We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine
Published Online:https://doi.org/10.2217/pgs-2017-0034

Gemcitabine is an anticancer agent acting against several solid tumors. It requires nucleoside transporters for cellular uptake and deoxycytidine kinase for activation into active gemcitabine-triphosphate, which is incorporated into the DNA and RNA. However, it can also be deaminated in the plasma. The intracellular level of gemcitabine-triphosphate is affected by scheduling or by combination with other chemotherapeutic regimens. Moreover, higher concentrations of gemcitabine-triphosphate may affect the toxicity, and possibly the clinical efficacy. As a consequence, different nucleoside analogs have been synthetized with the aim to increase the concentration of gemcitabine-triphosphate into cells. In this review, we summarize currently published evidence on pharmacological factors affecting the intracellular level of gemcitabine-triphosphate to guide future trials on the use of new nucleoside analogs.

References

  • 1 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. 53(11), 2406–2409 (1988).
  • 2 Toschi L, Finocchiario G, Bartolini S, Gioia V, Cappuzzo F. Role of Gemcitabine in cancer therapy. Future Oncol. 1(1), 7–17 (2005).
  • 3 Mini E, Nobili DS, Caciagli B, Landini I, Mazzei T. Cellular pharmacology of gemcitabine. Ann. Oncol. 17(Suppl. 5), v7–12 (2006).
  • 4 Bergman AM, Pinedo HM, Peters GJ. Determinants of resistance to 2’,2’-difluorodeoxycytidine (gemcitabine). Drug Resist. Updat. 5(1), 19–23 (2002).
  • 5 Galmarini CM, Mackey JR, Dumontet C. Nucleoside analogs and nucleobases in cancer treatment. Lancet Oncol. 3(7), 415–424 (2002).
  • 6 Eisenhauer EL, Zanagnolo V, Cohn DE et al. A Phase II study of gemcitabine, carboplatin and bevacizumab for the treatment of platinum-sensitive recurrent ovarian cancer. Gynecol. Oncol. 134(2), 262–266 (2014).
  • 7 Qian Z, Song Z, Zhang H, Wang X, Zhao J, Wang H. Gemcitabine, navelbine, and doxorubicin as treatment for patients with refractory or relapsed T-cell lymphoma. Biomed. Res. Int. 2015, 606–752 (2015).
  • 8 Ruiz van Haperen VW, Veerman G, Vermoken JB, Peters GJ. 2’,2’-difluoro-deoxycytidine (gemcitabine) incorporation into RNA and DNA of tumour cell lines. Biochem. Pharmacol. 46(4), 762–766 (1993).
  • 9 van Moorsel CJ, Smid K, Voom DA, Bergman AM, Pinedo HM. Peters GJ. Effect of gemcitabine and cisplatin combinations on ribonucleotide and deoxyribonucleotide pools in ovarian cancer cell lines. Int. J. Oncol. 22(1), 201–207 (2003).
  • 10 Storniolo AM, Enas NH, Brown CA, Voi M, Rothenberg ML, Schilsky RL. An investigational new drug treatment program for patients with gemcitabine. Results for over 3000 patients with pancreatic carcinoma. Cancer 85(6), 1261–1268 (1999).
  • 11 Young JD, Yao SY, Sun L, Cass CE, Baldwin SA. Human equilibrative nucleoside transporter (ENT) family of nucleoside and nucleobase transporter proteins. Xenobiotica 38(7–8), 995–1021 (2008).
  • 12 Johnson ZL, Lee JH, Lee K et al. Structural basis of nucleoside and nucleoside drug selectivity by concentrative nucleoside transporters. Elife 31(3), e03604 (2014).
  • 13 Spratlin JL, Mackey JR. Human equilibrative nucleoside transporter 1 (hENT1) in pancreatic adenocarcinoma: towards individualized treatment decisions. Cancers (Basel) 2(4), 2044–2054 (2010).
  • 14 Hung SW, Marrache S, Cummins S et al. Defective hCNT1 transport contributes to gemcitabine chemoresistance in ovarian cancer subtypes: overcoming transport defects using a nanoparticle approach. Cancer Lett. 359(2), 233–240 (2015).
  • 15 Honeywell R, Ruiz van Haperen VWT, Veerman G, Peters GJ Inhibition of thymidylate synthase by 2΄,2΄-difluoro-2’-deoxycytidine (Gemcitabine) and its metabolite 2’,2’-difluoro-2’-deoxyuridine. Int. J. Biochem. Cel. Biol. (60), 73–81 (2015).
  • 16 Gandhi V, Plunkett W. Modulatory activity of 2’,2’-difluorodeoxycytidine on the phosphorylation and cytotoxicity of arabinosyl nucleosides. Cancer Res. 50(12), 3675–3680 (1990).
  • 17 Abbruzzese JL, Grunewald R, Weeks EA et al. A Phase 1 clinical, plasma and cellular pharmacology study of gemcitabine. J Clin. Oncol. 9(3), 491–498 (1991).
  • 18 Grunewald R, Abbruzzese JL, Tarassoff P, Plunkett W. Saturation of 2’,2’-difluorodeoxycytidine 5’-triphosphate accumulation by mononuclear cells during a Phase I trial of gemcitabine. Cancer Chemother. Pharmacol. 27(4), 258–262 (1991).
  • 19 Huang P, Robertson LE, Wright S, Plunkett W. High molecular weight DNA fragmentation: a critical event in nucleoside analog-induced apoptosis in leukemia cells. Clin. Cancer Res. 1(9), 1005–1013 (1995).
  • 20 Garcia-Diaz M, Murray MS, Kunkel TA, Chou KM. Interaction between DNA Polymerase lambda and anticancer nucleoside analogs. J. Biol. Chem. 285(22), 16874–16879 (2010).
  • 21 Cerqueira NM, Fernandes PA, Ramos MJ. Understanding ribonucleotide reductase inactivation by gemcitabine. Chemistry 13(30), 8507–8515 (2007).
  • 22 Wang LR, Zhang GB, Chen J et al. RRM1 gene expression in peripheral blood is predictive of shorter survival in Chinese patients with advanced non-small-cell lung cancer treated by gemcitabine and platinum. J. Zhejiang Univ. Sci. B 12(3), 174–179 (2011).
  • 23 Minami K, Shinsato Y, Yamamoto M et al. Ribonucleotide reductase is an effective target to overcome gemcitabine resistance in gemcitabine-resistant pancreatic cancer cells with dual resistant factors. J. Pharmacol. Sci. 127(3), 319–325 (2011).
  • 24 Davidson JD, Ma L, Flagella M, Geeganage S, Gelbert LM, Slapak CA. An increase in the expression of ribonucleotide reductase large subunit 1 is associated with gemcitabine resistance in non-small cell lung cancer cell lines. Cancer Res. 64, 3761–3766 (2004).
  • 25 Bergman AM, Eijk PP, Ruiiz van Haperen VW et al. In vivo induction of resistance to gemcitabine results in increased expression of ribonucleotide reductase subunit M1 as the major determinant. Cancer Res. 65(20), 9510–9516 (2005).
  • 26 van Putten JWG, Groen HJM, Smid K, Peters GJ, Kampinga HH. End-joining deficiency and radiosensitization induced by gemcitabine. Cancer Res. 61(4), 1585–1591 (2001).
  • 27 Shewach DS, Lawrence TS. Antimetabolite radiosensitizers. J. Clin. Oncol. 25(26), 4043–4050 (2007).
  • 28 Fowler WC Jr, van Le L. Gemcitabine as a single-agent treatment for ovarian cancer. Gynecol. Oncol. 90(2), S21–S23 (2003).
  • 29 Kroep JR, Peters GJ, Nagourney RA. Clinical activity of gemcitabine as a single agent and in combination. In: Cancer Drug Discovery and Development. Peters GJ (Ed.). Human Press Inc., Totowa, NJ, USA, 253–288 (2006).
  • 30 Kroep JR, Smit EF, Giaccone G et al. Pharmacology of the paclitaxel-cisplatin, gemcitabine-cisplatin, and paclitaxel-gemcitabine combinations in patients with advanced non-small cell lung cancer. Cancer Chemother. Pharmacol. 58(4), 509–516 (2006).
  • 31 Abratt RP, Sandler A, Crino L et al. Combined cisplatin and gemcitabine for non-small cell lung cancer: influence of scheduling on toxicity and drug delivery. Sem. Oncol. 25(Suppl. 9), 35–43 (1998).
  • 32 Peters GJ, van der Wilt CL, van Moorsel CJ, Kroep JR, Bergman AM, Ackland SP. Basis for effective combination cancer chemotherapy with antimetabolites. Pharmacol. Ther. 87(2–3), 227–253 (2000).
  • 33 Huang P, Chubb S, Hertel LW, Grindey GB, Plunkett W. Action of 2’,2’-difluorodeoxycytidine on DNA sysnthesis. Cancer Res. 51(22), 6110–6117 (1991).
  • 34 Gandhi V, Plunkett W, DU M, Ayres M, Estey EH. Prolonged infusion of gemcitabine: clinical and pharmacodynamic studies during a Phase I trial in relapsed acute myelogenous leukemia. J. Clin. Oncol. 20(3), 665–673 (2002).
  • 35 Tempero M, Plunkett W, Ruiz van Haperen V et al. Randomized Phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. J. Clin. Oncol. 21(18), 3402–3408 (2003).
  • 36 Poplin E, Feng Y, Berlin J et al. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-mininfusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J. Clin. Oncol. 27(23), 3778–3785 (2009).
  • 37 van Moorsel CJ, Pinedo HM, Veerman G et al. Mechanisms of synergism between cisplatin and gemcitabine in ovarian and non-small-cell lung cancer cell lines. Brit. J. Cancer 80(7), 981–990 (1999).
  • 38 De Lange SM, van der Born K, Kroep JR et al. No evidence of gemcitabine accumulation during weekly administration. Eur. J. Clin. Pharmacol. 61(11), 843–849 (2005).
  • 39 Peters GJ, Clavel M, Noordhuis P et al. Clinical Phase I and pharmacology study of gemcitabine (2’2’-difluorodeoxycytidine) administered in a two-weekly schedule. J. Chemother. 19(2), 212–221 (2007).
  • 40 Sigmond J, Honeywell RJ, Postma TJ et al. Gemcitabine uptake in glioblastoma multiforme: potential as a radiosensitizer. Ann. Oncol. 20(1), 182–187 (2008).
  • 41 Kroep JR, Peters GJ, van Moorsel CJ et al. Gemcitabine-cisplatin: a schedule finding study. Ann. Oncol. 10(12), 1503–1510 (1999).
  • 42 van Moorsel CJ, Kroep JR, Pinedo HM et al. Pharmacokinetic schedule finding study of the combination of gemcitabine and cisplatin in patients with solid tumors. Ann. Oncol. 10(4), 441–448 (1999).
  • 43 Buesa JM, Losa R, Fernandez A et al. Phase I clinical trial of fixed-dose rate infusional gemcitabine and dacarbazine in the treatment of advanced soft tissue sarcoma, with assessment of gemcitabine triphosphate accumulation. Cancer 101(10), 2261–2269 (2004).
  • 44 Xiong HQ, Plunkett W, Wolff R, Du M, Lenzi R, Abbruzzese JL. A pharmacological study of celecoxib and gemcitabine in patients with advanced pancreatic cancer. Cancer Chemother. Pharmacol. 55(6), 559–564 (2004).
  • 45 Soo RA, Wang LZ, Tham LS et al. A multicentre randomised Phase II study of carboplatin in combination with gemcitabine at standard rate or fixed dose rate infusion in patients with advanced stage non-small-cell lung cancer. Ann. Oncol. 17(7), 1128–1133 (2006).
  • 46 Losa R, Fra J, Lopez-Pousa A et al. Phase II study with the combination of gemcitabine and DTIC in patients with advanced soft tissue sarcomas. Cancer Chemother. Pharmacol. 59(2), 251–259 (2007).
  • 47 Voortman J, Smit EF, Honeywell R et al. A parallel dose-escalation study of weekly and twice-weekly bortezomib in combination with gemcitabine and cisplatin in the first-line treatment of patients with advanced solid tumors. Clin. Cancer Res. 13(12), 3642–3651 (2007).
  • 48 Caffo O, Fallani S, Marangon E et al. Pharmacokinetic study of gemcitabine, given as prolonged infusion at fixed dose rate, in combination with cisplatin in patients with advanced non-small-cell lung cancer. Cancer Chemother. Pharmacol. 65(6), 1197–1202 (2010).
  • 49 Patel SR, Gandhi V, Jenkins J et al. Phase II clinical investigation of gemcitabine in advanced soft tissue sarcomas and window evaluation of dose rate on gemcitabine triphosphate accumulation. J. Clin. Oncol. 19(15), 3483–3489 (2001).
  • 50 Kroep JR, Giaccone G, Voom DA et al. Gemcitabine and paclitaxel: pharmacokinetic and pharmacodynamic interactions in patients with non-small-cell lung cancer. J. Clin. Oncol. 17(7), 2190–2197 (1999).
  • 51 Pollera CF, Ceribelli A, Crecco M, Crecco M, Oliva C, Calabresi F. Prolonged infusion gemcitabine: a clinical Phase I study at low (300 mg/m2) and high-dose (875 mg/m2) levels. Invest. New Drugs 15(2), 115–121 (1997).
  • 52 Schmid P, Akrivakis K, Flath B et al. Phase II trial of gemcitabine as prolonged infusion in metastatic breast cancer. Anticancer Drugs 10(7), 625–531 (1999).
  • 53 Heinemann V, Hertel LW, Grindey GB, Plunkett W. Comparison of the cellular pharmacokinetics and toxicity of 2’,2’-difluorodeoxycitidene and 1-beta-D-arabinofuranosylcytosine. Cancer Res. 48(14), 4024–4031 (1988).
  • 54 Grunewald R, Kantarjan H, Keating MJ, Abbruzzese J, Tarassoff P, Plunkett W. Pharmacologically directed design of the dose rate and chedule of 2’2’-difluorodeoxycytidine (gemcitabine) administration in leukemia. Cancer Res. 50(21), 6823–6826 (1990).
  • 55 Ceresa C, Giovannetti E, Voortman J et al. Bortezomib induces schedule-dependent modulation of gemcitabine pharmacokinetics and pharmacodynamics in non-small-cell lung cancer and blood mononuclear cells. Mol. Cancer Ther. 8(5), 1026–1036 (2009).
  • 56 Yip-Schneider MT, Barnard DS, Billings SD et al. Cycloxygenase 2 expression in human pancreatic adenocarcinomas. Carcinogenesis 21(2), 139–146 (2000).
  • 57 Maitra A, Ashfaq R, Gunn CR et al. Cyclooxygenase 2 expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasia: an immunohistochemical analysis with automated cellular imaging. Am. J. Clin. Pathol. 118(2), 194–201 (2002).
  • 58 Lorenz M, Slaughter HS, Wescott DM et al. Cycloxygenase-2 is essential for normal recovery from 5-fluorouracil-induced myelotoxicity in mice. Exp. Hematol. 27(10), 1494–1502 (1999).
  • 59 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 triphosphate in solid tumor cell lines and solid tumors. Biochem. Pharmacol. 48, 1327–1339 (1994).
  • 60 El-Naggar M, Omar M, Elgeriany A, Peters GJ, Mostafa A, Shehata S. Gemcitabine followed by radiotherapy in treatment of newly diagnosed high-grade gliomas – a single center experience. J. Cancer Metasta. Treat. 2, 188–194 (2016).
  • 61 van Moorsel CJ, Pinedo HM, Smid K et al. Schedule-dependent pharmacodynamic effects of gemcitabine and cisplatin in mice bearing Lewis lung murine non-small-cell lung tumours. Eur. J. Cancer 36(18), 2420–2429 (2000).
  • 62 Kroep JR, Giaccone G, Tolis C 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. British Journal of Cancer 83(8), 1069–1076 (2000).
  • 63 Nadkarni A, Burns JA, Gandolfi A et al. Nucleotide excision repair and transcription-coupled DNA repair abrogate the impact of DNA damage on transcription. J. Biol. Chem. 291(2), 848–861 (2015).
  • 64 Bergman AM, Ruiz van Haperen VW, Veerman G, Kuiper CM, Peters GJ. Synergistic interaction between cisplatin and gemcitabine in vitro. Clin. Cancer Res. 2(3), 521–530 (1996).
  • 65 van Moorsel CJ, Pinedo HM, Veerman G, Vermorken JB, Postmus PE, Peters GJ. Scheduling of gemcitabine and cisplatin in Lewis lung tumour bearing mice. Eur. J. Cancer 35(5), 808–814 (1999).
  • 66 Braakhuis BJ, Ruiz van Haperen VW, Welters MJ, Peters GJ. Schedule-dependent therapeutic efficacy of the combination of gemcitabine and cisplatin in head and neck cancer xenografts. Eur. J. Cancer 31A(13–14), 2335–2340 (1995).
  • 67 Ruiz van Haperen VW, 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 relation to chemosensitivity for 2’,2’-difluorodeoxycytidine. Biochem. Pharmacol. 51(7), 911–918 (1996).
  • 68 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(19), 4349–4357 (1998).
  • 69 Kroep JR, Loves WJ, VAN der Wilt CL et al. Pretreatment deoxycytidine kinase levels predict in vivo gemcitabine sensitivity. Mol. Cancer Ther. 1(6), 371–376 (2002).
  • 70 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. Clin. Cancer Res. 12(8), 2942–2997 (2006).
  • 71 El-Naggar M, Giovannetti E, Peters GJ. Molecular targets of gemcitabine action: rationale for development of novel drugs and drug combinations. Curr. Pharm. Design 18(19), 2811–2829 (2012).
  • 72 Greenhalf W, Ghaneh P, Neoptolemos JP et al. Pancreatic cancer hENT1 expression and survival from gemcitabine in patients from the ESPAC-3 Trial. J. Natl Cancer Inst. 106(1), djt347 (2014).
  • 73 Spratlin J, Sangha R, Glubrecht D et al. The absence of human equilibrative nucleoside transporter 1 is associated with reduced survival in patients with gemcitabine-treated pancreas adenocarcinoma. Clin. Cancer Res. 10(20), 6956–6961 (2004).
  • 74 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. Cancer Res. 66(7), 3928–3935 (2006).
  • 75 Marechal R, Mackey JR, Lai R et al. Human equilibrative nucleoside transporter 1 and human concentrative nucleoside transporter 3 predict survival after adjuvant gemcitabine therapy in resected pancreatic adenocarcinoma. Clin. Cancer Res. 15(8), 2913–2919 (2009).
  • 76 Adema AD, Bijnsdorp IV, Sandvold ML, Verheul HM, Peters GJ. Innovations and opportunities to improve conventional n(deoxy)ucleoside and fluoropyrimidine analogs in cancer. Curr. Med. Res. Opin. 16(35), 4632–4643 (2009).
  • 77 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, 456–466 (2011).
  • 78 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).
  • 79 Venugopal B, Awada A, Evans TR et al. A first-in-human Phase I and pharmacokinetic study of CP-4126 (CO-101), a nucleoside analog in patients with advanced solid tumours. Cancer Chemother. Pharmacol. 76(4), 785–792 (2015).
  • 80 Li D, Pant S, Ryan DP et al. A Phase II, open-label, multicenter study to evaluate the antitumor efficacy of CO-1.01 as second-line therapy for gemcitabine-refractory patients with stage IV pancreatic adenocarcinoma and negative tumor hENT1 expression. Pancreatology 14(5), 398–402 (2014).
  • 81 Poplin E, Wasan H, Rolfe L 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. 31(35), 4453–4461 (2013).
  • 82 Farrell JJ, Esaleh H, Garcia M et al. Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer. Gastroenterology 136(1), 187–195 (2009).
  • 83 Svrcek M, Cros J, Maréchal R, Bachet JB, Fléjou JF, Demetter P. Human equilibrative nucleoside transporter 1 testing in pancreatic ductal adenocarcinoma: a comparison between murine and rabbit antibodies. Histopathology 66, 457–462 (2015).
  • 84 Peters GJ. Novel developments in the use of antimetabolites. Nucleosides Nucleotides Nucleic Acids 33(4–6), 358–374 (2014).
  • 85 McGuigan C, Wang Y, Riley P. Synthesis and biological evaluation of substituted phosphate triester alkyllyso phospholipidis (ALPs) as novel potential anti-neoplastic agents. FEBS Lett. 372(2–3), 259–263 (1995).
  • 86 Slusarczyk M, Lopez MH, Balzarini J et al. Application of Protide technology to gemcitabine: a successsful approach to overcome the key cancer resistance mechanisms leads to a new agent (NUC-1031) in clinical development. J. Med. Chem. 57(4), 1531–1542 (2014).
  • 87 Blagden SP, Rizzuto I, Stavraka C et al. A first in human Phase I/II study of NUC-1031 in patients with advanced gynaecological cancers. J. Clin. Oncol. 33(Suppl.), Abstract 2547 (2015).
  • 88 Ghazaly EA, Joel S, Gribben JG et al. ProGem 1: Phase I first-in-human study of the novel nucleotide NUC-1031 in adult patients with advanced solid tumours. J. Clin. Oncol. 31(Suppl.), Abstract 2 (2013).