Skip to main content

Advertisement

SpringerLink
Log in

ATP chemosensitivity testing of new antitumor duplex drugs linking 3`-C-ethynylycytidine (ECyd) and 2´-deoxy-5-fluorouridine (5-FdU) in comparison to standard cytostatica and combinations thereof

  • SHORT REPORT
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Background 2´-Deoxy-5-fluorouridylyl-(5´-5´)-3´-C-ethynylcytidine [5-FdU(5´-5´)ECyd] and 3´-C-ethynylcytidinylyl-(5´->1-O)-2-O-octadecyl-sn-glycerylyl-(3-Ο−>5´)-2´-deoxy-5-fluorouridine [ECyd-lipid-5-FdU] are antitumor active duplex drugs and these heterodinucleoside phosphate analogues could be cleaved in vivo by wide-spread phosphodiesterases into different antitumor active antimetabolites. Methods We cultured breast MCF-7, MDA-MB-231 and ovarian OVCAR-29 and OAW-42 cancer cell lines and used the luminometric measuring of the ATP tumor chemosensitivity assay to assess the in vitro activity of 5-FdU(5´-5´)ECyd and ECyd-lipid-5-FdU in comparison to standard single cytostatic agents and combinations thereof currently used in anticancer therapies. To allow comparison between samples and different regimens IndexSUM was determined based on the percentage tumor cell growth inhibition at each test drug concentration. Additionally, the cytostatic efficacy of 5-FdU(5´-5´)ECyd and ECyd-lipid-5-FdU was evaluated at a minimum of five concentrations at 10 fold dilutions using 60 human tumor cell lines including ovarian and breast cancer cell lines from the National Cancer Institute (USA). Results 5-FdU(5´-5´)ECyd and ECyd-lipid-5-FdU have a high cytostatic efficacy reaching 50% tumor cell growth inhibition at concentrations ranging between nano- and micomolar. IndexSum values for broad range efficacy in MCF-7 breast cancer cells were comparable to values obtained for standard drug combinations. Higher cytostatic efficacy was observed in MDA-MB-231 cells. Conclusion The duplex drugs 5-FdU(5´-5´)ECyd and ECyd-lipid-5-FdU represent potential new chemotherapeutic drugs for breast and ovarian cancer cells which are comparable to currently used drug combinations and more potent in comparison to some monocytostatica used in cancer therapy.

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

References

  1. Krise JP, Stella VJ (1996) Prodrugs of phosphates, phosphonates, and phosphinates. Advanced Drug Delivery Reviews 19:287–310

    Article  CAS  Google Scholar 

  2. Wagner CR, Iyer VV, McIntee EJ (2000) Pronucleotides: toward the in vivo delivery of antiviral and anticancer nucleotides. Med Res Rev 20:417–451

    Article  PubMed  CAS  Google Scholar 

  3. Plunkett W, Gandhi V (2001) Purine and pyrimidine nucleoside analogs. Cancer Chemother Biol Response Modif 19:21–45

    PubMed  CAS  Google Scholar 

  4. Horber DH, Cattaneo-Pangrazzi RM, von Ballmoos P, Schott H, Ludwig PS, Eriksson S, Fichtner I, Schwendener RA (2000) Cytotoxicity, cell-cycle perturbations and apoptosis in human tumor cells by lipophilic N4-alkyl-1-beta-D-arabinofuranosylcytosine derivatives and the new heteronucleoside phosphate dimer arabinocytidylyl-(5’->5’)-N4-octadecyl-1-beta-D-arabinofuranosylcytosine. J Cancer Res Clin Oncol 126:311–319

    Article  PubMed  CAS  Google Scholar 

  5. Cattaneo-Pangrazzi RM, Schott H, Schwendener RA (2000) The novel heterodinucleoside dimer 5-FdU-NOAC is a potent cytotoxic drug and a p53-independent inducer of apoptosis in the androgen-independent human prostate cancer cell lines PC-3 and DU-145. Prostate 45:8–18

    Article  PubMed  CAS  Google Scholar 

  6. Saiko P, Horvath Z, Bauer W, Hoechtl T, Grusch M, Krupitza G, Rauko P, Mader RM, Jaeger W, Schott H, Novotny L, Fritzer-Szekeres M, Szekeres T (2004) In vitro and in vivo antitumor activity of novel amphiphilic dimers consisting of 5-fluorodeoxyuridine and arabinofuranosylcytosine. Int J Oncol 25:357–364

    PubMed  CAS  Google Scholar 

  7. Bijnsdorp IV, Schwendener RA, Schott H, Schott S, Fichtner I, Honeywell RJ, Losekoot N, Laan AC, Peters GJ (2008) In vitro activity and mechanism of action of a duplex and multidrug of ethynylcytidine and 5-fluorodeoxyuridine. Nucleic Acids Symp Ser (Oxf) 52:651

    Article  CAS  Google Scholar 

  8. Naito T, Yokogawa T, Takatori S, Goda K, Hiramoto A, Sato A, Kitade Y, Sasaki T, Matsuda A, Fukushima M, Wataya Y, Kim HS (2008) Role of RNase L in apoptosis induced by 1-(3-C-ethynyl-beta-D: -ribo-pentofuranosyl)cytosine. Cancer Chemother Pharmacol 63:837–850

    Article  PubMed  Google Scholar 

  9. Kazuno H, Shimamoto Y, Tsujimoto H, Fukushima M, Matsuda A, Sasaki T (2007) Mechanism of action of a new antitumor ribonucleoside, 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd, TAS-106), differs from that of 5-fluorouracil. Oncol Rep 17:1453–1460

    PubMed  CAS  Google Scholar 

  10. Sevin BU, Peng ZL, Perras JP, Ganjei P, Penalver M, Averette HE (1988) Application of an ATP-bioluminescence assay in human tumor chemosensitivity testing. Gynecol Oncol 31:191–204

    Article  PubMed  CAS  Google Scholar 

  11. Kurbacher CM, Cree IA, Bruckner HW, Brenne U, Kurbacher JA, Muller K, Ackermann T, Gilster TJ, Wilhelm LM, Engel H, Mallmann PK, Andreotti PE (1988) Use of an ex vivo ATP luminescence assay to direct chemotherapy for recurrent ovarian cancer. Anticancer Drugs 9:51–57

    Article  Google Scholar 

  12. Andreotti PE, Cree IA, Kurbacher CM, Hartmann DM, Linder D, Harel G, Gleibermann I, Caruso PA, Ricks SH, Untch M, Sartori C, Bruckner HW (1995) Chemosensitivity testing of human tumors using a microplate adenosine triphosphate luminescence assay: clinical correlation for cisplatin resistance of ovarian carcinoma. Cancer Res 55:5276–5282

    PubMed  CAS  Google Scholar 

  13. Neubauer H, Stefanova M, Solomayer E, Meisner C, Zwirner M, Wallwiener D, Fehm T (2008) Predicting resistance to platinum-containing chemotherapy with the ATP tumor chemo-sensitivity assay in primary ovarian cancer. Anticancer Res 28:949–955

    PubMed  Google Scholar 

  14. Sharma S, Neale MH, Di Nicolantonio F, Knight LA, Whitehouse PA, Mercer SJ, Higgins BR, Lamont A, Osborne R, Hindley AC, Kurbacher CM, Cree IA (2003) Outcome of ATP-based tumor chemosensitivity assay directed chemotherapy in heavily pre-treated recurrent ovarian carcinoma. BMC Cancer 3:19–28

    Article  PubMed  Google Scholar 

  15. Cree IA, Kurbacher CM, Untch M, Sutherland LA, Huner EM, Subedi AM, James EA, Dewar JA, Preece PE, Andreotti PE, Bruckner HW (1996) Correlation of the clinical response to chemotherapy in breast cancer with ex vivo chemosensitivity. Anticancer Drugs 7:630–635

    Article  PubMed  CAS  Google Scholar 

  16. Gerhardt RT, Perras JP, Sevin BU, Petru E, Ramos R, Guerra L, Averette HE (1991) Characterization of in vitro chemosensitivity of perioperative human ovarian malignancies by adenosine 1: triphosphate chemosensitivity assay. Am J Obstet Gynecol 165:245–255

    PubMed  CAS  Google Scholar 

  17. Di Nicolantonio F, Knight LA, Whitehouse PA, Mercer SJ, Sharma S, Charlton PA, Norris D, Cree IA (2004) The ex vivo characterization of XR5944 (MLN944) against a panel of human clinical tumor samples. Mol Cancer Ther 3:1631–1637

    PubMed  Google Scholar 

  18. Kangas L, Grönroos M, Nieminen AL (1984) Bioluminescence of cellular ATP: a new method for evaluating cytotoxic agents in vitro. Med Biol 62:338–343

    PubMed  CAS  Google Scholar 

  19. Rajala P, Kaasinen E, Rintala E, Jauhiainen K, Nurmi M, Alfthan O, Lähde M (1992) Cytostatic effect of different strains of Bacillus Calmette-Guérin on human bladder cancer cells in vitro alone and in combination with mitomycin C and interferon-alpha. Urol Res 20:215–217

    Article  PubMed  CAS  Google Scholar 

  20. Laaksovirta S, Rajala P, Nurmi M, Tammela TL, Laato M (1999) The cytostatic effect of 9-cis-retinoic acid, tretinoin, and isotretinoin on three different human bladder cancer cell lines in vitro. Urol Res 27:17–22

    Article  PubMed  CAS  Google Scholar 

  21. Knight LA, Kurbacher CM, Glaysher S, Fernando A, Reichelt R, Dexel S, Reinhold U, Cree IA (2009) Activity of mevalonate pathway inhibitors against breast and ovarian cancers in the ATP-based tumour chemosensitivity assay. BMC Cancer 9:38

    Article  PubMed  Google Scholar 

  22. Shoemaker RH (2006) Timeline: The NCI 60 human tumour cell line anticancer drug screen. Nature Reviews Cancer 6:813–823

    Article  PubMed  CAS  Google Scholar 

  23. Ludwig PS, Schwendener RA, Schott H (2005) Synthesis and anticancer activities of amphiphilic 5-fluoro-2’-deoxyuridylic acid prodrugs. Eur J Med Chem 40:494–504

    Article  PubMed  CAS  Google Scholar 

  24. Sommer H, Santi DV (1974) Purification and amino acid analysis of an active site peptide from thymidylate synthetase containing covalently bound 5-fluoro-2’-deoxyuridylate and methylenetetrahydrofolate. Biochem Biophys Res Commun. 57:68

    Article  Google Scholar 

  25. Takatori S, Kanda H, Takenaka K, Wataya Y, Matsuda A, Fukushima M, Shimamoto Y, Tanaka M, Sasaki T (1999) Antitumor mechanisms and metabolism of the novel antitumor nucleoside analogues, 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine and 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)uracil. Cancer Chemother Pharmacol 44:97–104

    Article  PubMed  CAS  Google Scholar 

  26. Azuma A, Matsuda A, Sasaki T, Fukushima M (2001) 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd, TAS-106)1: antitumor effect and mechanism of action. Nucleosides Nucleotides Nucleic Acids 20:609–619

    Article  PubMed  CAS  Google Scholar 

  27. Murata D, Endo Y, Obata T, Sakamoto K, Syouji Y, Kadohira M, Matsuda A, Sasaki T (2004) A crucial role of uridine/cytidine kinase 2 in antitumor activity of 3'-ethynyl nucleosides. Drug Metab Dispos 32:1178

    Article  PubMed  CAS  Google Scholar 

  28. Naito T, Yokogawa T, Kim HS, Matsuda A, Sasaki T, Fukushima M, Kitade Y, Wataya Y (2007) A novel apoptotic pathway of 3'-Ethynylcytidine (ECyd) involving the inhibition of RNA synthesis-the possibility of RNase L activated pathway as a target of ECyd. Nucleic Acids Symp Ser (Oxf) 2007(51):435–436

    Article  Google Scholar 

  29. Bijnsdorp IV, Schwendener RA, Schott H, Fichtner I, Smid K, Schott S, Laan AC, Peters GJ (2007) In vivo and in vitro activity and mechanism of action of the multidrug cytarabine-L-glycerylyl-fluorodeoxyuridine. Nucleosides Nucleotides Nucleic Acids 26:1619–1624

    Article  PubMed  CAS  Google Scholar 

  30. Takada A, Kamiya H, Shuto S, Matsuda A, Harashima H (2009) PK-PD modeling of 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine and the enhanced antitumor effect of its phospholipid derivatives in long-circulating liposomes. Int J Pharm 377:52–59

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank the National Cancer Institute Bethesda, USA for the in vitro anticancer testing of ECyd and both duplex drugs and Prof. Dr. Schott, Institute of Organic Chemistry, University of Tuebingen, Germanys for providing us with those duplex drugs.

Author information

Authors and Affiliations

  1. Medical School, Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg, 69115, Germany

    Sarah Schott

  2. Department of Obstetrics and Gynecology, University of Tuebingen, Tuebingen, 72076, Germany

    Markus Wallwiener, Beate Kootz, Harald Seeger, Tanja Fehm & Hans Neubauer

  3. Calwerstr. 7/6, Tuebingen, 72076, Germany

    Hans Neubauer

Authors
  1. Sarah Schott
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Markus Wallwiener
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Beate Kootz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Harald Seeger
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tanja Fehm
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hans Neubauer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hans Neubauer.

Additional information

Sarah Schott and Markus Wallwiener have contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schott, S., Wallwiener, M., Kootz, B. et al. ATP chemosensitivity testing of new antitumor duplex drugs linking 3`-C-ethynylycytidine (ECyd) and 2´-deoxy-5-fluorouridine (5-FdU) in comparison to standard cytostatica and combinations thereof. Invest New Drugs 29, 506–513 (2011). https://doi.org/10.1007/s10637-009-9355-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-009-9355-0

Keywords

Search

Navigation