Skip to main content

Advertisement

SpringerLink
Log in

A phase I, pharmacokinetic, and pharmacodynamic evaluation of the DNA methyltransferase inhibitor 5-fluoro-2′-deoxycytidine, administered with tetrahydrouridine

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Inhibitors of DNA (cytosine-5)-methyltransferases (DNMT) are active antineoplastic agents. We conducted the first-in-human phase I trial of 5-fluoro-2′-deoxycytidine (FdCyd), a DNMT inhibitor stable in aqueous solution, in patients with advanced solid tumors. Objectives were to establish the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of FdCyd + tetrahydrouridine (THU).

Methods

FdCyd + THU were administered by 3 h IV infusion on days 1–5 every 3 weeks, or days 1–5 and 8–12 every 4 weeks. FdCyd was administered IV with a fixed 350 mg/m2/day dose of THU to inhibit deamination of FdCyd. Pharmacokinetics of FdCyd, downstream metabolites and THU were assessed by LC–MS/MS. RBC γ-globin expression was evaluated as a pharmacodynamics biomarker.

Results

Patients were enrolled on the 3-week schedule at doses up to 80 mg/m2/day without dose-limiting toxicity (DLT) prior to transitioning to the 4-week schedule, which resulted in an MTD of 134 mg/m2/day; one of six patients had a first-cycle DLT (grade 3 colitis). FdCyd ≥40 mg/m2/day produced peak plasma concentrations >1 µM. Although there was inter-patient variability, γ-globin mRNA increased during the first two treatment cycles. One refractory breast cancer patient experienced a partial response (PR) of >90 % decrease in tumor size, lasting over a year.

Conclusions

The MTD was established at 134 mg/m2 FdCyd + 350 mg/m2 THU days 1–5 and 8–12 every 4 weeks. Based on toxicities observed over multiple cycles, good plasma exposures, and the sustained PR observed at 67 mg/m2/day, the phase II dose for our ongoing multi-histology trial is 100 mg/m2/day FdCyd with 350 mg/m2/day THU.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Lapeyre JN, Becker FF (1979) 5-Methylcytosine content of nuclear DNA during chemical hepatocarcinogenesis and in carcinomas which result. Biochem Biophys Res Commun 87(3):698–705

    Article  CAS  PubMed  Google Scholar 

  2. Baylin SB, Jones PA (2011) A decade of exploring the cancer epigenome—biological and translational implications. Nat Rev Cancer 11(10):726–734

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3(6):415–428

    CAS  PubMed  Google Scholar 

  4. Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R, Stone RM, Nelson D, Powell BL, DeCastro CM, Ellerton J, Larson RA, Schiffer CA, Holland JF (2002) Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol Res 20(10):2429–2440

    Article  CAS  Google Scholar 

  5. Kantarjian H, Issa JP, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J, Klimek V, Slack J, de Castro C, Ravandi F, Helmer R 3rd, Shen L, Nimer SD, Leavitt R, Raza A, Saba H (2006) Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 106(8):1794–1803

    Article  CAS  PubMed  Google Scholar 

  6. Quintas-Cardama A, Santos FP, Garcia-Manero G (2010) Therapy with azanucleosides for myelodysplastic syndromes. Nat Rev Clin Oncol 7(8):433–444

    Article  CAS  PubMed  Google Scholar 

  7. Smith SS, Kaplan BE, Sowers LC, Newman EM (1992) Mechanism of human methyl-directed DNA methyltransferase and the fidelity of cytosine methylation. Proc Natl Acad Sci USA 89(10):4744–4748

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Jones PA, Taylor SM (1980) Cellular differentiation, cytidine analogs and DNA methylation. Cell 20(1):85–93

    Article  CAS  PubMed  Google Scholar 

  9. Kaysen J, Spriggs D, Kufe D (1986) Incorporation of 5-fluorodeoxycytidine and metabolites into nucleic acids of human MCF-7 breast carcinoma cells. Cancer Res 46(9):4534–4538

    CAS  PubMed  Google Scholar 

  10. Kreis W, Watanabe KA, Fox JJ (1978) Structural requirements for the enzymatic deamination of cytosine nucleosides. Helv Chim Acta 61:1011–1016

    Article  CAS  Google Scholar 

  11. Beumer JH, Eiseman JL, Parise RA, Joseph E, Holleran JL, Covey JM, Egorin MJ (2006) Pharmacokinetics, metabolism, and oral bioavailability of the DNA methyltransferase inhibitor 5-fluoro-2′-deoxycytidine in mice. Clin Cancer Res 12(24):7483–7491

    Article  CAS  PubMed  Google Scholar 

  12. Kreis W, Woodcock TM, Gordon CS, Krakoff IH (1977) Tetrahydrouridine: physiologic disposition and effect upon deamination of cytosine arabinoside in man. Cancer Treat Rep 61(7):1347–1353

    CAS  PubMed  Google Scholar 

  13. Beumer JH, Parise RA, Newman EM, Doroshow JH, Synold TW, Lenz HJ, Egorin MJ (2008) Concentrations of the DNA methyltransferase inhibitor 5-fluoro-2′-deoxycytidine (FdCyd) and its cytotoxic metabolites in plasma of patients treated with FdCyd and tetrahydrouridine (THU). Cancer Chemother Pharmacol 62(2):363–368

    Article  CAS  PubMed  Google Scholar 

  14. Smith RD, Malley JD, Schechter AN (2000) Quantitative analysis of globin gene induction in single human erythroleukemic cells. Nucleic Acids Res 28(24):4998–5004

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. R Core Team (2014) A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna. http://www.R-project.org

    Google Scholar 

  16. Pinheiro JC, Bates DM (2000) Mixed-effects models in S and S-plus. Springer, New York

    Book  Google Scholar 

  17. Fathallah H, Atweh GF (2006) DNA hypomethylation therapy for hemoglobin disorders: molecular mechanisms and clinical applications. Blood Rev 20(4):227–234

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

A California Cancer Consortium Study. This manuscript is dedicated to the memory of Dr. Merrill J. Egorin, who would be a co-author if he were able to review the manuscript. Previous Presentation: Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, May 18–May 21, 2002, Orlando, FL and the 102nd Annual Meeting of the American Association for Cancer Research, April 2–6, 2011 Orlando, FL. An interim pharmacokinetic analysis has been published [13]. Research Support: Supported in part by U01CA062505, UM1CA186717, P30CA033572, N01-CM-52202, U01CA099168, UM1CA186690, and P30CA047904.

Conflict of interest

None.

Ethical standard

The manuscript has not been submitted to more than one journal for simultaneous consideration. The manuscript has not been published previously (partly or in full), nor split up into several parts. No data have been fabricated or manipulated (including images). No data, text, or theories by others are presented as if they were the author’s own. Consent to submit has been received explicitly from all co-authors, as well as from the responsible authorities—tacitly or explicitly—at the institute/organization where the work has been carried out, before the work is submitted. Authors whose names appear on the submission have contributed sufficiently to the scientific work and therefore share collective responsibility and accountability for the results.

Author information

Authors and Affiliations

  1. Department of Molecular Pharmacology, City of Hope Beckman Research Institute, 1500 East Duarte Road, Duarte, CA, 91010-3000, USA

    Edward M. Newman, Robert J. Morgan, M. Suzette Blanchard, Christopher Ruel, Mary I. Carroll, Jessie M. Hou & Chun Li

  2. National Cancer Institute, Bethesda, MD, USA

    Shivaani Kummar & James H. Doroshow

  3. Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    Jan H. Beumer & Julie L. Eiseman

  4. University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA

    Anthony B. El-Khoueiry & Heinz J. Lenz

Authors
  1. Edward M. Newman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert J. Morgan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shivaani Kummar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jan H. Beumer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Suzette Blanchard
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Christopher Ruel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anthony B. El-Khoueiry
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mary I. Carroll
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jessie M. Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Chun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Heinz J. Lenz
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Julie L. Eiseman
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. James H. Doroshow
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Edward M. Newman.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 70 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Newman, E.M., Morgan, R.J., Kummar, S. et al. A phase I, pharmacokinetic, and pharmacodynamic evaluation of the DNA methyltransferase inhibitor 5-fluoro-2′-deoxycytidine, administered with tetrahydrouridine. Cancer Chemother Pharmacol 75, 537–546 (2015). https://doi.org/10.1007/s00280-014-2674-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-014-2674-7

Keywords

Search

Navigation