Radiosensitization of Nonhypoxic Cells by Halogenated Pyrimidines

  • Timothy J. Kinsella
Part of the Medical Radiology book series (MEDRAD)

Abstract

Halogenated pyrimidine analogs such as iododeoxyuridine (IdUrd) have been recognized as potential clinical radiosensitizers for over two decades (Djordjevic and Szybalski 1960; Erik- son and Szybalski 1963; Kaplan and Tomlin 1960; Kinsella et al. 1984a). More recently, in vitro studies suggest these analogs may sensitize certain chemotherapy agents such as bleomycin and cisplatinum (Russo et al. 1986; Ackland et al. 1988), although the mechanism(s) of chemosensitization, like those of radiosensitization, are not clearly understood. However, incorporation into DNA is felt to be necessary for both types of sensitization (Ackland et al. 1988; Kinsella et al. 1987). IdUrd has been shown to be as effective a clinical radiosensitizer as bromodeoxyuridine (BrdUrd), with less systemic skin toxicity (Kinsella et al. 1985; Kinsella et al. 1984b). This skin toxicity is felt to result from photosensitization with fluorescent light and sunlight (Mitchell et al. 1984). Several clinical trials of IdUrd as a radiosensitizer show encouraging results and will be summarized later. Clinical testing of IdUrd as a chemosensitizer with bleomycin is underway as a phase I study sponsored by NCl (R. Schilsky, personal communication, 1990).

Keywords

Cisplatinum Oncol Sarcoma Pyrimidine Nucleoside 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Ackland SP, Schilsky RL, Bedcett, Weichselbaum RR (1988) Synergistic cytotoxicity and DNA strand break formation by bromodeoxyuridine and bleomycin in human tumor cells. Cancer Res 48: 4244–4289PubMedGoogle Scholar
  2. Bagshawe KD (1986) Reversed-role chemotherapy for resistant cancer. Lancet 2: 778–781CrossRefGoogle Scholar
  3. Bagshawe KD, Boden J, Boxer GM, et al. (1987) A cytotoxic DNA precursor is taken up selectively by human cancer xenografts. Br J Cancer 55: 299–30CrossRefGoogle Scholar
  4. Belanger K, Klecker RW Jr., Rowland J, Kinsella TJ, Collins JM (1986) Incorporation of iododeoxyuridine (IdUrd) into cellular DNA in patients receiving continuous intravenous infusion. Cancer Res 46: 6509–6512Google Scholar
  5. Belanger K, Colline JM, Klecker RW Jr. (1987) Technique for detection of DNA nucleobases by reversed-phase high-performance liquid chromatography optimized for quantitative determination of thymidine substitution by iododeoxyuridine. J Chromatogr 47: 57–63Google Scholar
  6. Bradley MO, Kohn KW (1979) x-ray induced DNA double strand break production and repair in mammalian cells as measured by neutral filter elution. Nucleic Acids Res 7: 793–804PubMedCrossRefGoogle Scholar
  7. Breitman TR (1983) The feedback inhibition of thymidine kinase. Biochem Biophys Acta 67: 153–158CrossRefGoogle Scholar
  8. Chang AE, Collins JM, Speth PA, et al. (1989) A phase I study of intra-arterial iododeoxyuridine in patients with colorectal liver metastases. J Clin Oncol 7: 662–668PubMedGoogle Scholar
  9. Chen MS, Shiau FT, Prusoff WH (1980) 5’-Amino-5’- deoxythymidine: Synthesis, specific phosphorylation by herpes virus thymidine kinase, and stability to pH of the enzymically formed diphosphate derivative. Antimicrob Agents Chemother 18: 433–436Google Scholar
  10. Cheng YC, Prusoff WH (1974) Mouse ascites sarcoma 180 deoxythymidine kinase. General properties and inhibition studies. Biochemistry 13: 1179–1185PubMedCrossRefGoogle Scholar
  11. Cohen A, Ullman B (1984) Role of intracellular dTTP levels in fluorodeoxyuridine toxicity. Biochem Pharmacol 33: 3298–3301PubMedCrossRefGoogle Scholar
  12. Djordjevic B, Szybalski W (1960) Genetics of human cell lines III. Incorporation of 5’-bromo- and 5- iododeoxyuridine into the deoxyribonucleic acid of human cells and its effect on radiation sensitivity. J Exp Med 112: 509–531CrossRefGoogle Scholar
  13. Erikson RL, Szybalski W (1963) Molecular radiobiology of human cell lines V. Comparative radiosensitizing properties of 5-halodeoxycytidines and 5-bromouracil. Cancer Res 23: 122–130Google Scholar
  14. Fischer PH, Baxter D (1982) Enzyme regulatory-site directed drugs: modulation of thymidine triphosphate inhibition of thymidine kinase by 5’-amino-5’- deoxythymidine. Mol Pharmacol 22: 231–234PubMedGoogle Scholar
  15. Fischer PH, Vazquez-Padua MA, Reznikoff CA, Ratschan WJ (1986a) Preferential stimulation of iododeoxyuridine phosphorylation by 5’-aminothymidine in human bladder cancer cells in vitro. Cancer Res 46: 4522–4526PubMedGoogle Scholar
  16. Fischer PH, Vazquez-Padua MA, Reznikoff, CA (1986b) Perturbation of thymidine kinase regulation: A novel chemotherapeutic approach. Adv Enzyme Regul 25: 21- 34CrossRefGoogle Scholar
  17. Fischer PH, Fang T-T, Lin T-S, Hampton A, Bruggink J (1988) Structure activity analysis of antagonism of the feedback inhibition of thymidine kinase. Biochem Pharmacol 37: 1293–1298PubMedCrossRefGoogle Scholar
  18. Goz B (1978) The effects of incorporation of 5-halogenated deoxyuridines into the DNA of eukaryotic cells. Pharmacol Rev 29: 249–272Google Scholar
  19. Gratzner HG (1982) Monoclonal antibody to 5-bromo and 5-iododeoxyuridine; a new reagent for detection of DNA replication. Science 218: 474–475PubMedCrossRefGoogle Scholar
  20. Hoshino T, Nagashima T, Murovic J, Levin EM, Levin VA, Rupp SM (1985) Cell kinetic studies of in situ human brain tumours with bromodeoxyuridine. Cytometry 6: 627–632CrossRefGoogle Scholar
  21. Jackson D, Kinsella TJ, Rowland J, et al (1987) Halogen- ated pyrimidines as radiosensitizers in the treatment of glioblastoma multiforme. Am J Clin Oncol 10: 437–443PubMedCrossRefGoogle Scholar
  22. Kaplan HS, Tomlin PA (1960) Enhancement of x-ray sensitivity of E. coli by 5-bromouracil. Radiat Res 12: 447- 448Google Scholar
  23. Kinsella TJ, Glatstein E (1987) Clinical experience with intravenous radiosensitizers in unresectable sarcomas. Cancer 59: 908–915PubMedCrossRefGoogle Scholar
  24. Kinsella TJ, Mitchell JB, Russo A, Morstyn G, Glatstein E (1984a) The use of halogenated thymidine analogs as clinical radiosensitizers: rationale, current status, and future prospects: nonhypoxic cell sensitizers. Int J Radiat Oncol Biol Phys 10: 1399–1406PubMedCrossRefGoogle Scholar
  25. Kinsella TJ, Mitchell JB, Russo A, et al. (1984b) Continuous intravenous infusion of bromodeoxyuridine (BUdR) as a clinical radiosensitizer. J Clin Oncol 2: 1144–1150PubMedGoogle Scholar
  26. Kinsella TJ, Russo A Mitchell JB, Collins JM, Rowland J, Wright D, Glatstein E (1985) Phase I study of intravenous iododeoxyuridine as a clinical radiosensitizer. Int J Radiat Oncol Biol Phys 11: 1941–1946PubMedCrossRefGoogle Scholar
  27. Kinsella TJ, Collins JM, Rowland J, et al. (1988) Pharmacology and Phase I/II study of continuous intravenous infusions of iododeoxyuridine (IdUrd) and hyperfrac- tionated radiotherapy in patients with glioblastoma multiforme. J Clin Oncol 6: 871–879PubMedGoogle Scholar
  28. Kinsella TJ, Dobson PP, Mitchell JB, Fornace AJ Jr (1987) Enhancement of x-ray induced DNA damage by pre- treatment with halogenated pyrimidine analogs. Int J Radiat Oncol Biol Phys 13: 733–739PubMedCrossRefGoogle Scholar
  29. Klecker RW Jr, Jenkins JF, Kinsella TJ, Fine RL, Strong JM, Collins JM (1985) Clinical pharmacology of 5-iodo- 2’-deoxyuridine and 5-iodouracil, and endogenous pyrimidine modulation. Clin Pharmacol Therapeutics 38: 45–51CrossRefGoogle Scholar
  30. Mitchell JB, Kinsella TJ, Russo A, et al. (1983) Radiosen- sitization of hematopoietic precursor cells (CFU-C) in glioblastoma patients receiving intermittent intravenous infusions of bromodeoxyuridine (BUdR). Int J Radiat Oncol Biol Phys 9: 457–463PubMedCrossRefGoogle Scholar
  31. Mitchell JB, Morstyn G, Russo A, Kinsella TJ, Fornace A J Jr, McPherson S, Glatstein E (1984) Differing sensitivity to fluorescent light in Chinese hamster cells containing equally incorporated quantities of BUdR versus IUdR. Int J Radiat Oncol Biol Phys 10: 1447–1452PubMedCrossRefGoogle Scholar
  32. Morstyn G, Hsu SM, Kinsella TJ, Gratzner H, Russo A, Mitchell JB (1983) Bromodeoxyuridine in tumors and chromosomes detected with a monoclonal antibody. J Clin Invest 72: 1844–1850PubMedCrossRefGoogle Scholar
  33. Morstyn G, Kinsella TJ, Hsu S-M, Russo A, Gratzner H, Mitchell JB (1984) Identification of bromodeoxyuridine in malignant and normal cells following therapy: relationship to complications. Int J Radiat Oncol Biol Phys 10: 1441–1445PubMedCrossRefGoogle Scholar
  34. O’Dwyer PJ, King SA, Hoth DF, Leyland-Jones B (1987) Role of thymidine in biochemical modulation: a review. Cancer Res 47: 3911–3919PubMedGoogle Scholar
  35. Pavan-Langstom D, Park NH, Lass J et al. (1987) 5’- Amino-5’-deoxythymidine: Topical therapeutic efficacy in ocular herpes and systemic teratogenic and toxicity studies (41386). Proc Soc Exp Biol Med 170: 1–7Google Scholar
  36. Phillips TL, Bodell WJ, Uhl V, Ross GY, Rasmussen J, Mitchell JB (1989) Correlation of exposure time, concentration and incorporation of IdUrd in V79 cells with radiation response. Int J Radiat Oncol Biol Phys 16: 1251–1255CrossRefGoogle Scholar
  37. Russo A, DeGraff W, Kinsella TJ, Gamson J, Glatstein E, Mitchell JB (1986) Potentiation of chemotherapy cytotoxicity following iododeoxyuridine incorporation of Chinese hamster cells. Int J Radiat Oncol Biol Phys 12: 1371–1374PubMedCrossRefGoogle Scholar
  38. Sirotnak FM, Barrueco JR (1987) Membrane transport and the antineoplastic action of nucleoside analogues. Cancer Metastasis Rev 6: 459–480PubMedCrossRefGoogle Scholar
  39. Spears CP, Shahinian AH, Moran RG, Heidelberger C, Corbett TH (1982) In vivo kinetics of thymidylate synthetase inhibition in 5-fluorouracil-sensitive and -resistant murine colon adenocarcinomas. Cancer Res 42: 450–456PubMedGoogle Scholar
  40. Speth PA, Kinsella TJ, Chang AE, Klecker RW, Belanger K, Collins JM (1988a) Selective incorporation of iododeoxyuridine into DNA of hepatic metastases versus normal human liver. Clin Pharm Therapeutics 44: 369- 375CrossRefGoogle Scholar
  41. Speth PA, Kinsella TJ, Belanger K, Klecker RW, Smith R, Rowland JB, Collins JM (1988b) Fluorodeoxyuridine modulation of the incorporation of iododeoxyuridine into DNA of granulocytes: a phase I and clinical pharmacological study. Cancer Res 48: 2933–293PubMedGoogle Scholar
  42. Speth PA, Kinsella TJ, Chang AE, et al. (1989) Iododeoxyuridine (IdUrd) incorporation into DNA of human hematopoietic cells, normal liver and hepatic metastases in man as a radiosensitizer and as a marker for cell kinetic studies. Int J Radiat Oncol Biol Phys 16: 1247- 1250CrossRefGoogle Scholar
  43. Szybalski W (1974) x-ray sensitization by halopyrimidines. Cancer Chemother Rep 58: 539–557PubMedGoogle Scholar
  44. Tochner Z, Kinsella TJ, Rowland J, Glatstein E (1989) Treatment of unresectable sarcomas of adults with hyperfractionated irradiation and iododeoxyuridine. Br J Radiol 19: 107–111Google Scholar
  45. Vazquez-Padua MA, Fischer PH, Christian BJ, Reznikoff CA (1989) Basis for the differential modulation of IdUrd uptake by 5’-AdThd among various cell types. Cancer Res 49: 2415–2421PubMedGoogle Scholar
  46. Ward JF (1975) Molecular mechanisms of radiation- induced damage to nuleic acid. Adv Radiat Biol 5: 181–239Google Scholar
  47. Wilson GD, McNally NJ, Dunphy E, Kiarcher H, Pfragner R (1985) The labelling index of human and mouse tumours assessed by bromodeoxyuridine staining in vitro and in vivo and flow cytometry. Cytometry 6: 641–647PubMedCrossRefGoogle Scholar
  48. Zimbrick JD, Ward JF, Myers LS Jr (1969) Studies on the chemical basis of cellular radiosensitization by 5- bromouracil substitution in DNA. II. Pulse and steady- state radiolysis of bromouracil-substituted and unsubsti- tuted DNA. Int J Radiat Biol 16: 525–534CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1991

Authors and Affiliations

  • Timothy J. Kinsella
    • 1
  1. 1.Department of Human OncologyUniversity of Wisconsin School of Medicine, Clinical Cancer CenterMadisonUSA

Personalised recommendations