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Drug Evaluation

RX-3117 (fluorocyclopentenyl cytosine): a novel specific antimetabolite for selective cancer treatment

, , , , , , , , , , & ORCID Icon show all
Pages 311-322 | Received 20 Nov 2018, Accepted 13 Feb 2019, Published online: 16 Mar 2019

References

  • Peters GJ. Novel developments in the use of antimetabolites. Nucleosides Nucleotides Nucleic Acids. 2014;33(4–6):358–374.
  • Elnaggar M, Giovannetti E, Peters GJ. Molecular targets of gemcitabine action: rationale for development of novel drugs and drug combinations. Curr Pharm Des. 2012;18(19):2811–2829.
  • Hubeek I, Kaspers GJL, Ossenkoppele GJ, et al. Cytosine arabinoside. Metabolism, mechanisms of resistance and clinical pharmacology. In: Peters GJ, editor. From: cancer drug discovery and development: deoxynucleoside analogs in cancer therapy. Totowa, NJ: Humana Press Inc., USA; 2006. p. 119–151.
  • Santos FPS, Kantarjian H, Garcia-Manero G, et al. Decitabine in the treatment of myelodysplastic syndromes. Expert Rev Anticancer Ther. 2010;10(1):9–22.
  • Kaminskas E. FDA drug approval summary: azacitidine (5-azacytidine, vidazaTM) for injectable suspension. Oncologist. 2005;10(3):176–182.
  • Peters GJ, Jansen G. Resistance to antimetabolites. In: Schilsky RL, Milano GA, Ratain MJ, editors. Principles of antineoplastic drug development and pharmacology. New York: Marcel Dekker, Inc.; 1996. p. 543–585. Chapter 25.
  • Schimmel KJM, Gelderblom H, Guchelaar HJ. Cyclopentenyl cytosine (CPEC): an overview of its in vitro and in vivo activity. Curr Cancer Drug Targets. 2007;7(5):504–509.
  • Murata D, Endo Y, Obata T, et al. A crucial role of uridine/cytidine kinase 2 in antitumor activity of 3‘-ethynyl nucleosides. Drug Metab Dispos. 2004;32(10):1178–1182.
  • Abdelrahim M, Matsuda A, Naing A. TAS-106: preclinical, clinical and beyond. Oncology. 2013;85(6):356–363. .
  • Zhao LX, Yun M, Kim HO, et al. Design, synthesis, and anticancer activity of fluorocyclopentenyl-pyrimidines. Nucleic Acids Symp Ser. 2005;107–108. doi:10.1093/nass/49.1.107.
  • Jeong LS, Zhao LX, Choi WJ, et al. Synthesis and antitumor activity of fluorocyclopentenyl-pyrimidines. Nucleosides Nucleotides Nucleic Acids. 2007;26(6–7):713–716.
  • Peters GJ, Smid K, Vecchi L, et al. Metabolism, mechanism of action and sensitivity profile of fluorocyclopentenylcytosine (RX-3117; TV-1360). Invest New Drugs. 2013;31(6):1444–1457.
  • Yang MY, Lee YB, Ahn CH, et al. A novel cytidine analog, RX-3117, shows potent efficacy in xenograft models, even in tumors that are resistant to gemcitabine. Anticancer Res. 2014;34(12):6951–6959.
  • Choi WJ, Chung H-J, Chandra G, et al. Fluorocyclopentenyl-cytosine with broad spectrum and potent antitumor activity. J Med Chem. 2012;55(9):4521–4525.
  • Martin CS, Wong JY, Liang JM, et al. Global temporal patterns of pancreatic cancer and association with socioeconomic development. Sci Rep. 2017;7:3165.
  • [Accessed 2019 January 28]. Availabe from https://seer.cancer.gov/statfacts/html/
  • Oettle H1, Neuhaus P, Hochhaus A, et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013;310(14):1473–1481.
  • Cartwright TH, Parisi M, Espirito JL, et al. Clinical outcomes with first-line chemotherapy in a large retrospective study of patients with metastatic pancreatic cancer treated in a US community oncology setting. Drugs Real World Outcomes. 2018;5(3):149–159.
  • Pastor-Anglada M, Pérez-Torras S. Emerging roles of nucleoside transporters. Front Pharmacol. 2018Jun6;9:606..
  • Grant S, Bhalla K, Gleyzer M. Effect of uridine on response of 5-azacytidine-resistant human leukemic cells to inhibitors of de Novo pyrimidine synthesis. Cancer Res. 1984;44:5505–5510.
  • Momparler RL. Pharmacology of 5-aza-2′-deoxycytidine (decitabine). Semin Hematol. 2005;42((SUPPL):2.
  • Heinemann V, Hertel LW, Grindey GB, et al. Comparison of the cellular pharmacokinetics and toxicity of 2 ′,2 ′-difluorodeoxycytidine and 1-β-D-arabinofuranosylcytosine. Cancer Res. 1988;48(14):4024–4031. doi:/PMID: 3383195.
  • Van Rompay AR, Norda A, Lindén K, et al. Phosphorylation of uridine and cytidine nucleoside analogs by two human uridine-cytidine kinases. Mol Pharmacol. 2001;59(5):1181–1186.
  • Sarkisjan D, Julsing JR, Smid K, et al. The cytidine analog fluorocyclopentenylcitosine (RX-3117) is activated by uridine- cytidine kinase 2. PLoS One. 11:e0162901.
  • Honeywell RJ, Sarkisjan D, Kathmann I, et al. Sensitive liquid chromatography mass spectrometry (LC-MS) assay reveals novel insights on DNA methylation and incorporation of gemcitabine, its metabolite difluorodeoxyuridine, deoxyuridine and RX-3117 into DNA. Nucleosides Nucleotides Nucleic Acids. 2016;35:652–662.
  • Bergman AM, Pinedo HM, Peters GJ. Determinants of resistance to 2‘,2’ -difluorodeoxycytidine (gemcitabine). Drug Resist Updat. 2002;5(1):19–33.
  • Ciccolini J, Serdjebi C, Peters GJ, et al. Pharmacokinetics and pharmacogenetics of Gemcitabine as a mainstay in adult and pediatric oncology: an EORTC-PAMM perspective. Cancer Chemother Pharmacol. 2016 Jul;78(1):1–12. .
  • Rampazzo C, Tozzi MG, Dumontet C, et al. The druggability of intracellular nucleotide-degrading enzymes. Cancer Chemother Pharmacol. 2016 May;77(5):883–893. .
  • Sarkisjan D, van den Berg J, Smit E, et al. The radiosensitizing effect of fluorocyclopentenyl-cytosine (RX-3117) in ovarian and lung cancer cell lines. Nucleosides Nucleotides Nucleic Acids. 2016;35(10–12):619–630.
  • Sarkisjan D, Steenbergen RDM, Cloos J, et al. Re-emerging antimetabolites with novel mechanism of action with respect to epigenetic regulation: basic aspects. In: Ueda T, editor. Chemotherapy for leukemia: novel drugs and treatment. Springer Nature, Singapore Pte Ltd; 2017. p. 311–326. Chapter 18.
  • Peters GJ, Sarkisjan D, Julsing JR, et al. Inhibition of DNA methyltransferase by RX-3117 (fluorocyclopentenylcytosine) leads to upregulation of hypomethylated targets. Proc AACR 107th annual meeting; New Orleans, Louisiana; 2016. Abstract #4725.
  • Sarkisjan D, Pronk F, Kruin R, et al. A novel mechanism of DNA methyltransferase (DNMT1) downregulation by epigenetic modulation with RX-3117 (fluoropentenylcytosine). Proc. AACR 109th annual meeting; Chicago, Illinois 2018. abstract #5861.
  • Frank J, Lee YB, Kim DJ, et al. RX-3117, a novel hypomethylating agent, shows promising therapeutic activity in combination with nab-paclitaxel and check-point inhibitors in preclinical models. Ann Oncol. 2017;28(suppl_5). doi:10.1093/annonc/mdx367.046.
  • Udvaros I, Rethy A, Lang I, et al. A phase 1 exploratory study of RX-3117 to determine oral bioavailability in cancer subjects with solid tumors. J Clin Oncol. 2015;33. Suppl; abstre13545.
  • Rasco D, Peterson C, Mazhari R, et al. RX-3117, an oral antimetabolite to treat advanced solid tumors (ST): phase 1 and ongoing phase 2a results. Ann Oncol. 2016;27(Supplement 6):vi114–vi135.
  • Chung V, Merchan JR, Ocean AJ, et al. RX­3117: activity of an oral antimetabolite nucleoside in subjects with pancreatic cancer–preliminary results of stage II of the phase Ia/IIb study. J Clin Oncol. 2018;36:suppl 4S. abstr 396.
  • Babiker H, Schlegel P, Benaim E, et al. RX-3117, a novel, oral nucleoside analog, in combination with nab-paclitaxel (nab-pac) in first-line metastatic pancreatic cancer (met-pc): safety, tolerability and preliminary response. Proceedins of the 5th NCI Pancreatic Cancer Symposium; 2018. Maryland, USA: National Institutes of Health in Bethesda.
  • Babiker H, Schlegel P, Hicks LG, et al. A phase 1/2 study of RX-3117, an oral antimetabolite nucleoside, in combination with nab-paclitaxel (nab-pac) as first line treatment of metastatic pancreatic cancer (met-PC): preliminary results. J Clin Oncol. 2019;37:(suppl 4). abstr 420.
  • Adashek J, Pal SK, Chung VM, et al. Preliminary results from an ongoing phase 2a study of RX-3117, an oral nucleoside analogue to treat advanced urothelial cancer (aUC). J Clin Oncol. 2018;36:suppl. abstr 4543.
  • 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. 2006 1;66(7):3928–3935.
  • 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. 2004 Oct 15;10(20):6956–6961.
  • Svrcek M, Cros J, Maréchal R, et al. Human equilibrative nucleoside transporter 1 testing in pancreatic ductal adenocarcinoma: a comparison between murine and rabbit antibodies. Histopathology. 2015 Feb;66(3):457–462.
  • 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. 2011 Jun;29(3):456–466. .
  • 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. 2013 Dec 10;31(35):4453–4461.
  • van Kuilenburg AB, Meinsma R. The pivotal role of uridine-cytidine kinases in pyrimidine metabolism and activation of cytotoxic nucleoside analogues in neuroblastoma. Biochim Biophys Acta. 2016 Sep;1862(9):1504–1512. . Epub 2016 May 27.
  • Lee YB, Kim DJ, George C, et al. Evaluation of UCK2 protein expression as a potential predictive biomarker of RX/3117. AACR 108th annual meeting, Washington, DC; 2017. Abstract #1790.
  • Peters GJ, Sarkisjan D, El Hassouni B, et al. Unusual mechanism of resistance to the novel cytidine analog fluorocyclopentenylcytosine (RX-3117). Proceedings AACR 110th Annual meeting Atlanta, Georgia; 2019. Abstract #1267.
  • Honeywell RJ, Sarkisjan D, Kristensen MH, et al. DNA methyltransferases expression in normal tissues and various human cancer cell lines, xenografts and tumors. Nucleosides Nucleotides Nucleic Acids. 2019, epub ahead of print.