The clinical rationale for S-phase radiosensitization in human tumors

Nonhypoxic cell radiosensitizers, principally the halogenated pyrimidines and hydroxyurea, have been studied in the laboratory and clinical setting for more than 30 years. Early clinical experience in the 1960s and 1970s with the thymidine analogs 5-bromodeoxyuridine (BUdR) and 5-iododeoxyuridine (IUdR) was disappointing because normal tissue toxicity eliminated any potential for therapeutic gain. Inadequate delivery systems for intravenous and intraarterial infusions also contributed to the decline of this strategy. More recently, laboratory investigations have revealed further information regarding the mechanism of IUdR/BUdR radiosensitization. This knowledge provided a rationale for the sequence and timing of drug and radiation exposure, which could be both effective and tolerable. Advancing technology also provided safer infusion devices, and a resurgence in clinical trials combining IUdR or BUdR and radiation resulted. Current laboratory studies are now providing data on tumor cell kinetics, which is being applied to ongoing clinical trials. Fluoropyrimidines, principally 5-fluorouracil (5-FU), were also used in early clinical trials and unlike IUdR/BUdR were found to have significant activity as single agents against a variety of tumor types. The clinical integration of 5-FU and radiation occurred more slowly, but recent trials have demonstrated a therapeutic gain. Improved rates of local control and survival with combined 5-FU and radiation versus radiation alone have now been demonstrated in patients with rectal, esophageal, and anal carcinomas. However, the mechanism of interaction between the fluoropyrimidines and radiation remains uncertain and continues to be investigated with the hope of improved clinical outcome. As the cellular pathways influenced by the halogenated pyrimidines have been defined, the potential for biochemical modulation of these agents has been recognized. Leucovorin, the most commonly applied modulator, has been shown to enhance the activity of 5-FU in patients with metastatic colorectal carcinoma. These studies serve as an example for current trials that use biochemical modulators of IUdR, BUdR, and 5-FU as radiosensitizers. Hydroxyurea, currently used in the treatment of chronic leukemia, has also been considered a radiosensitizer. As with IUdR/BUdR, the clinical trials have often been inconclusive and interest in this radiosensitizer has waned. A poor understanding of the mechanism of action and tumor cell/normal tissue kinetics may be responsible for the lack of overall success with this strategy. Current investigations of cell kinetics in humans and potential mechanisms of hydroxyurea action could provide information critical to future trials of hydroxyurea radiosensitization.