Radiosensitization and cell kinetics: clinical implications for S-phase-specific radiosensitizers.
Rapid repopulation of tumor cells during conventional radiation therapy has been recently recognized as a factor that might significantly impair tumor response in several different tumor sites. One clinical strategy to overcome rapid tumor proliferation is to use S-phase-specific radiosensitizers such as hydroxyurea and the halopyrimidines 5-iododeoxyuridine (IUDR), 5-bromo-2'-deoxyuridine (BUDR), 5-fluoro-2'-deoxy-beta-uridine (FUDR), and 5-fluorouracil (5-FU). Indeed, several recent clinical trials have shown the positive antiproliferative effects of these radiosensitizers in various human tumors. In spite of this resurgence of clinical interest, the basic mechanism(s) of radiosensitization is not clearly understood. Although the halopyrimidines have similar biochemical pathways involving two key regulatory enzymes, thymidine kinase and thymidylate synthase, it appears that DNA-incorporation is important for radiosensitization by BUDR and IUDR but not for FUDR or 5-FU. Recent laboratory data suggest that biochemical modulation of the key regulatory enzymes can result in selective tumor radiosensitization with halopyrimidines. Hydroxyurea, like 5-FU, sensitizes cells when present prior to and following irradiation; this interaction may be related to cell synchronization as well as altered DNA damage repair. Exploiting differences in cell proliferation and cellular metabolism of these S-phase-specific radiosensitizers in tumors and normal tissues will be a major focus of clinical research in human tumor radiosensitization over the next few years.
Kinsella
T J
TJ
Department of Human Oncology, University of Wisconsin Medical School, Madison.
D002453:Cell Cycle; D017024:Chemotherapy, Adjuvant; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000532:radiotherapy*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D016196:S Phase / Q000187:drug effects*
D011838:Radiation-Sensitizing Agents; D006918:Hydroxyurea