322
Views
9
CrossRef citations to date
0
Altmetric
Review

Nucleoside analogs: ready to enter the era of precision medicine?

, , , , &
Pages 865-877 | Received 25 Mar 2016, Accepted 16 May 2016, Published online: 30 May 2016

References

  • Chang C, Swaan PW, Ngo LY, et al. Molecular requirements of the human nucleoside transporters hCNT1, hCNT2, and hENT1. Mol Pharmacol. 2004;65(3):558–570.
  • Marce S, Molina-Arcas M, Villamor N, et al. Expression of human equilibrative nucleoside transporter 1 (hENT1) and its correlation with gemcitabine uptake and cytotoxicity in mantle cell lymphoma. Haematologica. 2006;91(7):895–902.
  • Kawada N, Uehara H, Katayama K, et al. Human equilibrative nucleoside transporter 1 level does not predict prognosis in pancreatic cancer patients treated with neoadjuvant chemoradiation including gemcitabine. J Hepato-Biliary-Pancreat Sci. 2012;19(6):717–722.
  • Kobayashi H, Murakami Y, Uemura K, et al. Human equilibrative nucleoside transporter 1 expression predicts survival of advanced cholangiocarcinoma patients treated with gemcitabine-based adjuvant chemotherapy after surgical resection. Ann Surg. 2012;256(2):288–296.
  • Matsumura N, Nakamura Y, Kohjimoto Y, et al. The prognostic significance of human equilibrative nucleoside transporter 1 expression in patients with metastatic bladder cancer treated with gemcitabine-cisplatin-based combination chemotherapy. BJU Int. 2011;108(2 Pt 2):E110–6.
  • Oguri T, Achiwa H, Muramatsu H, et al. The absence of human equilibrative nucleoside transporter 1 expression predicts nonresponse to gemcitabine-containing chemotherapy in non-small cell lung cancer. Cancer Lett. 2007;256(1):112–119.
  • Ormanns S, Heinemann V, Raponi M, et al. Human equilibrative nucleoside transporter 1 is not predictive for gemcitabine efficacy in advanced pancreatic cancer: translational results from the AIO-PK0104 phase III study with the clone SP120 rabbit antibody. Eur J Cancer. 2014;50(11):1891–1899.
  • Santini D, Schiavon G, Vincenzi B, et al. Human equilibrative nucleoside transporter 1 (hENT1) levels predict response to gemcitabine in patients with biliary tract cancer (BTC). Curr Cancer Drug Targets. 2011;11(1):123–129.
  • Sasaki H, Murakami Y, Uemura K, et al. Concurrent analysis of human equilibrative nucleoside transporter 1 and ribonucleotide reductase subunit 1 expression increases predictive value for prognosis in cholangiocarcinoma patients treated with adjuvant gemcitabine-based chemotherapy. Br J Cancer. 2014;111(7):1275–1284.
  • Nordh S. hENT1 expression is predictive of gemcitabine outcome in pancreatic cancer: A systematic review. World J Gastroenterol. 2014;20(26):8482.
  • Jordheim LP, Dumontet C. Do hENT1 and RRM1 predict the clinical benefit of gemcitabine in pancreatic cancer? Biomark Med. 2013;7(4):663–671.
  • Liu Z-Q, Han Y-C, Zhang X, et al. Prognostic value of human equilibrative nucleoside transporter1 in pancreatic cancer receiving gemcitabin-based chemotherapy: a meta-analysis. Plos ONE [Internet]. 2014;9(1). [cited 2016 Feb 24]. Available from : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3903621/
  • 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. 2009;15(8):2913– 2919.
  • Lane J, Martin TA, McGuigan C, et al. The differential expression of hCNT1 and hENT1 i n breast cancer and the possible impact on breast cancer therapy. J Exp Ther Oncol. 2010;8(3):203–210.
  • Lee S-Y, Im S-A, Park YH, et al. Genetic polymorphisms of SLC28A3, SLC29A1 and RRM1 predict clinical outcome in patients with metastatic breast cancer receiving gemcitabine plus paclitaxel chemotherapy. Eur J Cancer Oxf Engl 1990. 2014;50(4):698–705.
  • Hubeek I, Stam RW, Peters GJ, et al. The human equilibrative nucleoside transporter 1 mediates in vitro cytarabine sensitivity in childhood acute myeloid leukaemia. Br J Cancer. 2005;93(12):1388–1394.
  • Stam RW, Den Boer ML, Meijerink JPP, et al. Differential mRNA expression of Ara-C-metabolizing enzymes explains Ara-C sensitivity in MLL gene-rearranged infant acute lymphoblastic leukemia. Blood. 2003;101(4):1270–1276.
  • Galmarini CM, Thomas X, Calvo F, et al. In vivo mechanisms of resistance to cytarabine in acute myeloid leukaemia. Br J Haematol. 2002;117(4):860–868.
  • Galmarini CM, Thomas X, Calvo F, et al. Potential mechanisms of resistance to cytarabine in AML patients. Leuk Res. 2002;26(7):621–629.
  • Wan H, Zhu J, Chen F, et al. SLC29A1 single nucleotide polymorphisms as independent prognostic predictors for survival of patients with acute myeloid leukemia: an in vitro study. J Exp Clin Cancer Res CR [Internet]. 2014;33(1). [cited 2016 Feb 23]. Available from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234887/
  • Miyamoto Y, Lenz H-J, Baba H. A novel antimetabolite: TAS-102 for metastatic colorectal cancer. Expert Rev Clin Pharmacol. 2016;9(3):355–365.
  • García-González X, Cortejoso L, García MI, et al. Variants in CDA and ABCB1 are predictors of capecitabine-related adverse reactions in colorectal cancer. Oncotarget. 2015;6(8):6422–6430.
  • Homminga I, Zwaan CM, Manz CY, et al. In vitro efficacy of forodesine and nelarabine (ara-G) in pediatric leukemia. Blood. 2011;118(8):2184–2190.
  • Lamba JK, Crews K, Pounds S, et al. Pharmacogenetics of deoxycytidine kinase: identification and characterization of novel genetic variants. J Pharmacol Exp Ther. 2007;323(3):935–945.
  • Baker JAR, Wickremsinhe ER, Li CH, et al. Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Drug Metab Dispos. 2013;41(3):541–545.
  • Klanova M, Lorkova L, Vit O, et al. Downregulation of deoxycytidine kinase in cytarabine-resistant mantle cell lymphoma cells confers cross-resistance to nucleoside analogues gemcitabine, fludarabine and cladribine, but not to other classes of anti-lymphoma agents. Mol Cancer. 2014;13:159.
  • Bergman AM, Pinedo HM, Peters GJ. Determinants of resistance to 2′,2′-difluorodeoxycytidine (gemcitabine). Drug Resist Updat. 2002;5(1):19–33.
  • Bergman AM, Pinedo HM, Jongsma APM, et al. Decreased resistance to gemcitabine (2′,2′-difluorodeoxycitidine) of cytosine arabinoside-resistant myeloblastic murine and rat leukemia cell lines: role of altered activity and substrate specificity of deoxycytidine kinase. Biochem Pharmacol. 1999;57(4):397–406.
  • Banklau C, Jindadamrongwech S, Sawangpanich R, et al. Effect of genetic alterations of cytarabine- metabolizing enzymes in childhood acute lymphoblastic leukemia. Hematol Oncol Stem Cell Ther. 2010;3(3):103–108.
  • Song JH, Kim SH, Kweon SH, et al. Defective expression of deoxycytidine kinase in cytarabine-resistant acute myeloid leukemia cells. Int J Oncol. 2009;34(4):1165– 1171.
  • Gabor KM, Schermann G, Lautner-Csorba O, et al. Impact of single nucleotide polymorphisms of cytarabine metabolic genes on drug toxicity in childhood acute lymphoblastic leukemia: SNPs in cytarabine toxicity in pediatric ALL. Pediatr Blood Cancer. 2015;62(4):622–628.
  • Kakihar T, Fukuda T, Tanaka A, et al. Expression of Deoxycytidine Kinase (dCK) gene in leukemic cells in childhood: decreased expression of dCK gene in relapsed leukemia. Leuk Lymphoma. 1998;31(3–4):405–409.
  • Van der Wilt CL, Kroep JR, Loves WJP, et al. Expression of deoxycytidine kinase in leukaemic cells compared with solid tumour cell lines, liver metastases and normal liver. Eur J Cancer. 2003;39(5):691–697.
  • McAllister F, Pineda DM, Jimbo M, et al. dCK expression correlates with 5-fluorouracil efficacy and HuR cytoplasmic expression in pancreatic cancer. Cancer Biol Ther. 2014;15(6):688–698.
  • Roumier C, Cheok MH. Pharmacogenomics in acute myeloid leukemia. Pharmacogenomics. 2009;10(11):1839–1851.
  • Kocabas NA, Aksoy P, Pelleymounter LL, et al. Gemcitabine pharmacogenomics: deoxycytidine kinase and cytidylate kinase gene resequencing and functional genomics. Drug Metab Dispos Biol Fate Chem. 2008;36(9):1951–1959.
  • Woo HI, Kim KK, Choi H, et al. Effect of genetic polymorphisms on therapeutic response and clinical outcomes in pancreatic cancer patients treated with gemcitabine. Pharmacogenomics. 2012;13(9):1023–1035.
  • Cividini F, Filoni DN, Pesi R, et al. IMP-GMP specific cytosolic 5ʹ-nucleotidase regulates nucleotide pool and prodrug metabolism. Biochim Biophys Acta. 2015;1850(7):1354–1361.
  • Mitra AK, Crews KR, Pounds S, et al. Genetic variants in cytosolic 5ʹ-nucleotidase II are associated with its expression and cytarabine sensitivity in HapMap cell lines and in patients with acute myeloid leukemia. J Pharmacol Exp Ther. 2011;339(1):9–23.
  • Falk IJ, Fyrberg A, Paul E, et al. Decreased survival in normal karyotype AML with single-nucleotide polymorphisms in genes encoding the AraC metabolizing enzymes cytidine deaminase and 5ʹ-nucleotidase. Am J Hematol. 2013;88(12):1001–1006.
  • Ciccolini J, Fina F, Bezulier K, et al. Transmission of apoptosis in human colorectal tumor cells exposed to capecitabine, xeloda, is mediated via Fas 1 Mol. Cancer Ther. 2002;1(11):923– 927.
  • Terranova-Barberio M, Roca MS, Zotti AI, et al. Valproic acid potentiates the anticancer activity of capecitabine in vitro and in vivo in breast cancer models via induction of thymidine phosphorylase expression. Oncotarget. 2015;7(7):7715–7731
  • Ciccolini J, Peillard L, Evrard A, et al. Enhanced antitumor activity of 5-fluorouracil in combination with 2ʹ-deoxyinosine in human colorectal cell lines and human colon tumor xenografts. Clin Cancer Res Off J Am Assoc Cancer Res. 2000;6(4):1529–1535.
  • Ciccolini J, Evrard A, Cuq P. Thymidine phosphorylase and fluoropyrimidines efficacy: a Jekyll and Hyde story. Curr Med Chem Anti-Cancer Agents. 2004;4(2):71–81.
  • Elamin YY, Rafee S, Osman NO, et al. Thymidine phosphorylase in cancer; enemy or friend?. Cancer Microenviron Off J Int Cancer Microenviron Soc. 2015;9:33–43.
  • Lu M, Gao J, Wang X, et al. Expressions of thymidylate synthase, thymidine phosphorylase, Class III β-tubulin, and excision repair cross-complementing group 1predict response in advanced gastric cancer patients receiving capecitabine plus paclitaxel or cisplatin. Chin J Cancer Res. 2011;23(4):288–294.
  • Milano G, Etienne-Grimaldi M-C, Mari M, et al. Candidate mechanisms for capecitabine-related hand–foot syndrome. Br J Clin Pharmacol. 2008;66(1):88–95.
  • Mini E, Nobili S, Caciagli B, et al. Cellular pharmacology of gemcitabine. Ann Oncol. 2006;17(suppl 5):v7–12.
  • Ciccolini J, Mercier C, Dahan L, et al. Integrating pharmacogenetics into gemcitabine dosing–time for a change? Nat Rev Clin Oncol. 2011;8(7):439–444.
  • 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 Off J Am Assoc Cancer Res. 2006;12(8):2492–2497.
  • Olive KP, Jacobetz MA, Davidson CJ, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009;324(5933):1457–1461.
  • Silvestris N, Gnoni A, Brunetti AE, et al. Target therapies in pancreatic carcinoma. Curr Med Chem. 2014;21(8):948–965.
  • Eadon MT, Wheeler HE, Stark AL, et al. Genetic and epigenetic variants contributing to clofarabine cytotoxicity. Hum Mol Genet. 2013;22(19):4007–4020.
  • Villafranca E, Okruzhnov Y, Dominguez MA, et al. Polymorphisms of the repeated sequences in the enhancer region of the thymidylate synthase gene promoter may predict downstaging after preoperative chemoradiation in rectal cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2001;19(6):1779–1786.
  • Iacopetta B, Grieu F, Joseph D, et al. A polymorphism in the enhancer region of the thymidylate synthase promoter influences the survival of colorectal cancer patients treated with 5-fluorouracil. Br J Cancer. 2001;85(6):827–831.
  • Marsh S, McKay JA, Cassidy J, et al. Polymorphism in the thymidylate synthase promoter enhancer region in colorectal cancer. Int J Oncol. 2001;19(2):383–386.
  • Joerger M, Huitema ADR, Boot H, et al. Germline TYMS genotype is highly predictive in patients with metastatic gastrointestinal malignancies receiving capecitabine-based chemotherapy. Cancer Chemother Pharmacol. 2015;75(4):763– 772.
  • Gao J, He Q, Hua D, et al. Polymorphism of TS 3ʹ-UTR predicts survival of Chinese advanced gastric cancer patients receiving first-line capecitabine plus paclitaxel. Clin Transl Oncol Off Publ Fed Span Oncol Soc Natl Cancer Inst Mex. 2013;15(8):619–625.
  • Loganayagam A, Arenas Hernandez M, Corrigan A, et al. Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity. Br J Cancer. 2013;108(12):2505–2515.
  • Sharma R, Hoskins JM, Rivory LP, et al. Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphisms and toxicity to capecitabine in advanced colorectal cancer patients. Clin Cancer Res Off J Am Assoc Cancer Res. 2008;14(3):817–825.
  • Weekes CD, Nallapareddy S, Rudek MA, et al. Thymidylate synthase (TYMS) enhancer region genotype-directed phase II trial of oral capecitabine for 2nd line treatment of advanced pancreatic cancer. Invest New Drugs. 2011;29(5):1057–1065.
  • Rosmarin D, Palles C, Pagnamenta A, et al. A candidate gene study of capecitabine-related toxicity in colorectal cancer identifies new toxicity variants at DPYD and a putative role for ENOSF1 rather than TYMS. Gut. 2015;64(1):111–120.
  • Etienne-Grimaldi M-C, Milano G, Maindrault-Gœbel F, et al. Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and FOLFOX response in colorectal cancer patients. Br J Clin Pharmacol. 2010;69(1):58–66.
  • Cecchin E, Agostini M, Pucciarelli S, et al. Tumor response is predicted by patient genetic profile in rectal cancer patients treated with neo-adjuvant chemo-radiotherapy. Pharmacogenomics J. 2011;11(3):214–226.
  • Haller DG, Cassidy J, Clarke SJ, et al. Potential regional differences for the tolerability profiles of fluoropyrimidines. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26(13):2118–2123.
  • Van Huis-Tanja LH, Gelderblom H, Punt CJA, et al. MTHFR polymorphisms and capecitabine-induced toxicity in patients with metastatic colorectal cancer. Pharmacogenet Genomics. 2013;23(4):208–218.
  • Zhao J, Li W, Zhu D, et al. Association of single nucleotide polymorphisms in MTHFR and ABCG2 with the different efficacy of first-line chemotherapy in metastatic colorectal cancer. Med Oncol. 2014;31(1):802.
  • Rosmarin D, Palles C, Church D, et al. Genetic markers of toxicity from capecitabine and other fluorouracil-based regimens: investigation in the QUASAR2 study, systematic review, and meta-analysis. J Clin Oncol. 2014;32(10):1031–1039.
  • Navaratnam N, Sarwar R. An overview of cytidine deaminases. Int J Hematol. 2006;83(3):195–200.
  • Lilly E Monography of Gemzar. 2006; Available from: www.gemzar.com
  • 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 Clin Oncol. 1997;15(6):2403–2413.
  • Abraham A, Varatharajan S, Abbas S, et al. Cytidine deaminase genetic variants influence RNA expression and cytarabine cytotoxicity in acute myeloid leukemia. Pharmacogenomics. 2012;13(3):269–282.
  • Serdjebi C, Milano G, Ciccolini J. Role of cytidine deaminase in toxicity and efficacy of nucleosidic analogs. Expert Opin Drug Metab Toxicol. 2015;11(5):665–672.
  • Yue L, Saikawa Y, Ota K, et al. A functional single-nucleotide polymorphism in the human cytidine deaminase gene contributing to ara-C sensitivity. Pharmacogenetics. 2003;13(1):29–38.
  • Neff T, Blau CA. Forced expression of cytidine deaminase confers resistance to cytosine arabinoside and gemcitabine. Exp Hematol. 1996;24(11):1340–1346.
  • Kirch HC, Schroder J, Hoppe H, et al. Recombinant gene products of two natural variants of the human cytidine deaminase gene confer different deamination rates of cytarabine in vitro. Exp Hematol. 1998;26(5):421–425.
  • Chabner BA, Drake JC, Johns DG. Deamination of 5-azacytidine by a human leukemia cell cytidine deaminase. Biochem Pharmacol. 1973;22(21):2763–2765.
  • Ciccolini J, Dahan L, André N, et al. Cytidine deaminase residual activity in serum is a predictive marker of early severe toxicities in adults after gemcitabine-based chemotherapies. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28(1):160– 165.
  • Okamura T, Kigasawa K, Takeuchi T, et al. Cytidine deaminase activity in abnormal pregnancy. Int J Gynaecol Obstet. 1993;41(1):53–60.
  • Mercier C, Raynal C, Dahan L, et al. Toxic death case in a patient undergoing gemcitabine-based chemotherapy in relation with cytidine deaminase downregulation. Pharmacogenet Genomics. 2007;17(10):841– 844.
  • Tibaldi C, Giovannetti E, Vasile E, et al. 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. 2008;14(6):1797–1803.
  • Tibaldi C, Giovannetti E, Tiseo M, et al. Correlation of cytidine deaminase polymorphisms and activity with clinical outcome in gemcitabine-/platinum-treated advanced non-small-cell lung cancer patients. Ann Oncol. 2012;23(3):670–677.
  • Okazaki T, Javle M, Tanaka M, et al. Single nucleotide polymorphisms of gemcitabine metabolic genes and pancreatic cancer survival and drug toxicity. Clin Cancer Res. 2010;16(1):320–329.
  • Carpi FM, Vincenzetti S, Ubaldi J, et al. CDA gene polymorphisms and enzyme activity: genotype-phenotype relationship in an Italian-Caucasian population. Pharmacogenomics. 2013;14(7):769–781.
  • Ludovini V, Floriani I, Pistola L, et al. 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. 2011;6(12):2018–2026.
  • Joerger M. Covariate pharmacokinetic model building in oncology and its potential clinical relevance. Aaps J. 2012;14(1):119–132.
  • Serdjebi C, Gagnière J, Desramé J, et al. FFCD-1004 clinical trial: impact of cytidine deaminase activity on clinical outcome in gemcitabine-monotherapy treated patients. PloS One. 2015;10(8):e0135907.
  • Fanciullino R, Mercier C, Serdjebi C, et al. Lethal toxicity after administration of azacytidine: implication of the cytidine deaminase-deficiency syndrome. Pharmacogenet Genomics. 2015;25(6):317–321.
  • Mercier C, Dupuis C, Blesius A, et al. Early severe toxicities after capecitabine intake: possible implication of a cytidine deaminase extensive metabolizer profile. Cancer Chemother Pharmacol. 2009;63(6):1177–1180.
  • Dahan L, Ciccolini J, Evrard A, et al. Sudden death related to toxicity in a patient on capecitabine and irinotecan plus bevacizumab intake: pharmacogenetic implications. J Clin Oncol. 2012;30(4):e41–e44.
  • Serdjebi C, Seitz JF, Ciccolini J, et al. Rapid deaminator status is associated with poor clinical outcome in pancreatic cancer patients treated with a gemcitabine-based regimen. Pharmacogenomics. 2013;14(9):1047–1051.
  • Micozzi D, Carpi FM, Pucciarelli S, et al. Human cytidine deaminase: a biochemical characterization of its naturally occurring variants. Int J Biol Macromol. 2014;63:64–74.
  • Gilbert JA, Salavaggione OE, Ji Y, et al. Gemcitabine pharmacogenomics: cytidine deaminase and deoxycytidylate deaminase gene resequencing and functional genomics. Clin Cancer Res. 2006;12(6):1794–1803.
  • Sugiyama E, Kaniwa N, Kim SR, et al. Pharmacokinetics of gemcitabine in Japanese cancer patients: the impact of a cytidine deaminase polymorphism. J Clin Oncol. 2007;25(1):32–42.
  • Sugiyama E, Kaniwa N, Kim SR, et al. Population pharmacokinetics of gemcitabine and its metabolite in Japanese cancer patients: impact of genetic polymorphisms. Clin Pharmacokinet. 2010;49(8):549–558.
  • Caronia D, Martin M, Sastre J, et al. A polymorphism in the cytidine deaminase promoter predicts severe capecitabine-induced hand-foot syndrome. Clin Cancer Res. 2011;17(7):2006–2013.
  • Fanciullino R, Mercier C, Serdjebi C, et al. Yin and yang of cytidine deaminase roles in clinical response to azacitidine in the elderly: a pharmacogenetics tale. Pharmacogenomics. 2015;16(17):1907–1912.
  • Ciccolini J, Evrard A, M’Batchi L, et al. CDA deficiency as a possible culprit for life-threatening toxicities after cytarabine plus 6-mercaptopurine therapy: pharmacogenetic investigations. Pharmacogenomics. 2012;13(4):393–397.
  • Peters GJ, Honeywell RJ, Maulandi M, 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(4–6):403–412.
  • Van Kuilenburg AB. Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil. Eur J Cancer. 2004;40(7):939–950.
  • Etienne MC, Lagrange JL, Dassonville O, et al. Population study of dihydropyrimidine dehydrogenase in cancer patients. J Clin Oncol Off J Am Soc Clin Oncol. 1994;12(11):2248–2253.
  • Tuchman M, Roemeling RV, Hrushesky WA, et al. Dihydropyrimidine dehydrogenase activity in human blood mononuclear cells. Enzyme. 1989;42(1):15–24.
  • Ciccolini J, Mercier C, Dahan L, et al. Toxic death-case after capecitabine + oxaliplatin (XELOX) administration: probable implication of dihydropyrimidine deshydrogenase deficiency. Cancer Chemother Pharmacol. 2006;58(2):272–275.
  • Largillier R, Etienne-Grimaldi MC, Formento JL, et al. Pharmacogenetics of capecitabine in advanced breast cancer patients. Clin Cancer Res. 2006;12(18):5496–5502.
  • Meulendijks D, van Hasselt JGC, Huitema ADR, et al. Renal function, body surface area, and age are associated with risk of early-onset fluoropyrimidine-associated toxicity in patients treated with capecitabine-based anticancer regimens in daily clinical care. Eur J Cancer Oxf Engl 1990. 2016;54:120–130.
  • Mercier C, Ciccolini J. Severe or lethal toxicities upon capecitabine intake: is DPYD genetic polymorphism the ideal culprit? Trends Pharmacol Sci. 2007;28(12):597–598.
  • Gross E, Busse B, Riemenschneider M, et al. Strong association of a common dihydropyrimidine dehydrogenase gene polymorphism with fluoropyrimidine-related toxicity in cancer patients. PloS One. 2008;3(12):e4003.
  • Deenen MJ, Tol J, Burylo AM, et al. Relationship between single nucleotide polymorphisms and haplotypes in DPYD and toxicity and efficacy of capecitabine in advanced colorectal cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2011;17(10):3455–3468.
  • Froehlich TK, Amstutz U, Aebi S, et al. Clinical importance of risk variants in the dihydropyrimidine dehydrogenase gene for the prediction of early-onset fluoropyrimidine toxicity. Int J Cancer. 2015;136(3):730–739.
  • Offer SM, Fossum CC, Wegner NJ, et al. Comparative functional analysis of DPYD variants of potential clinical relevance to dihydropyrimidine dehydrogenase activity. Cancer Res. 2014;74(9):2545–2554.
  • Ciccolini J. Editorial: targeted therapy, targeted dosing and targeted delivery in oncology: where do we stand? Curr Top Med Chem. 2012;12(15):1638.
  • Beumer JH. Without therapeutic drug monitoring, there is no personalized cancer care. Clin Pharmacol Ther. 2013;93(3):228–230.
  • Giacomini KM, Yee SW, Ratain MJ, et al. Pharmacogenomics and patient care: one size does not fit all. Sci Transl Med. 2012;4(153):153ps18.
  • Andre F, Ciccolini J, Spano JP, et al. Personalized medicine in oncology: where have we come from and where are we going? Pharmacogenomics. 2013;14(8):931–939.
  • Monjanel-Mouterde S, Lejeune C, Ciccolini J, et al. Bayesian population model of methotrexate to guide dosage adjustments for folate rescue in patients with breast cancer. J Clin Pharm Ther. 2002;27(3):189–195.
  • Di Paolo A, Ibrahim T, Danesi R, et al. Relationship between plasma concentrations of 5-fluorouracil and 5-fluoro-5,6-dihydrouracil and toxicity of 5-fluorouracil infusions in cancer patients. Ther Drug Monit. 2002;24(5):588–593.
  • Dupuis C, Mercier C, Yang C, et al. High-dose methotrexate in adults with osteosarcoma: a population pharmacokinetics study and validation of a new limited sampling strategy. Anticancer Drugs. 2008;19(3):267–273.
  • Mercier C, Ciccolini J, Pourroy B, et al. Dose individualization of carboplatin after a 120-hour infusion schedule: higher dose intensity but fewer toxicities. Ther Drug Monit. 2006;28(2):212–218.
  • Salas S, Mercier C, Ciccolini J, et al. Therapeutic drug monitoring for dose individualization of cisplatin in testicular cancer patients based upon total platinum measurement in plasma. Ther Drug Monit. 2006;28(4):532–539.
  • Paci A, Vassal G, Moshous D, et al. Pharmacokinetic behavior and appraisal of intravenous busulfan dosing in infants and older children: the results of a population pharmacokinetic study from a large pediatric cohort undergoing hematopoietic stem-cell transplantation. Ther Drug Monit. 2012;34(2):198–208.
  • Van Warmerdam LJ, Rodenhuis S, Ten Bokkel Huinink WW, et al. Evaluation of formulas using the serum creatinine level to calculate the optimal dosage of carboplatin. Cancer Chemother Pharmacol. 1996;37(3):266–270.
  • Schmitt A, Gladieff L, Laffont CM, et al. Factors for hematopoietic toxicity of carboplatin: refining the targeting of carboplatin systemic exposure. J Clin Oncol. 2010;28(30):4568–4574.
  • Launay M, Dahan L, Duval M, et al. Beating the odds: efficacy and toxicity of dihydropyrimidine dehydrogenase-driven adaptive dosing of 5-FU in patients with digestive cancer. Br J Clin Pharmacol. 2016;81(1):124–130.
  • Deenen MJ, Meulendijks D, Cats A, et al. Upfront genotyping of DPYD*2A to Individualize fluoropyrimidine therapy: a safety and cost analysis. J Clin Oncol Off J Am Soc Clin Oncol. 2016;34(3):227–234.
  • Soo RA, Lim HL, Wang LZ, et al. Phase I trial of fixed dose-rate gemcitabine in combination with carboplatin in chemonaive advanced non-small-cell lung cancer: a cancer therapeutics research group study. Cancer Chemother Pharmacol. 2003;52(2):153–158.
  • Fogli S, Danesi R, De Braud F, et al. Drug distribution and pharmacokinetic/pharmacodynamic relationship of paclitaxel and gemcitabine in patients with non-small-cell lung cancer. Ann Oncol Off J Eur Soc Med Oncol ESMO. 2001;12(11):1553–1559.
  • Hiddemann W, Schleyer E, Unterhalt M, et al. Optimizing therapy for acute myeloid leukemia based on differences in intracellular metabolism of cytosine arabinoside between leukemic blasts and normal mononuclear blood cells. Ther Drug Monit. 1996;18(4):341–349.
  • Heinemann V, Estey E, Keating MJ, et al. Patient-specific dose rate for continuous infusion high-dose cytarabine in relapsed acute myelogenous leukemia. J Clin Oncol Off J Am Soc Clin Oncol. 1989;7(5):622–628.
  • Kantarjian HM, Estey EH, Plunkett W, et al. Phase I-II clinical and pharmacologic studies of high-dose cytosine arabinoside in refractory leukemia. Am J Med. 1986;81(3):387–394.
  • Shnider BI, Baig M, Colsky J. A phase I study of 5-azacytidine (NSC-102816). J Clin Pharmacol. 1976;16(4):205–212.
  • Braiteh F, Soriano AO, Garcia-Manero G, et al. Phase I study of epigenetic modulation with 5-azacytidine and valproic acid in patients with advanced cancers. Clin Cancer Res Off J Am Assoc Cancer Res. 2008;14(19):6296–6301.
  • Uchida T, Ogawa Y, Kobayashi Y, et al. Phase I and II study of azacitidine in Japanese patients with myelodysplastic syndromes. Cancer Sci. 2011;102(9):1680–1686.
  • Cogle CR, Scott BL, Boyd T, et al. Oral azacitidine (CC-486) for the treatment of myelodysplastic syndromes and acute myeloid leukemia. The Oncologist. 2015;20(12):1404–1412.
  • Van Groeningen CJ, Leyva A, O’Brien AM, et al. Phase I and pharmacokinetic study of 5-aza-2ʹ-deoxycytidine (NSC 127716) in cancer patients. Cancer Res. 1986;46(9):4831–4836.
  • Appleton K, Mackay HJ, Judson I, et al. Phase I and pharmacodynamic trial of the DNA methyltransferase inhibitor decitabine and carboplatin in solid tumors. J Clin Oncol Off J Am Soc Clin Oncol. 2007;25(29):4603–4609.
  • Long-Boyle JR, Green KG, Brunstein CG, et al. High fludarabine exposure and relationship with treatment-related mortality after nonmyeloablative hematopoietic cell transplantation. Bone Marrow Transplant. 2011;46(1):20–26.
  • Bonate PL, Cunningham CC, Gaynon P, et al. Population pharmacokinetics of clofarabine and its metabolite 6-ketoclofarabine in adult and pediatric patients with cancer. Cancer Chemother Pharmacol. 2011;67(4):875–890.
  • Gandhi V, Kilpatrick JM, Plunkett W, et al. A proof-of-principle pharmacokinetic, pharmacodynamic, and clinical study with purine nucleoside phosphorylase inhibitor immucillin-H (BCX-1777, forodesine). Blood. 2005;106(13):4253–4260.
  • Pronk LC, Vasey P, Sparreboom A, et al. A phase I and pharmacokinetic study of the combination of capecitabine and docetaxel in patients with advanced solid tumours. Br J Cancer. 2000;83(1):22–29.
  • Villalona-Calero MA, Blum JL, Jones SE, et al. A phase I and pharmacologic study of capecitabine and paclitaxel in breast cancer patients. Ann Oncol Off J Eur Soc Med Oncol ESMO. 2001;12(5):605–614.
  • Gieschke R, Burger H-U, Reigner B, et al. Population pharmacokinetics and concentration-effect relationships of capecitabine metabolites in colorectal cancer patients. Br J Clin Pharmacol. 2003;55(3):252–263.
  • Derissen EJB, Jacobs BAW, Huitema ADR, et al. Exploring the intracellular pharmacokinetics of the 5-fluorouracil nucleotides during capecitabine treatment. Br J Clin Pharmacol. 2016;81(5):949–957.
  • Doi T, Ohtsu A, Yoshino T, et al. Phase I study of TAS-102 treatment in Japanese patients with advanced solid tumours. Br J Cancer. 2012;107(3):429–434.
  • Overman MJ, Varadhachary G, Kopetz S, et al. Phase 1 study of TAS-102 administered once daily on a 5-day-per-week schedule in patients with solid tumors. Invest New Drugs. 2008;26(5):445–454.
  • Shahrokni A, Rajebi MR, Saif MW. Toxicity and efficacy of 5-fluorouracil and capecitabine in a patient with TYMS gene polymorphism: A challenge or a dilemma? Clin Colorectal Cancer. 2009;8(4):231–234.
  • Wheeler HE, Maitland ML, Dolan ME, et al. Cancer pharmacogenomics: strategies and challenges. Nat Rev Genet. 2013;14(1):23–34.
  • Uchida K, Danenberg PV, Danenberg KD, et al. Thymidylate synthase, dihydropyrimidine dehydrogenase, ERCC1, and thymidine phosphorylase gene expression in primary and metastatic gastrointestinal adenocarcinoma tissue in patients treated on a phase I trial of oxaliplatin and capecitabine. BMC Cancer. 2008;8:386.
  • Bins S, Ratain MJ, Mathijssen RHJ. Conventional dosing of anticancer agents: precisely wrong or just inaccurate? Clin Pharmacol Ther. 2014;95(4):361–364.
  • Widmer N, Bardin C, Chatelut E, et al. Review of therapeutic drug monitoring of anticancer drugs part two–targeted therapies. Eur J Cancer. 2014;50(12):2020–2036.
  • Paci A, Veal G, Bardin C, et al. Review of therapeutic drug monitoring of anticancer drugs part 1–cytotoxics. Eur J Cancer. 2014;50(12):2010–2009.
  • Fuchs A, Csajka C, Thoma Y, et al. Benchmarking therapeutic drug monitoring software: a review of available computer tools. Clin Pharmacokinet. 2013;52(1):9–22.
  • Iasonos A, O’Quigley J. Adaptive dose-finding studies: a review of model-guided phase I clinical trials. J Clin Oncol Off J Am Soc Clin Oncol. 2014;32(23):2505–2511.
  • Bruno R, Mercier F, Claret L. Model-based drug development in oncology: what’s next? Clin Pharmacol Ther. 2013;93(4):303–305.
  • Cook N, Hansen AR, Siu LL, et al. Early phase clinical trials to identify optimal dosing and safety. Mol Oncol. 2015;9(5):997–1007.
  • Harrington JA, Wheeler GM, Sweeting MJ, et al. Adaptive designs for dual-agent phase I dose-escalation studies. Nat Rev Clin Oncol. 2013;10(5):277–288.
  • Chefrour M, Fischel J-L, Formento P, et al. Erlotinib in combination with capecitabine (5ʹdFUR) in resistant pancreatic cancer cell lines. J Chemother Florence Italy. 2010;22(2):129–133.
  • Barbolosi D, Ciccolini J, Lacarelle B, et al. Computational oncology - mathematical modelling of drug regimens for precision medicine. Nat Rev Clin Oncol. 2016;13(4):242–254.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.