Radiobiology and clinical application of halogenated pyrimidine radiosensitizers

Halogenated pyrimidines (HP) represent a unique class of non-hypoxic cell radiosensitizers currently under clinical re-investigation. In order for halogenated pyrimidines to sensitize cells to radiation, they must be incorporated into cellular DNA. In the case of human tumors, which have in general rather long cell cycle times, this may require many days of continuous drug infusion to achieve adequate replacement of the DNA base thymidine with HP. In vitro studies support the relationship between the extent of radiosensitization and the percentage of thymidine replacement. Recent clinical studies evaluating the role of iododeoxyuridine (IdUrd) as a radiation sensitizer in large unresectable sarcomas have been extremely encouraging. To support and expand upon these positive clinical findings more information and research is needed regarding: (1) the mechanism of HP-induced radiosensitization; (2) the percentage of HP thymidine replacement in human tumors achievable and how it relates to treatment outcome; (3) the means of increasing HP incorporation in tumor and minimizing incorporation in normal tissues; (4) a better understanding of optimal timing between HP administration and radiation treatment; and (5) methods to evaluate which tumors are appropriate candidates for HP therapy. While presently limited to use in conventional high dose-rate X-ray therapy, laboratory studies suggest that HP might also be effective in low dose-rate brachytherapy and for selected high LET clinical beams. HPs probably will not be 'general' non-hypoxic cell radiosensitizers for all tumor types, but with appropriate tumor-type/anatomical site selection and refinement in their administration, HPs may prove beneficial in cancer treatment.