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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 1/2016

Open Access 01-07-2016 | Review Article

Pharmacokinetics and pharmacogenetics of Gemcitabine as a mainstay in adult and pediatric oncology: an EORTC-PAMM perspective

Authors: Joseph Ciccolini, Cindy Serdjebi, Godefridus J. Peters, Elisa Giovannetti

Published in: Cancer Chemotherapy and Pharmacology | Issue 1/2016

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Abstract

Gemcitabine is an antimetabolite ranking among the most prescribed anticancer drugs worldwide. This nucleoside analog exerts its antiproliferative action after tumoral conversion into active triphosphorylated nucleotides interfering with DNA synthesis and targeting ribonucleotide reductase. Gemcitabine is a mainstay for treating pancreatic and lung cancers, alone or in combination with several cytotoxic drugs (nab-paclitaxel, cisplatin and oxaliplatin), and is an option in a variety of other solid or hematological cancers. Several determinants of response have been identified with gemcitabine, i.e., membrane transporters, activating and inactivating enzymes at the tumor level, or Hedgehog signaling pathway. More recent studies have investigated how germinal genetic polymorphisms affecting cytidine deaminase, the enzyme responsible for the liver disposition of gemcitabine, could act as well as a marker for clinical outcome (i.e., toxicity, efficacy) at the bedside. Besides, constant efforts have been made to develop alternative chemical derivatives or encapsulated forms of gemcitabine, as an attempt to improve its metabolism and pharmacokinetics profile. Overall, gemcitabine is a drug paradigmatic for constant searches of the scientific community to improve its administration through the development of personalized medicine in oncology.
Literature
1.
Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15:2403–2413PubMed
2.
Sandler A, Ettinger DS (1999) Gemcitabine: single-agent and combination therapy in non-small cell lung cancer. Oncologist 4:241–251PubMed
3.
Shelley MD, Jones G, Cleves A, Jones G, Cleves A, Wilt TJ, Mason MD, Kynaston HG (2012) Intravesical gemcitabine therapy for non-muscle invasive bladder cancer (NMIBC): a systematic review. BJU Int 109:496–505PubMedCrossRef
4.
Kroep JR, Giaccone G, Tolis C, Voorn DA, Loves WJ, Groeningen CJ, Pinedo HM, Peters GJ (2000) 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 83:1069–1076PubMedPubMedCentralCrossRef
5.
Kim TM, Kim S, Ahn YO, Lee SH, Kim DW, Heo DS (2014) Anti-cancer activity of gemcitabine against natural killer cell leukemia/lymphoma. Leuk Lymphoma 55:940–943PubMedCrossRef
6.
Mini E, Nobili S, Caciagli B, Landini I, Mazzei T (2006) Cellular pharmacology of gemcitabine. Ann Oncol 17(Suppl 5):v7–v12PubMedCrossRef
7.
8.
van Riel JM, Peters GJ, Mammatas LH, Honeywell RJ, Laan AC, Ruyter R, van den Berg FG, Giaccone G, van Groeningen CJ (2009) A phase I and pharmacokinetic study of gemcitabine given by 24-h hepatic arterial infusion. Eur J Cancer 45:2519–2527. doi:10.​1016/​j.​ejca.​2009.​05.​025 PubMedCrossRef
9.
10.
Elnaggar M, Giovannetti E, Peters GJ (2012) Molecular targets of gemcitabine action: rationale for development of novel drugs and drug combinations. Curr Pharm Des 18:2811–2829PubMedCrossRef
11.
Mackey JR, Mani RS, Selner M, Mowles D, Young JD, Belt JA, Crawford CR, Cass CE (1998) Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. Cancer Res 58:4349–4357PubMed
12.
Peters GJ, van der Wilt CL, van Moorsel CJ, Kroep JR, Bergman AM, Ackland SP (2000) Basis for effective combination cancer chemotherapy with antimetabolites. Pharmacol Ther 87:227–253PubMedCrossRef
13.
van Bree C, Castro Kreder N, Loves WJ, Franken NA, Peters GJ, Haveman J (2002) Sensitivity to ionizing radiation and chemotherapeutic agents in gemcitabine-resistant human tumor cell lines. Int J Radiat Oncol Biol Phys 54:237–244PubMedCrossRef
14.
Giovannetti E, Mey V, Nannizzi S, Pasqualetti G, Marini L, Del Tacca M, Danesi R (2005) Cellular and pharmacogenetics foundation of synergistic interaction of pemetrexed and gemcitabine in human non-small-cell lung cancer cells. Mol Pharmacol 68:110–118PubMed
15.
Kroep JR, Loves WJ, van der Wilt CL, Alvarez E, Talianidis I, Boven E, Braakhuis BJ, van Groeningen CJ, Pinedo HM, Peters GJ (2002) Pretreatment deoxycytidine kinase levels predict in vivo gemcitabine sensitivity. Mol Cancer Ther 1:371–376PubMed
16.
Huang P, Chubb S, Hertel LW, Grindey GB, Plunkett W (1991) Action of 2′,2′-difluorodeoxycytidine on DNA synthesis. Cancer Res 51:6110–6117PubMed
17.
Ruiz van Haperen V, Veerman G, Vermorken JB, Peters GJ (1993) 2′,2′-Difluoro-deoxycytidine (gemcitabine) incorporation into RNA and DNA of tumour cell lines. Biochem Pharmacol 46:762–766PubMedCrossRef
18.
Heinemann V, Xu YZ, Chubb S, Sen A, Hertel LW, Grindey GB, Plunkett W (1990) Inhibition of ribonucleotide reduction in CCRF-CEM cells by 2′,2′-difluorodeoxycytidine. Mol Pharmacol 38:567–572PubMed
19.
Peters GJ, Clavel M, Noordhuis P, Geyssen GJ, Laan AC, Guastalla J, Edzes HT, Vermorken JB (2007) Clinical phase I and pharmacology study of gemcitabine (2′, 2′-difluorodeoxycytidine) administered in a two-weekly schedule. J Chemother 19:212–221PubMedCrossRef
20.
Heinemann V, Xu YZ, Chubb S, Sen A, Hertel LW, Grindey GB, Plunkett W (1992) Cellular elimination of 2′,2′- difluorodeoxycytidine 5′-triphosphate: a mechanism of self-potentiation. Cancer Res 52:533–539PubMed
21.
Hodge LS, Taub ME, Tracy TS (2011) The deaminated metabolite of gemcitabine, 2′,2′-difluorodeoxyuridine, modulates the rate of gemcitabine transport and intracellular phosphorylation via deoxycytidine kinase. Drug Metab Dispos 39:2013–2016. doi:10.​1124/​dmd.​111.​040790 PubMedCrossRef
22.
Heinemann V, Schulz L, Issels RD, Plunkett W (1995) Gemcitabine: a modulator of intracellular nucleotide and deoxynucleotide metabolism. Semin Oncol 22(4 Suppl 11):11–18PubMed
23.
Van Moorsel CJA, Bergman AM, Veerman G, Voorn DA, Ruiz van Haperen VWT, Kroep JR, Pinedo HM, Peters GJ (2000) Differential effects of gemcitabine on ribonucleotide pools of twenty-one solid tumour and leukemia cell lines. Biochim Biophys Acta 1474:5–12PubMedCrossRef
24.
Honeywell RJ, Ruiz van Haperen VW, Veerman G, Smid K, Peters GJ (2015) Inhibition of thymidylate synthase by 2′,2′-difluoro-2′-deoxycytidine (Gemcitabine) and its metabolite 2′,2′-difluoro-2′-deoxyuridine. Int J Biochem Cell Biol 60:73–81. doi:10.​1016/​j.​biocel.​2014.​12.​010 PubMedCrossRef
25.
Abbruzzese JL, Grunewald R, Weeks EA, Gravel D, Adams T, Nowak B, Mineishi S, Tarassoff P, Satterlee W, Raber MN (1991) A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol 9:491–498PubMed
26.
Peters GJ, Schornagel JH, Milano GA (1993) Clinical pharmacokinetics of anti-metabolites. Cancer Surv 17:123–156PubMed
27.
van Moorsel CJ, Kroep JR, Pinedo HM, Veerman G, Voorn DA, Postmus PE, Vermorken JB, van Groeningen CJ, van der Vijgh WJ, Peters GJ (1999) Pharmacokinetic schedule finding study of the combination of gemcitabine and cisplatin in patients with solid tumors. Ann Oncol 10:441–448PubMedCrossRef
28.
Kroep JR, Giaccone G, Voorn DA, Smit EF, Beijnen JH, Rosing H, van Moorsel CJ, van Groeningen CJ, Postmus PE, Pinedo HM, Peters GJ (1999) Gemcitabine and paclitaxel: pharmacokinetic and pharmacodynamic inter- actions in patients with non-small-cell lung cancer. J Clin Oncol 17:2190–2197PubMed
29.
Kuenen BC, Rosen L, Smit EF, Parson MR, Levi M, Ruijter R, Huisman H, Kedde MA, Noordhuis P, van der Vijgh WJ, Peters GJ, Cropp GF, Scigalla P, Hoekman K, Pinedo HM, Giaccone G (2002) Dose-finding and pharmacokinetic study of cisplatin, gemcitabine, and SU5416 in patients with solid tumors. J Clin Oncol 20:1657–1667PubMedCrossRef
30.
Kroep JR, Smit EF, Giaccone G, Van der Born K, Beijnen JH, Van Groeningen CJ, Van der Vijgh WJ, Postmus PE, Pinedo HM, Peters GJ (2006) Pharmacology of the paclitaxel-cisplatin, gemcitabine-cisplatin, and paclitaxel-gemcitabine combinations in patients with advanced non-small cell lung cancer. Cancer Chemother Pharmacol 58:509–516PubMedCrossRef
31.
de Lange SM, van der Born K, Kroep JR, Jensen HA, Pfeiffer P, Cleverly A, van Groeningen CJ, Peters GJ (2005) No evidence of gemcitabine accumulation during weekly administration. Eur J Clin Pharmacol 61:843–849PubMedCrossRef
32.
Ruiz van Haperen VW, Veerman G, Boven E, Noordhuis P, Vermorken JB, Peters GJ (1994) Schedule dependence of sensitivity to 2′,2′-difluorodeoxycytidine (Gemcitabine) in relation to accumulation and retention of its triphosphate in solid tumour cell lines and solid tumours. Biochem Pharmacol 48:1327–1339PubMedCrossRef
33.
Pauwels B, Korst AE, Lambrechts HA, Pattyn GG, de Pooter CM, Lardon F, Vermorken JB (2006) The radiosensitising effect of difluorodeoxyuridine, a metabolite of gemcitabine, in vitro. Cancer Chemother Pharmacol 58:219–228PubMedCrossRef
34.
Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O’Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd (2009) Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 27:3778–3785. doi:10.​1200/​JCO.​2008.​20.​9007 PubMedPubMedCentralCrossRef
35.
Faivre S, Le Chevalier T, Monnerat C, Lokiec F, Novello S, Taieb J, Pautier P, Lhommé C, Ruffié P, Kayitalire L, Armand JP, Raymond E (2002) Phase I-II and pharmacokinetic study of gemcitabine combined with oxaliplatin in patients with advanced non-small-cell lung cancer and ovarian carcinoma. Ann Oncol 13:1479–1489PubMedCrossRef
36.
Voortman J, Smit EF, Honeywell R, Kuenen BC, Peters GJ, Van de Velde H, Giaccone G (2007) 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 13:3642–3651PubMedCrossRef
37.
Theodore C, Geoffrois L, Vermorken JB, Caponigro F, Fiedler W, Chollet P, Ravaud A, Peters GJ, Balincourt C, Fumoleau P (2005) Multicentre EORTC study 16997: feasibility and phase II trial of farnesyl transferase inhibitor and gemcitabine combination in salvage treatment of advanced urothelial tract cancers. Eur J Cancer 41:1150–1157PubMedCrossRef
38.
Giaccone G, González-Larriba JL, Van Oosterom AT, Alfonso R, Smit EF, Martens M, Peters GJ, Van der Vijgh WJF, Smith R, Averbuch S, Fandi A (2004) Combination therapy with gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, gemcitabine and cisplatin in patients with advanced solid tumors. Ann Oncol 15:831–838PubMedCrossRef
39.
Koolen SL, Witteveen PO, Jansen RS, Langenberg MH, Kronemeijer RH, Nol A, Garcia-Ribas I, Callies S, Benhadji KA, Slapak CA, Beijnen JH, Voest EE, Schellens JH (2011) Phase I study of Oral gemcitabine prodrug (LY2334737) alone and in combination with erlotinib in patients with advanced solid tumors. Clin Cancer Res 17:6071–6082PubMedCrossRef
40.
Ceresa C, Giovannetti E, Voortman J, Laan AC, Honeywell R, Giaccone G, Peters GJ (2009) Bortezomib induces schedule-dependent modulation of gemcitabine pharmacokinetics and pharmacodynamics in non-small cell lung cancer and blood mononuclear cells. Mol Cancer Ther 8:1026–1036. doi:10.​1158/​1535-7163.​MCT-08-0700 PubMedCrossRef
41.
Honeywell RJ, Giovannetti E, Peters GJ (2011) Determination of the phosphorylated metabolites of gemcitabine and of difluorodeoxyuridine by LCMSMS. Nucleosides Nucleotides Nucleic Acids 30:1203–1213PubMedCrossRef
42.
Grunewald R, Kantarjian H, Keating MJ, Abbruzzese J, Tarassoff P, Plunkett W (1990) Pharmacologically directed design of the dose rate and schedule of 2′,2′-difluorodeoxycytidine (Gemcitabine) administration in leukemia. Cancer Res 50:6823–6826PubMed
43.
Grunewald R, Abbruzzese JL, Tarassoff P, Plunkett W (1991) Saturation of 2′,2′-difluorodeoxycytidine 5′-triphosphate accumulation by mononuclear cells during a phase I trial of gemcitabine. Cancer Chemother Pharmacol 27:258–262PubMedCrossRef
44.
Grunewald R, Kantarjian H, Du M, Faucher K, Tarassoff P, Plunkett W (1992) Gemcitabine in leukemia: a phase I clinical, plasma, and cellular pharmacology study. J Clin Oncol 10:406–413PubMed
45.
Pollera CF, Ceribelli A, Crecco M, Oliva C, Calabresi F (1997) Prolonged infusion gemcitabine: a clinical phase I study at low—(300 mg/m2) and high-dose (875 mg/m2) levels. Invest New Drugs 15:115–121PubMedCrossRef
46.
Tempero M, Plunkett W, Ruiz Van Haperen V, Hainsworth J, Hochster H, Lenzi R, Abbruzzese J (2003) Randomized phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. J Clin Oncol 21:3402–3408PubMedCrossRef
47.
Bengala C, Guarneri V, Giovannetti E, Lencioni M, Fontana E, Mey V, Fontana A, Boggi U, Del Chiaro M, Danesi R, Ricci S, Mosca F, Del Tacca M, Conte PF (2005) Prolonged fixed dose rate infusion of gemcitabine with autologous haemopoietic support in advanced pancreatic adenocarcinoma. Br J Cancer 93:35–40PubMedPubMedCentralCrossRef
48.
49.
50.
Cattel L, Airoldi M, Delprino L, Passera R, Milla P, Pedani F (2006) Pharmacokinetic evaluation of gemcitabine and 2′,2′-difluorodeoxycytidine-5′-triphosphate after prolonged infusion in patients affected by different solid tumors. Ann Oncol 17(Suppl 5):v142–v147PubMedCrossRef
51.
Ciccolini J, Dahan L, André N, Evrard A, Duluc M, Blesius A, Yang C, Giacometti S, Brunet C, Raynal C, Ortiz A, Frances N, Iliadis A, Duffaud F, Seitz JF, Mercier C (2010) Cytidine deaminase residual activity in serum is a predictive marker of early severe toxicities in adults after gemcitabine-based chemotherapies. J Clin Oncol 28:160–165PubMedCrossRef
52.
Mercier C, Raynal C, Dahan L, Ortiz A, Evrard A, Dupuis C, Blesius A, Duluc M, Franceschini F, Giacometti S, Salas S, Milano G, Favre R, Seitz JF, Ciccolini J (2007) Toxic death case in a patient undergoing gemcitabine-based chemotherapy in relation with cytidine deaminase downregulation. Pharmacogenet Genomics 17:841–844PubMedCrossRef
53.
Raynal C, Ciccolini J, Mercier C, Boyer JC, Polge A, Lallemant B, Mouzat K, Lumbroso S, Brouillet JP, Evrard A (2010) High-resolution melting analysis of sequence variations in the cytidine deaminase gene (CDA) in patients with cancer treated with gemcitabine. Ther Drug Monit 32:53–56PubMedCrossRef
54.
Farrell JJ, Bae K, Wong J, Guha C, Dicker AP, Elsaleh H (2012) Cytidine deaminase single-nucleotide polymorphism is predictive of toxicity from gemcitabine in patients with pancreatic cancer: rTOG 9704. Pharmacogenomics J 12:395–403PubMedCrossRef
55.
Tibaldi C, Giovannetti E, Tiseo M, Leon LG, D’Incecco A, Loosekoot N, Bartolotti M, Honeywell R, Cappuzzo F, Ardizzoni A, Peters GJ (2012) Correlation of cytidine deaminase polymorphisms and activity with clinical outcome in gemcitabine-/platinum-treated advanced non-small-cell lung cancer patients. Ann Oncol 23:670–677PubMedCrossRef
56.
Serdjebi C, Seitz JF, Ciccolini J, Duluc M, Norguet E, Fina F, Lacarelle B, Ouafik L, Dahan L (2013) Rapid deaminator status is associated with poor clinical outcome in pancreatic cancer patients treated with a gemcitabine-based regimen. Pharmacogenomics 14:1047–1051PubMedCrossRef
57.
Micozzi D, Carpi FM, Pucciarelli S, Polzonetti V, Polidori P, Vilar S, Williams B, Costanzi S, Vincenzetti S (2014) Human cytidine deaminase: a biochemical characterization of its naturally occurring variants. Int J Biol Macromol 63:64–74PubMedCrossRef
58.
Schroder JK, Kirch C, Seeber S, Schutte J (1998) Structural and functional analysis of the cytidine deaminase gene in patients with acute myeloid leukaemia. Br J Haematol 103:1096–1103PubMedCrossRef
59.
Fitzgerald SM, Goyal RK, Osborne WR, Roy JD, Wilson JW, Ferrell RE (2006) Identification of functional single nucleotide polymorphism haplotypes in the cytidine deaminase promoter. Hum Genet 119:276–283PubMedCrossRef
60.
Teng YS, Anderson JE, Giblett ER (1975) Cytidine deaminase: a new genetic polymorphism demonstrated in human granulocytes. Am J Hum Genet 27:492–497PubMedPubMedCentral
61.
Gilbert JA, Salavaggione OE, Ji Y, Pelleymounter LL, Eckloff BW, Wieben ED, Ames MM, Weinshilboum RM (2006) Gemcitabine pharmacogenomics: cytidine deaminase and deoxycytidylate deaminase gene resequencing and functional genomics. Clin Cancer Res 12:1794–1803PubMedCrossRef
62.
Ludovini V, Floriani I, Pistola L, Minotti V, Meacci M, Chiari R, Garavaglia D, Tofanetti FR, Flacco A, Siggillino A, Baldelli E, Tonato M, Crinò L (2011) Association of cytidine deaminase and xeroderma pigmentosum group D polymorphisms with response, toxicity, and survival in cisplatin/gemcitabine-treated advanced non-small cell lung cancer patients. J Thorac Oncol 6:2018–2026PubMedCrossRef
63.
Maring JG, Wachters FM, Slijfer M, Maurer JM, Boezen HM, Uges DR, de Vries EG, Groen HJ (2010) Pharmacokinetics of gemcitabine in non-small-cell lung cancer patients: impact of the 79A>C cytidine deaminase polymorphism. Eur J Clin Pharmacol 66:611–617PubMedPubMedCentralCrossRef
64.
Mercier C, Dupuis C, Blesius A, Fanciullino R, Yang CG, Padovani L, Giacometti S, Frances N, Iliadis A, Duffaud F, Ciccolini J (2009) Early severe toxicities after capecitabine intake: possible implication of a cytidine deaminase extensive metabolizer profile. Cancer Chemother Pharmacol 63:1177–1780PubMedCrossRef
65.
Parmar S, Seeringer A, Denich D, Gärtner F, Pitterle K, Syrovets T, Ohmle B, Stingl JC (2011) Variability in transport and biotransformation of cytarabine is associated with its toxicity in peripheral blood mononuclear cells. Pharmacogenomics 12:503–514PubMedCrossRef
66.
Mahlknecht U, Dransfeld CL, Bulut N, Kramer M, Thiede C, Ehninger G, Schaich M (2009) SNP analyses in cytarabine metabolizing enzymes in AML patients and their impact on treatment response and patient survival: identification of CDA SNP C-451T as an independent prognostic parameter for survival. Leukemia 23:1929–1932PubMedCrossRef
67.
Soo RA, Wang LZ, Ng SS, Chong PY, Yong WP, Lee SC, Liu JJ, Choo TB, Tham LS, Lee HS, Goh BC, Soong R (2009) Distribution of gemcitabine pathway genotypes in ethnic Asians and their association with outcome in non-small cell lung cancer patients. Lung Cancer 63:121–127PubMedCrossRef
68.
Sugiyama E, Kaniwa N, Kim SR, Kikura-Hanajiri R, Hasegawa R, Maekawa K, Saito Y, Ozawa S, Sawada J, Kamatani N, Furuse J, Ishii H, Yoshida T, Ueno H, Okusaka T, Saijo N (2007) Pharmacokinetics of gemcitabine in Japanese cancer patients: the impact of a cytidine deaminase polymorphism. J Clin Oncol 25:32–42PubMedCrossRef
69.
Mercier C, Evrard A, Ciccolini J (2007) Genotype-based methods for anticipating gemcitabine-related severe toxicities may lead to false-negative results. J Clin Oncol 25:4855; author reply 4855-6
70.
Giovannetti E, Tibaldi C, Falcone A, Danesi R, Peters GJ (2010) Impact of cytidine deaminase polymorphisms on toxicity after gemcitabine: the question is still ongoing. J Clin Oncol 28:e221–e222PubMedCrossRef
71.
Caronia D, Martin M, Sastre J, de la Torre J, García-Sáenz JA, Alonso MR, Moreno LT, Pita G, Díaz-Rubio E, Benítez J, González-Neira A (2011) A polymorphism in the cytidine deaminase promoter predicts severe capecitabine-induced hand-foot syndrome. Clin Cancer Res 17:2006–2013PubMedCrossRef
72.
Serdjebi C, Ciccolini J, Fina F, Delarue A, Verschuur A, Lacarelle B, Ouafik L, André N (2014) Recipient/donor contradictory genotypes with impact on drug pharmacogenetics after liver transplant: a deadly gift? Pharmacogenet Genomics 24:527–529PubMed
73.
Yue L, Saikawa Y, Ota K, Tanaka M, Nishimura R, Uehara T, Maeba H, Ito T, Sasaki T, Koizumi S (2003) A functional single-nucleotide polymorphism in the human cytidine deaminase gene contributing to ara-C sensitivity. Pharmacogenetics 13:29–38PubMedCrossRef
74.
Ueno H, Kaniwa N, Okusaka T, Ikeda M, Morizane C, Kondo S, Sugiyama E, Kim SR, Hasegawa R, Saito Y, Yoshida T, Saijo N, Sawada J (2009) Homozygous CDA*3 is a major cause of life-threatening toxicities in gemcitabine-treated Japanese cancer patients. Br J Cancer 100:870–873PubMedPubMedCentralCrossRef
75.
Giovannetti E, Laan AC, Vasile E, Tibaldi C, Nannizzi S, Ricciardi S, Falcone A, Danesi R, Peters GJ (2008) Correlation between cytidine deaminase genotype and gemcitabine deamination in blood samples. Nucleosides Nucleotides Nucleic Acids 27:720–725PubMedCrossRef
76.
Tibaldi C, Giovannetti E, Vasile E, Mey V, Laan AC, Nannizzi S, Di Marsico R, Antonuzzo A, Orlandini C, Ricciardi S, Del Tacca M, Peters GJ, Falcone A, Danesi R (2008) Correlation of CDA, ERCC1, and XPD polymorphisms with response and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients. Clin Cancer Res 14:1797–1803PubMedCrossRef
77.
Abraham A, Varatharajan S, Abbas S, Zhang W, Shaji RV, Ahmed R, Abraham A, George B, Srivastava A, Chandy M, Mathews V, Balasubramanian P (2012) Cytidine deaminase genetic variants influence RNA expression and cytarabine cytotoxicity in acute myeloid leukemia. Pharmacogenomics 13:269–282PubMedCrossRef
78.
Xu J, Zhou Y, Zhang J, Chen Y, Zhuang R, Liu T, Cai W (2012) High incidence of severe neutropenia after gemcitabine-based chemotherapy in Chinese cancer patients with CDA 79A>C mutation. Clin Chim Acta 413:1284–1287PubMedCrossRef
79.
Baker JA, Wickremsinhe ER, Li CH, Oluyedun OA, Dantzig AH, Hall SD, Qian YW, Ring BJ, Wrighton SA, Guo Y (2013) Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Drug Metab Dispos 41:541–545PubMedCrossRef
80.
Mahfouz RZ, Jankowska A, Ebrahem Q, Gu X, Visconte V, Tabarroki A, Terse P, Covey J, Chan K, Ling Y, Engelke KJ, Sekeres MA, Tiu R, Maciejewski J, Radivoyevitch T, Saunthararajah Y (2013) Increased CDA expression/activity in males contributes to decreased cytidine analogue half-life and likely contributes to worse outcomes with 5-azacytidine or decitabine therapy. Clin Cancer Res 19:938–948PubMedPubMedCentralCrossRef
81.
82.
Grepin R, Guyot M, Jacquin M, Durivault J, Chamorey E, Sudaka A, Serdjebi C, Lacarelle B, Scoazec JY, Negrier S, Simonnet H, Pages G (2012) Acceleration of clear cell renal cell carcinoma growth in mice following bevacizumab/Avastin treatment: the role of CXCL cytokines. Oncogene 31:1683–1694PubMedCrossRef
83.
Yonemori K, Ueno H, Okusaka T, Yamamoto N, Ikeda M, Saijo N, Yoshida T, Ishii H, Furuse J, Sugiyama E, Kim SR, Kikura-Hanajiri R, Hasegawa R, Saito Y, Ozawa S, Kaniwa N, Sawada J (2005) Severe drug toxicity associated with a single-nucleotide polymorphism of the cytidine deaminase gene in a Japanese cancer patient treated with gemcitabine plus cisplatin. Clin Cancer Res 11:2620–2624PubMedCrossRef
84.
Ciccolini J, Evrard A, Lacarelle B (2012) A CDD polymorphism as predictor of capecitabine-induced hand-foot syndrome-letter. Clin Cancer Res 18:317PubMedCrossRef
85.
Sugiyama E, Lee SJ, Lee SS, Kim WY, Kim SR, Tohkin M, Hasegawa R, Okuda H, Kawamoto M, Kamatani N, Sawada J, Kaniwa N, Saito Y, Shin JG (2009) Ethnic differences of two non-synonymous single nucleotide polymorphisms in CDA gene. Drug Metab Pharmacokinet 24:553–556PubMedCrossRef
86.
Mackey JR, Mani RS, Selner M, Mowles D, Young JD, Belt JA, Crawford CR, Cass CE (1998) Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. Cancer Res 58:4349–4357PubMed
87.
Giovannetti E, Del Tacca M, Mey V, Funel N, Nannizzi S, Ricci S, Orlandini C, Boggi U, Campani D, Del Chiaro M, Iannopollo M, Bevilacqua G, Mosca F, Danesi R (2006) Transcription analysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemcitabine. Cancer Res 66:3928–3935PubMedCrossRef
88.
Farrell JJ, Elsaleh H, Garcia M, Lai R, Ammar A, Regine WF, Abrams R, Benson AB, Macdonald J, Cass CE, Dicker AP, Mackey JR (2009) Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer. Gastroenterology 136:187–195. doi:10.​1053/​j.​gastro.​2008.​09.​067 PubMedCrossRef
89.
Maréchal R, Mackey JR, Lai R, Demetter P, Peeters M, Polus M, Cass CE, Young J, Salmon I, Devière J, Van Laethem JL (2009) Human equilibrative nucleoside transporter 1 and human concentrative nucleoside transporter 3 predict survival after adjuvant gemcitabine therapy in resected pancreatic adenocarcinoma. Clin Cancer Res 15:2913–2919PubMedCrossRef
90.
Sebastiani V, Ricci F, Rubio-Viqueira B, Kulesza P, Yeo CJ, Hidalgo M, Klein A, Laheru D, Iacobuzio-Donahue CA (2006) Immunohistochemical and genetic evaluation of deoxycytidine kinase in pancreatic cancer: relationship to molecular mechanisms of gemcitabine resistance and survival. Clin Cancer Res 12:2492–2497PubMedPubMedCentralCrossRef
91.
Bepler G, Kusmartseva I, Sharma S, Gautam A, Cantor A, Sharma A, Simon G (2006) RRM1 modulated in vitro and in vivo efficacy of gemcitabine and platinum in non-small-cell lung cancer. J Clin Oncol 24:4731–4737PubMedCrossRef
92.
93.
94.
Xu M, Li L, Liu Z, Jiao Z, Xu P, Kong X, Huang H, Zhang Y (2013) ABCB2 (TAP1) as the downstream target of SHH signaling enhances pancreatic ductal adenocarcinoma drug resistance. Cancer Lett 333:152–158PubMedCrossRef
95.
Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, Madhu B, Goldgraben MA, Caldwell ME, Allard D, Frese KK, Denicola G, Feig C, Combs C, Winter SP, Ireland-Zecchini H, Reichelt S, Howat WJ, Chang A, Dhara M, Wang L, Rückert F, Grützmann R, Pilarsky C, Izeradjene K, Hingorani SR, Huang P, Davies SE, Plunkett W, Egorin M, Hruban RH, Whitebread N, McGovern K, Adams J, Iacobuzio-Donahue C, Griffiths J, Tuveson DA (2009) Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324:1457–1461PubMedPubMedCentralCrossRef
96.
97.
Tredan O, Galmarini CM, Patel K, Tannock IF (2007) Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst 99:1441–1454PubMedCrossRef
98.
Adema AD, Smid K, Losekoot N, Honeywell RJ, Verheul HM, Myhren F, Sandvold ML, Peters GJ (2012) Metabolism and accumulation of the lipophilic deoxynucleoside analogs elacytarabine and CP-4126. Invest New Drugs 30:1908–1916. doi:10.​1007/​s10637-011-9756-8 PubMedCrossRef
99.
Poplin E, Wasan H, Rolfe L, Raponi M, Ikdahl T, Bondarenko I, Davidenko I, Bondar V, Garin A, Boeck S, Ormanns S, Heinemann V, Bassi C, Evans TR, Andersson R, Hahn H, Picozzi V, Dicker A, Mann E, Voong C, Kaur P, Isaacson J, Allen A (2013) 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 31:4453–4461PubMedCrossRef
100.
Yamamoto N, Nokihara H, Yamada Y, Uenaka K, Sekiguchi R, Makiuchi T, Slapak CA, Benhadji KA, Tamura T (2013) Phase I study of oral gemcitabine prodrug (LY2334737) in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol 71:1645–1655PubMedCrossRef
101.
Faivre SJ, Olszanski AJ, Weigang-Köhler K, Riess H, Cohen RB, Wang X, Myrand SP, Wickremsinhe ER, Horn CL, Ouyang H, Callies S, Benhadji KA, Raymond E (2015) Phase I dose escalation and pharmacokinetic evaluation of two different schedules of LY2334737, an oral gemcitabine prodrug, in patients with advanced solid tumors. Invest New Drugs 33:1206–1216PubMedCrossRef
102.
Slusarczyk M, Lopez MH, Balzarini J, Mason M, Jiang WG, Blagden S, Thompson E, Ghazaly E, McGuigan C (2014) 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 57:1531–1542
103.
Ghazaly EA, Joel S, Gribben JG, Mohammad T, Emiloju O, Stavraka C, Hopkins T, Gabra H, Wasan H, Habib NA, Leonard RCF, McGuigan C, Slusarczyk M, Blagden SP (2013) ProGem1: Phase I first-in-human study of the novel nucleotide NUC-1031 in adult patients with advanced solid tumors. J Clin Oncol 31 suppl:abstr 2576
104.
Blagden SP, Rizzuto I, Stavraka C, O’Shea D, Suppiah P, Patel M, Loyse N, Sukumaran A, Bharwani N, Rockall A, Gabra H, El-Bahrawy M, Wasan HS, Leonard RCF, Habib NG, McGuigan C, Gribben JG, Ghazaly EA (2015) A first in human Phase I/II study of NUC-1031 in patients with advanced gynecological cancers. J Clin Oncol 33 suppl:abstr. 2547
105.
Adema AD, Bijnsdorp IV, Sandvold ML, Verheul HM, Peters GJ (2009) Innovations and opportunities to improve conventional (deoxy)nucleoside and fluoropyrimidine analogs in cancer. Curr Med Chem 16:4632–4643PubMedCrossRef
106.
Patra CR, Bhattacharya R, Wang E, Katarya A, Lau JS, Dutta S, Muders M, Wang S, Buhrow SA, Safgren SL, Yaszemski MJ, Reid JM, Ames MM, Mukherjee P, Mukhopadhyay D (2008) Targeted delivery of gemcitabine to pancreatic adenocarcinoma using cetuximab as a targeting agent. Cancer Res 68:1970–1978PubMedCrossRef
107.
Reddy LH, Khoury H, Paci A, Deroussent A, Ferreira H, Dubernet C, Decleves X, Besnard M, Chacun H, Lepetre-Mouelhi S, Desmaele D, Rousseau B, Laugier C, Cintrat JC, Vassal G, Couvreur P (2008) Squalenoylation favorably modifies the in vivo pharmacokinetics and biodistribution of gemcitabine in mice. Drug Metab Dispos 36:1570–1577PubMedCrossRef
108.
Pasut G, Canal F, Dalla VL, Arpicco S, Veronese FM, Schiavon O (2008) Antitumoral activity of PEG-gemcitabine prodrugs targeted by folic acid. J Control Release 127:239–248PubMedCrossRef
109.
Celia C, Malara N, Terracciano R, Cosco D, Paolino D, Fresta M, Savino R (2008) Liposomal delivery improves the growth-inhibitory and apoptotic activity of low doses of gemcitabine in multiple myeloma cancer cells. Nanomedicine 4:155–166PubMed
110.
Joerger M, Burgers JA, Baas P, Doodeman VD, Smits PH, Jansen RS, Vainchtein LD, Rosing H, Huitema AD, Beijnen JH, Schellens JH (2012) Gene polymorphisms, pharmacokinetics, and hematological toxicity in advanced non-small-cell lung cancer patients receiving cisplatin/gemcitabine. Cancer Chemother Pharmacol 69:25–33. doi:10.​1007/​s00280-011-1670-4 PubMedCrossRef
111.
Peters GJ, Honeywell RJ, Maulandi M, Giovannetti E, Losekoot N, Etienne-Grimaldi MC, Milano G, Serdjebi C, Ciccolini J, EORTC-Pharmacology and Molecular Mechanism Group (2014) Selection of the best blood compartment to measure cytidine deaminase activity to stratify for optimal gemcitabine or cytarabine treatment. Nucleosides Nucleotides Nucleic Acids 33:403–412PubMedCrossRef
112.
113.
Okazaki T, Javle M, Tanaka M, Abbruzzese JL, Li D (2010) Single nucleotide polymorphisms of gemcitabine metabolic genes and pancreatic cancer survival and drug toxicity. Clin Cancer Res 16:320–329PubMedCrossRef
Metadata
Title
Pharmacokinetics and pharmacogenetics of Gemcitabine as a mainstay in adult and pediatric oncology: an EORTC-PAMM perspective
Authors
Joseph Ciccolini
Cindy Serdjebi
Godefridus J. Peters
Elisa Giovannetti
Publication date
01-07-2016
Publisher
Springer Berlin Heidelberg
Published in
Cancer Chemotherapy and Pharmacology / Issue 1/2016
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-016-3003-0

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