Radiolytic Reduction Activating Prodrugs Possessing 5-Fluorouracil-Releasing Ability : Radiation Sensitizing Effect on Mouse Tumors

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Radiolytic reduction activating prodrugs consisting of 5-fluorouracil (5FU) and 2-oxoalkyl substituents at N1, that show no antitumor activity, but release 5FU as a well-specified antitumor agent within hypoxic cells upon irradiation, were studied to obtain a structure-activity relationship for radiotherapy of cancer. The followings are results in the several assays for determining their potential of clinical application.(1) Among a series of radiolytic reduction activating prodrugs, several 5FU derivatives bearing certain 2-oxoalkyl substituents that showed higher 5FU-releasing reactivity in the radiation chemical assay were synthesized on a large scale to submit for in vivo assay using mouse tumors.(2) The survival fractions of SCCVII tumor cells suspended in the pre-irradiated (7.5-22.5 Gy) culture medium were evaluated to correlate with the incubation time, by which a quantitative relationship between the cytotoxicity and the amount of 5FU released was obtained.(3) The cytotoxicity … More and the in vitro radiosensitizing activity toward SCCVII tumor cells were evaluated under oxic and hypoxic conditions dosages of prodrugs, which were correlated with intracelluar concentration of 5FU released upon irradiation. The structure-cytotoxicity and structure-activity relationships derived from the in vitro data were utilized as a guiding principle for molecular design and synthetic study.(4) The ICィイD250ィエD2 values of a series of prodrugs were evaluated to correlate with molecular structures and in vitro radiosensitizing activity.(5) Pharmacokinetic analyses were performed to evaluate drug concentrations in plasma and tumor tissues after i.v. injection, using mice bearing SCCVII or EMT6 solid tumors. The time-dependent itratumor concentrations of 5FU released were also analyzed under various timings of irradiation, thereby correlating with the 5FU-releasing ability of prodrugs. These analyses provided a guiding principle for molecular design of better prodrugs with respect to the pharmacokinetic characteristics. Less