International Journal of Radiation Oncology * Biology * Physics
Volume 69, Issue 4 , Pages 1254-1261 , 15 November 2007

5-Iodo-2-Pyrimidinone-2′-Deoxyribose–Mediated Cytotoxicity and Radiosensitization in U87 Human Glioblastoma Xenografts

  • Timothy J. Kinsella, M.D.

      Affiliations

    • Department of Radiation Oncology, University Hospitals Case Medical Center, Cleveland, OH
    • Corresponding Author InformationReprint requests to: Timothy J. Kinsella, M.D., Department of Radiation Oncology, University Hospitals Case Medical Center, 11100 Euclid Avenue, B181, Cleveland, OH 44106-6068. Tel: (216) 844-2530; Fax: (216) 844-4799
    • ,
  • Michael T. Kinsella, B.S.

      Affiliations

    • Department of Radiation Oncology, University Hospitals Case Medical Center, Cleveland, OH
    • ,
  • Yuji Seo, M.D.

      Affiliations

    • Department of Radiation Oncology, University Hospitals Case Medical Center, Cleveland, OH
    • ,
  • Gregory Berk, M.D.

      Affiliations

    • Hana Biosciences, South San Francisco, CA

Received 25 May 2007 ,Revised 10 August 2007 ,Accepted 10 August 2007.

References 

  1. American Cancer Society . Cancer facts and figures 2006. Atlanta, GA: American Cancer Sociey; 2006;p. 10
  2. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. [see comment] N Engl J Med. 2005;352:987–996
  3. Kinsella TJ. An approach to the radiosensitization of human tumors. Cancer J Sci Am. 1996;2:184–193
  4. Kinsella TJ, Collins J, Rowland J, et al. Pharmacology and phase I/II study of continuous intravenous infusions of iododeoxyuridine and hyperfractionated radiotherapy in patients with glioblastoma multiforme. J Clin Oncol. 1988;6:871–879
  5. Sullivan FJ, Herscher LL, Cook JA, et al. National Cancer Institute (phase II) study of high-grade glioma treated with accelerated hyperfractionated radiation and iododeoxyuridine: Results in anaplastic astrocytoma. Int J Radiat Oncol Biol Phys. 1994;30:583–590
  6. Urtasun RC, Kinsella TJ, Farnan N, et al. Survival improvement in anaplastic astrocytoma, combining external radiation with halogenated pyrimidines: Final report of RTOG 86-12, Phase I-II study. [see comment] Int J Radiat Oncol Biol Phys. 1996;36:1163–1167
  7. Prados M, Scott C, Rotman M, et al. A retrospective comparison of survival data from the Northern California Oncology Group (NCOG) and Radiation Therapy Oncology Group (RTOG) trials for glioblastoma multiforme and anaplastic astrocytoma. Int J Radiat Oncol Biol Phys. 1998;40:653–659
  8. Groves MD, Maor MH, Myers C, et al. A phase II trial of high-dose bromodeoxyuridine with accelerated fractionation radiotherapy followed by procarbazine, lomustine and vincristine for glioblastoma multiforme. Int J Radiat Oncol Biol Phys. 1999;45:127–135
  9. Schulz CA, Mehta MP, Badie B, et al. Continuous 28-day iododeoxyuridine infusion and hyperfractionated accelerated radiotherapy for malignant glioma: A phase I clinical study. Int J Radiat Oncol Biol Phys. 2004;59:1107–1115
  10. Efange SM, Alessi EM, Shih HC, et al. Synthesis and biological activities of 2-pyrimidinone nucleosides. 2. 5-Halo-2-pyrimidinone 2′-deoxyribonucleosides. J Med Chem. 1985;28:904–910
  11. Chang CN, Doong SL, Cheng YC. Conversion of 5-iodo-2-pyrimidinone-2′-deoxyribose to 5-iodo-deoxyuridine by aldehyde oxidase. Implication in hepatotropic drug design. Biochem Pharmacol. 1992;43:2269–2273
  12. Kinsella TJ, Kunugi KA, Vielhuber KA, et al. An in vivo comparison of oral 5-iodo-2′-deoxyuridine and 5-iodo-2-pyrimidinone-2′-deoxyribose toxicity, pharmacokinetics, and DNA incorporation in athymic mouse tissues and the human colon cancer xenograft, HCT-116. Cancer Res. 1994;54:2695–2700
  13. Kinsella TJ, Kunugi KA, Vielhuber KA, et al. Preclinical evaluation of 5-iodo-2-pyrimidinone-2′-deoxyribose as a prodrug for 5-iodo-2′-deoxyuridine-mediated radiosensitization in mouse and human tissues. Clin Cancer Res. 1998;4:99–109
  14. Kinsella TJ, Vielhuber KA, Kunugi KA, et al. Preclinical toxicity and efficacy study of a 14-day schedule of oral 5-iodo-2-pyrimidinone-2′-deoxyribose as a prodrug for 5-iodo-2′-deoxyuridine radiosensitization in U251 human glioblastoma xenografts. Clin Cancer Res. 2000;6:1468–1475
  15. Kinsella TJ, Schupp JE, Davis TW, et al. Preclinical study of the systemic toxicity and pharmacokinetics of 5-iodo-2-pyrimidinone-2′-deoxyribose as a radiosensitizing prodrug in two, non-rodent animal species: Implications for phase I study design. Clin Cancer Res. 2000;6:3670–3679
  16. Seo Y, Yan T, Schupp JE, et al. Differential radiosensitization in DNA mismatch repair-proficient and -deficient human colon cancer xenografts with 5-iodo-2-pyrimidinone-2′-deoxyribose. Clin Cancer Res. 2004;10:7520–7528
  17. Seo Y, Yan T, Schupp JE, et al. Schedule-dependent drug effects of oral 5-iodo-2-pyrimidinone-2′-deoxyribose as an in vivo radiosensitizer in U251 human glioblastoma xenografts. Clin Cancer Res. 2005;11:7499–7505
  18. Kinsella TJ, Kinsella MT, Hong SW, et al. Toxicology and pharmacokinetic study of orally administered 5-iodo-2-pyrimidinone-2′-deoxyribose (IPdR) × 28 days in Fischer-344 rats: Impact on initial phase I trial design of IPdR-mediated radiosensitization. Cancer Chemother Pharmacol. 2007;June 12 [Epub ahead of print]
  19. Schulz C, Gaffney D, Lindstrom M, et al. Iododeoxyuridine radiosensitization of human glioblastoma cells exposed to acute and chronic gamma irradiation: Mechanistic, implications and clinical relevance. Cancer J Sci Am. 1995;1:151–161
  20. Camphausen K, Purow B, Sproull M, et al. Influence of in vivo growth on human glioma cell line gene expression: Convergent profiles under orthotopic conditions. Proc Natl Acad Sci U S A. 2005;102:8287–8292
  21. Blasberg RG, Roelcke U, Weinreich R, et al. Imaging brain tumor proliferative activity with [124I]iododeoxyuridine. Cancer Res. 2000;60:624–635
  22. Berry SE, Garces C, Hwang HS, et al. The mismatch repair protein, hMLH1, mediates 5-substituted halogenated thymidine analogue cytotoxicity, DNA incorporation, and radiosensitization in human colon cancer cells. Cancer Res. 1999;59:1840–1845
  23. Berry SE, Davis TW, Schupp JE, et al. Selective radiosensitization of drug-resistant MutS homologue-2 (MSH2) mismatch repair-deficient cells by halogenated thymidine (dThd) analogues: Msh2 mediates dThd analogue DNA levels and the differential cytotoxicity and cell cycle effects of the dThd analogues and 6-thioguanine. Cancer Res. 2000;60:5773–5780
  24. Berry SE, Kinsella TJ. Targeting DNA mismatch repair for human tumor radiosensitization. Semin Radiat Oncol. 2001;11:300–315
  25. Friedman HS, Dong Q, Scholds S, et al. Methylator resistance mediated by mismatch repair deficiency in a glioblastoma multiforme xenograft. Cancer Res. 1997;57:2933–2936
  26. Friedman HS, McLendon RE, Kerby T, et al. DNA mismatch repair and O6-alkylguanine-DNA alkyltransferase analysis and response to Temodal in new diagnosed malignant glioma. J Clin Oncol. 1998;16:3851–3857
  27. Cahill DP, Levine KK, Betensky RA, et al. Loss of the mismatch repair protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment. Clin Cancer Res. 2007;13:2038–2045
  28. Taverna P, Liu L, Hwang HS, et al. Methoxyamine potentiates DNA single strand breaks and double strand breaks induced by temozolomide in colon cancer cells. Mutat Res. 2001;485:269–281
  29. Taverna P, Hwang HS, Schupp JE, et al. Inhibition of base excision repair potentiates iododeoxyuridine-induced cytotoxicity and radiosensitization. Cancer Res. 2003;63:838–846
  30. Yan T, Seo Y, Schupp JE, et al. Methoxyamine potentiates iododeoxyuridine-induced radiosensitization by altering cell cycle kinetics and enhancing senescence. Mol Cancer Ther. 2006;5:893–902

 Supported in part by National Institutes of Health Grant CA50595, by Hana Biosciences, and by the University Radiation Medicine Foundation.

 Conflict of interest: none.

PII: S0360-3016(07)03867-9

doi: 10.1016/j.ijrobp.2007.08.004

International Journal of Radiation Oncology * Biology * Physics
Volume 69, Issue 4 , Pages 1254-1261 , 15 November 2007

Article Tools

* Image Usage & Resolution