International Journal of Radiation Oncology * Biology * Physics
Volume 73, Issue 3 , Pages 904-912 , 1 March 2009

A Systematic Assessment of Radiation Dose Enhancement by 5-Aza-2′-Deoxycytidine and Histone Deacetylase Inhibitors in Head-and-Neck Squamous Cell Carcinoma

  • Harlinde De Schutter, M.D.

      Affiliations

    • Laboratory of Experimental Radiotherapy, Leuvens Kanker Instituut, University Hospitals Leuven, Leuven, Belgium
  • ,
  • Marlies Kimpe, M.Sc.

      Affiliations

    • Laboratory of Experimental Radiotherapy, Leuvens Kanker Instituut, University Hospitals Leuven, Leuven, Belgium
  • ,
  • Sofie Isebaert, M.Sc.

      Affiliations

    • Laboratory of Experimental Radiotherapy, Leuvens Kanker Instituut, University Hospitals Leuven, Leuven, Belgium
  • ,
  • Sandra Nuyts, M.D., Ph.D.

      Affiliations

    • Laboratory of Experimental Radiotherapy, Leuvens Kanker Instituut, University Hospitals Leuven, Leuven, Belgium
    • Department of Radiation Oncology, Leuvens Kanker Instituut, University Hospitals Leuven, Leuven, Belgium
    • Corresponding Author InformationReprint requests to: Sandra Nuyts, M.D., Ph.D., Department of Radiation Oncology, UH Leuven–Campus Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. Tel: (0032) 16-34-7600; Fax: (0032) 16-34-6905

Received 24 June 2008 ,Revised 20 October 2008 ,Accepted 23 October 2008.

References 

  1. Esteller M, Corn PG, Baylin SB, et al. A gene hypermethylation profile of human cancer. Cancer Res. 2001;61:3225–3229
  2. Ishida E, Nakamura M, Ikuta M, et al. Promotor hypermethylation of p14ARF is a key alteration for progression of oral squamous cell carcinoma. Oral Oncol. 2005;41:614–622
  3. Viswanathan M, Tsuchida N, Shanmugam G. Promoter hypermethylation profile of tumor-associated genes p16, p15, hMLH1, MGMT and E-cadherin in oral squamous cell carcinoma. Int J Cancer. 2003;105:41–46
  4. de Moraes RV, Oliveira DT, Landman G, et al. E-Cadherin abnormalities resulting from CPG methylation promoter in metastatic and nonmetastatic oral cancer. Head Neck. 2008;30:85–92
  5. Ha PK, Califano JA. Promoter methylation and inactivation of tumour-suppressor genes in oral squamous-cell carcinoma. Lancet Oncol. 2006;7:77–82
  6. Righini CA, de Fraipont F, Timsit JF, et al. Tumor-specific methylation in saliva: A promising biomarker for early detection of head and neck cancer recurrence. Clin Cancer Res. 2007;13:1179–1185
  7. Esteller M. Epigenetic gene silencing in cancer: The DNA hypermethylome. Hum Mol Genet. 2007;16(Suppl. 1):R50–R59
  8. Braakhuis BJ, van Dongen GA, van Walsum M, et al. Preclinical antitumor activity of 5-aza-2′-deoxycytidine against human and neck cancer xenografts. [corrected] Invest New Drugs. 1988;6:299–304
  9. Issa JP, Garcia-Manero G, Giles FJ, et al. Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2′-deoxycytidine (decitabine) in hematopoietic malignancies. Blood. 2004;103:1635–1640
  10. Kim MS, Blake M, Baek JH, et al. Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer Res. 2003;63:7291–7300
  11. Suzuki M, Shinohara F, Nishimura K, et al. Epigenetic regulation of chemosensitivity to 5-fluorouracil and cisplatin by zebularine in oral squamous cell carcinoma. Int J Oncol. 2007;31:1449–1156
  12. Whang YM, Choi EJ, Seo JH, et al. Hyperacetylation enhances the growth-inhibitory effect of all-trans retinoic acid by the restoration of retinoic acid receptor beta expression in head and neck squamous carcinoma (HNSCC) cells. Cancer Chemother Pharmacol. 2005;56:543–555
  13. Cameron EE, Bachman KE, Myohanen S, et al. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet. 1999;21:103–107
  14. Gore SD, Baylin S, Sugar E, et al. Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res. 2006;66:6361–6369
  15. Zhu WG, Otterson GA. The interaction of histone deacetylase inhibitors and DNA methyltransferase inhibitors in the treatment of human cancer cells. Curr Med Chem Anticancer Agents. 2003;3:187–199
  16. Cerna D, Camphausen K, Tofilon PJ. Histone deacetylation as a target for radiosensitization. Curr Top Dev Biol. 2006;73:173–204
  17. Chinnaiyan P, Vallabhaneni G, Armstrong E, et al. Modulation of radiation response by histone deacetylase inhibition. Int J Radiat Oncol Biol Phys. 2005;62:223–229
  18. Zhang Y, Jung M, Dritschilo A, et al. Enhancement of radiation sensitivity of human squamous carcinoma cells by histone deacetylase inhibitors. Radiat Res. 2004;161:667–674
  19. Kim WJ, Vo QN, Shrivastav M, et al. Aberrant methylation of the ATM promoter correlates with increased radiosensitivity in a human colorectal tumor cell line. Oncogene. 2002;21:3864–3871
  20. Sakakura C, Miyagawa K, Fukuda KI, et al. Frequent silencing of RUNX3 in esophageal squamous cell carcinomas is associated with radioresistance and poor prognosis. Oncogene. 2007;26:5927–5938
  21. Dote H, Cerna D, Burgan WE, et al. Enhancement of in vitro and in vivo tumor cell radiosensitivity by the DNA methylation inhibitor zebularine. Clin Cancer Res. 2005;11:4571–4579
  22. Herman JG, Graff JR, Myohanen S, et al. Methylation-specific PCR: A novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A. 1996;93:9821–9826
  23. To KF, Chan MW, Leung WK, et al. Constitutional activation of IL-6-mediated JAK/STAT pathway through hypermethylation of SOCS-1 in human gastric cancer cell line. Br J Cancer. 2004;91:1335–1341
  24. Roy K, Wang L, Makrigiorgos GM, et al. Methylation of the ATM promoter in glioma cells alters ionizing radiation sensitivity. Biochem Biophys Res Commun. 2006;344:821–826
  25. Geng L, Cuneo KC, Fu A, et al. Histone deacetylase (HDAC) inhibitor LBH589 increases duration of gamma-H2AX foci and confines HDAC4 to the cytoplasm in irradiated non-small cell lung cancer. Cancer Res. 2006;66:11298–11304
  26. Giles F, Fischer T, Cortes J, et al. A phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies. Clin Cancer Res. 2006;12:4628–4635
  27. Siu LL, Pili R, Duran I, et al. Phase I study of MGCD0103 given as a three-times-per-week oral dose in patients with advanced solid tumors. J Clin Oncol. 2008;26:1940–1947

 Presented at the 7th International Conference on Head and Neck Cancer (American Head and Neck Society Meeting), San Francisco, CA, July 19–23, 2008.

 Supported by the Fonds voor Wetenschappelijk Onderzoek–Vlaanderen, the Vlaamse Liga tegen Kanker, and the Klinisch OnderzoeksFonds. LBH589 was provided by Novartis, and MGCD0103 was provided by MethylGene.

 Conflict of interest: none.

PII: S0360-3016(08)03674-2

doi: 10.1016/j.ijrobp.2008.10.032

International Journal of Radiation Oncology * Biology * Physics
Volume 73, Issue 3 , Pages 904-912 , 1 March 2009