Radiosensitization of Nonhypoxic Cells by Halogenated Pyrimidines
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).
KeywordsCisplatinum Oncol Sarcoma Pyrimidine Nucleoside
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- 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
- 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
- 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
- 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
- Goz B (1978) The effects of incorporation of 5-halogenated deoxyuridines into the DNA of eukaryotic cells. Pharmacol Rev 29: 249–272Google Scholar
- Kaplan HS, Tomlin PA (1960) Enhancement of x-ray sensitivity of E. coli by 5-bromouracil. Radiat Res 12: 447- 448Google Scholar
- 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
- 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
- Ward JF (1975) Molecular mechanisms of radiation- induced damage to nuleic acid. Adv Radiat Biol 5: 181–239Google Scholar