et al. Immunohistochemical hENT1 expression as a prognostic biomarker in patients with resected pancreatic ductal adenocarcinoma undergoing adjuvant gemcitabine-based chemotherapy. Br J Surg 2017;104:328-36.
25. Nishio R, Tsuchiya H, Yasui T, Matsuura S, Kanki K, et al. Disrupted plasma membrane localization of equilibrative nucleoside transporter 2 in the chemoresistance of human pancreatic cells to gemcitabine (dFdCyd). Cancer Sci 2011;102:622-9.
26. Mohelnikova-Duchonova B, Brynychova V, Oliverius M, Honsova E, Kala Z, et al. Differences in transcript levels of ABC transporters between pancreatic adenocarcinoma and nonneoplastic tissues. Pancreas 2013;42:707-16.
27. Bhutia YD, Hung SW, Patel B, Lovin D, Govindarajan R. CNT1 expression influences proliferation and chemosensitivity in drug-resistant pancreatic cancer cells. Cancer Res 2011;71:1825-35.
28. Skrypek N, Duchene B, Hebbar M, Leteurtre E, van Seuningen I, et al. The MUC4 mucin mediates gemcitabine resistance of human pancreatic cancer cells via the Concentrative Nucleoside Transporter family. Oncogene 2013;32:1714-23.
29. Chen P, Chien PY, Khan AR, Sheikh S, Ali SM, et al.
30. Bergman AM, Adema AD, Balzarini J, Bruheim S, Fichtner I, et al. Antiproliferative activity, mechanism of action and oral antitumor activity of CP-4126, a fatty acid derivative of gemcitabine, in
31. Poplin E, Wasan H, Rolfe L, Raponi M, Ikdahl T, et al. Randomized, multicenter, phase II study of CO-101 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma: including a prospective evaluation of the role of hENT1 in gemcitabine or CO-101 sensitivity. J Clin Oncol 2013;31:4453-61.
32. Raffenne J, Nicolle R, Puleo F, Le Corre D, Boyez C, et al. hENT1 testing in pancreatic ductal adenocarcinoma: are we ready? a multimodal evaluation of hENT1 status. Cancers (Basel) 2019;11.
33. Guo Z, Wang F, Di Y, Yao L, Yu X, et al. Antitumor effect of gemcitabine-loaded albumin nanoparticle on gemcitabine-resistant pancreatic cancer induced by low hENT1 expression. Int J Nanomedicine 2018;13:4869-80.
34. Couvreur P, Stella B, Reddy LH, Hillaireau H, Dubernet C, et al. Squalenoyl nanomedicines as potential therapeutics. Nano Lett 2006;6:2544-8.
35. Bildstein L, Dubernet C, Marsaud V, Chacun H, Nicolas V, et al. Transmembrane diffusion of gemcitabine by a nanoparticulate squalenoyl prodrug: an original drug delivery pathway. J Control Release 2010;147:163-70.
36. Chitkara D, Mittal A, Behrman SW, Kumar N, Mahato RI. Self-assembling, amphiphilic polymer-gemcitabine conjugate shows enhanced antitumor efficacy against human pancreatic adenocarcinoma. Bioconjug Chem 2013;24:1161-73.
37. Wonganan P, Lansakara PD, Zhu S, Holzer M, Sandoval MA, et al. Just getting into cells is not enough: mechanisms underlying 4-(N)-stearoyl gemcitabine solid lipid nanoparticle’s ability to overcome gemcitabine resistance caused by RRM1 overexpression. J Control Release 2013;169:17-27.
38. Frances A, Cordelier P. The emerging role of cytidine deaminase in human diseases: a new opportunity for therapy? Mol Ther 2020;28:357-66.
39. Heinemann V, Xu YZ, Chubb S, Sen A, Hertel LW, et al. Cellular elimination of 2’,2’-difluorodeoxycytidine 5’-triphosphate: a mechanism of self-potentiation. Cancer Res 1992;52:533-9.
40. Abbruzzese JL, Grunewald R, Weeks EA, Gravel D, Adams T, et al. A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol 1991;9:491-8.
41. Chalmers IM, Thomson GT, Desjardins P. Serum cytidine deaminase as a laboratory test for acute inflammation in rheumatoid arthritis. Ann Rheum Dis 1988;47:173-4.
42. Peters GJ, Honeywell RJ, Maulandi M, Giovannetti E, Losekoot N, et al. Selection of the best blood compartment to measure cytidine deaminase activity to stratify for optimal gemcitabine or cytarabine treatment. Nucleosides Nucleotides Nucleic Acids 2014;33:403-12.
43. Sugiyama E, Kaniwa N, Kim SR, Hasegawa R, Saito Y, et al. Population pharmacokinetics of gemcitabine and its metabolite in Japanese cancer patients: impact of genetic polymorphisms. Clin Pharmacokinet 2010;49:549-58.
44. Micozzi D, Carpi FM, Pucciarelli S, Polzonetti V, Polidori P, et al. Human cytidine deaminase: a biochemical characterization of its naturally occurring variants. Int J Biol Macromol 2014;63:64-74.
45. Serdjebi C, Seitz JF, Ciccolini J, Duluc M, Norguet E, et al. Rapid deaminator status is associated with poor clinical outcome in pancreatic cancer patients treated with a gemcitabine-based regimen. Pharmacogenomics 2013;14:1047-51.
46. Ding X, Chen W, Fan H, Zhu B. Cytidine deaminase polymorphism predicts toxicity of gemcitabine-based chemotherapy. Gene 2015;559:31-7.
47. Neff T, Blau CA. Forced expression of cytidine deaminase confers resistance to cytosine arabinoside and gemcitabine. Exp Hematol 1996;24:1340-6.
48. van Haperen VW, Veerman G, Vermorken JB, Pinedo HM, Peters G. Regulation of phosphorylation of deoxycytidine and 2’,2’-difluorodeoxycytidine (gemcitabine); effects of cytidine 5’-triphosphate and uridine 5’-triphosphate in relation to chemosensitivity for 2’,2’-difluorodeoxycytidine. Biochem Pharmacol 1996;51:911-8.
49. Ruiz van Haperen VW, Veerman G, Braakhuis BJ, Vermorken JB, Boven E, et al. Deoxycytidine kinase and deoxycytidine deaminase activities in human tumour xenografts. Eur J Cancer 1993;29A:2132-7.
50. Mameri H, Bieche I, Meseure D, Marangoni E, Buhagiar-Labarchede G, et al. Cytidine deaminase deficiency reveals new therapeutic opportunities against cancer. Clin Cancer Res 2017;23:2116-26.
51. Zauri M, Berridge G, Thezenas ML, Pugh KM, Goldin R, et al. CDA directs metabolism of epigenetic nucleosides revealing a therapeutic window in cancer. Nature 2015;524:114-8.
52. Ye FG, Song CG, Cao ZG, Xia C, Chen DN, et al. Cytidine deaminase axis modulated by miR-484 differentially regulates cell proliferation and chemoresistance in breast cancer. Cancer Res 2015;75:1504-15.
53. Rajabpour A, Afgar A, Mahmoodzadeh H, Radfar JE, Rajaei F, et al. MiR-608 regulating the expression of ribonucleotide reductase M1 and cytidine deaminase is repressed through induced gemcitabine chemoresistance in pancreatic cancer cells. Cancer Chemother Pharmacol 2017;80:765-75.
54. Frese KK, Neesse A, Cook N, Bapiro TE, Lolkema MP, et al. nab-Paclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer. Cancer Discov 2012;2:260-9.
55. McCormack JJ, Marquez VE, Liu PS, Vistica DT, Driscoll JS. Inhibition of cytidine deaminase by 2-oxopyrimidine riboside and related compounds. Biochem Pharmacol 1980;29:830-2.
56. Betts L, Xiang S, Short SA, Wolfenden R, Carter CW Jr. Cytidine deaminase. The 2.3 A crystal structure of an enzyme: transition-state analog complex. J Mol Biol 1994;235:635-56.
57. Zhou L, Cheng X, Connolly BA, Dickman MJ, Hurd PJ, et al. Zebularine: a novel DNA methylation inhibitor that forms a covalent complex with DNA methyltransferases. J Mol Biol 2002;321:591-9.
58. Hanze AR. Nucleic acids. IV. The catalytic reduction of pyrimidine nucleosides (human liver deaminase inhibitors). J Am Chem Soc 1967;89:6720-5.
59. Beumer JH, Eiseman JL, Gilbert JA, Holleran JL, Yellow-Duke AE, et al. Plasma pharmacokinetics and oral bioavailability of the 3,4,5,6-tetrahydrouridine (THU) prodrug, triacetyl-THU (taTHU), in mice. Cancer Chemother Pharmacol 2011;67:421-30.
60. Ferraris D, Duvall B, Delahanty G, Mistry B, Alt J, et al. Design, synthesis, and pharmacological evaluation of fluorinated tetrahydrouridine derivatives as inhibitors of cytidine deaminase. J Med Chem 2014;57:2582-8.
61. Chung SJ, Fromme JC, Verdine GL. Structure of human cytidine deaminase bound to a potent inhibitor. J Med Chem 2005;48:658-60.
62. Weizman N, Krelin Y, Shabtay-Orbach A, Amit M, Binenbaum Y, et al. Macrophages mediate gemcitabine resistance of pancreatic adenocarcinoma by upregulating cytidine deaminase. Oncogene 2014;33:3812-9.
63. Amit M, Gil Z. Macrophages increase the resistance of pancreatic adenocarcinoma cells to gemcitabine by upregulating cytidine deaminase. Oncoimmunology 2013;2:e27231.
64. Eckford PD, Sharom FJ. ABC efflux pump-based resistance to chemotherapy drugs. Chem Rev 2009;109:2989-3011.
65. Goodell MA, Rosenzweig M, Kim H, Marks DF, DeMaria M, et al. Dye efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species. Nat Med 1997;3:1337-45.
66. Fukuda K, Saikawa Y, Ohashi M, Kumagai K, Kitajima M, et al. Tumor initiating potential of side population cells in human gastric cancer. Int J Oncol 2009;34:1201-7.
67. Borst P. Cancer drug pan-resistance: pumps, cancer stem cells, quiescence, epithelial to mesenchymal transition, blocked cell death pathways, persisters or what? Open Biol 2012;2:120066.
68. Polgar O, Bates SE. ABC transporters in the balance: is there a role in multidrug resistance? Biochem Soc Trans 2005;33:241-5.
69. Bergman AM, Munch-Petersen B, Jensen PB, Sehested M, Veerman G, et al. Collateral sensitivity to gemcitabine (2’,2’-difluorodeoxycytidine) and cytosine arabinoside of daunorubicin- and VM-26-resistant variants of human small cell lung cancer cell lines. Biochem Pharmacol 2001;61:1401-8.
70. Bergman AM, Pinedo HM, Talianidis I, Veerman G, Loves WJ, et al. Increased sensitivity to gemcitabine of P-glycoprotein and multidrug resistance-associated protein-overexpressing human cancer cell lines. Br J Cancer 2003;88:1963-70.
71. Adema AD, Floor K, Smid K, Honeywell RJ, Scheffer GL, et al. Overexpression of MRP4 (ABCC4) and MRP5 (ABCC5) confer resistance to the nucleoside analogs cytarabine and troxacitabine, but not gemcitabine. Springerplus 2014;3:732.
72. Rudin D, Li L, Niu N, Kalari KR, Gilbert JA, et al. Gemcitabine cytotoxicity: interaction of efflux and deamination. J Drug Metab Toxicol 2011;2:1-10.
73. Bouffard DY, Laliberte J, Momparler RL. Kinetic studies on 2’,2’-difluorodeoxycytidine (Gemcitabine) with purified human deoxycytidine kinase and cytidine deaminase. Biochem Pharmacol 1993;45:1857-61.
74. Wang L, Munch-Petersen B, Herrstrom Sjoberg A, Hellman U, Bergman T, et al. Human thymidine kinase 2: molecular cloning and characterisation of the enzyme activity with antiviral and cytostatic nucleoside substrates. FEBS Lett 1999;443:170-4.
75. Saiki Y, Yoshino Y, Fujimura H, Manabe T, Kudo Y, et al. DCK is frequently inactivated in acquired gemcitabine-resistant human cancer cells. Biochem Biophys Res Commun 2012;421:98-104.
76. Nakano T, Saiki Y, Kudo C, Hirayama A, Mizuguchi Y, et al. Acquisition of chemoresistance to gemcitabine is induced by a loss-of-function missense mutation of
77. Tang K, Zhang Z, Bai Z, Ma X, Guo W, et al. Enhancement of gemcitabine sensitivity in pancreatic cancer by co-regulation of dCK and p8 expression. Oncol Rep 2011;25:963-70.
78. Funamizu N, Okamoto A, Kamata Y, Misawa T, Uwagawa T, et al. Is the resistance of gemcitabine for pancreatic cancer settled only by overexpression of deoxycytidine kinase? Oncol Rep 2010;23:471-5.
79. Sierzega M, Pach R, Kulig P, Legutko J, Kulig J. Prognostic implications of expression profiling for gemcitabine-related genes (hENT1, dCK, RRM1, RRM2) in patients with resectable pancreatic adenocarcinoma receiving adjuvant chemotherapy. Pancreas 2017;46:684-9.
80. Ohmine K, Kawaguchi K, Ohtsuki S, Motoi F, Ohtsuka H, et al. Quantitative targeted proteomics of pancreatic cancer: Deoxycytidine kinase protein level correlates to progression-free survival of patients receiving gemcitabine treatment. Mol Pharm 2015;12:3282-91.
81. Costantino CL, Witkiewicz AK, Kuwano Y, Cozzitorto JA, Kennedy EP, et al. The role of HuR in gemcitabine efficacy in pancreatic cancer: HuR Up-regulates the expression of the gemcitabine metabolizing enzyme deoxycytidine kinase. Cancer Res 2009;69:4567-72.
82. Tatarian T, Jiang W, Leiby BE, Grigoli A, Jimbo M, et al. Cytoplasmic HuR status predicts disease-free survival in resected pancreatic cancer: a post-hoc analysis from the International Phase III ESPAC-3 Clinical Trial. Ann Surg 2018;267:364-9.
83. Slusarczyk M, Lopez MH, Balzarini J, Mason M, Jiang WG, et al. Application of ProTide technology to gemcitabine: a successful approach to overcome the key cancer resistance mechanisms leads to a new agent (NUC-1031) in clinical development. J Med Chem 2014;57:1531-42.
84. Blagden SP, Rizzuto I, Suppiah P, O’Shea D, Patel M, et al. Anti-tumour activity of a first-in-class agent NUC-1031 in patients with advanced cancer: results of a phase I study. Br J Cancer 2018;119:815-22.
85. McNamara MG, Goyal L, Doherty M, Springfeld C, Cosgrove D, et al. NUC-1031/cisplatin versus gemcitabine/cisplatin in untreated locally advanced/metastatic biliary tract cancer (NuTide:121). Future Oncol 2020; doi: 10.2217/fon-2020-0247.
86. Daifuku R, Koratich M, Stackhouse M. Vitamin E phosphate nucleoside prodrugs: a platform for intracellular delivery of monophosphorylated nucleosides. Pharmaceuticals (Basel) 2018;11.
87. Shewach DS, Hahn TM, Chang E, Hertel LW, Lawrence TS. Metabolism of 2’,2’-difluoro-2’-deoxycytidine and radiation sensitization of human colon carcinoma cells. Cancer Res 1994;54:3218-23.
88. Gregoire V, Rosier JF, De Bast M, Bruniaux M, De Coster B, et al. Role of deoxycytidine kinase (dCK) activity in gemcitabine’s radioenhancement in mice and human cell lines
89. Van Den Neste E, Smal C, Cardoen S, Delacauw A, Frankard J, et al. Activation of deoxycytidine kinase by UV-C-irradiation in chronic lymphocytic leukemia B-lymphocytes. Biochem Pharmacol 2003;65:573-80.
90. Sigmond J, Haveman J, Kreder NC, Loves WJ, van Bree C, et al. Enhanced activity of deoxycytidine kinase after pulsed low dose rate and single dose gamma irradiation. Nucleosides Nucleotides Nucleic Acids 2006;25:1177-80.
91. Yang C, Lee M, Hao J, Cui X, Guo X, et al. Deoxycytidine kinase regulates the G2/M checkpoint through interaction with cyclin-dependent kinase 1 in response to DNA damage. Nucleic Acids Res 2012;40:9621-32.
92. Beyaert M, Starczewska E, Van Den Neste E, Bontemps F. A crucial role for ATR in the regulation of deoxycytidine kinase activity. Biochem Pharmacol 2016;100:40-50.
93. McSorley T, Ort S, Hazra S, Lavie A, Konrad M. Mimicking phosphorylation of Ser-74 on human deoxycytidine kinase selectively increases catalytic activity for dC and dC analogues. FEBS Lett 2008;582:720-4.
94. Sharma B, Crist RM, Adiseshaiah PP. Nanotechnology as a delivery tool for precision cancer therapies. AAPS J 2017;19:1632-42.
95. Elechalawar CK, Hossen MN, Shankarappa P, Peer CJ, Figg WD, et al. Targeting pancreatic cancer cells and stellate cells using designer nanotherapeutics
