Modeling principles of protective thyroid blocking.

PURPOSE: In the case of a nuclear incident, the release of radioiodine must be expected. Radioiodine accumulates in the thyroid and by irradiation enhances the risk of cancer. Large doses of stable (non-radioactive) iodine may inhibit radioiodine accumulation and protect the thyroid ('thyroid blocking'). Protection is based on a competition at the active carrier site in the cellular membrane and an additional temporary inhibition of the organification of iodide (Wolff-Chaikoff effect). Alternatively, other agents like e.g. perchlorate that compete with iodide for the uptake into the thyrocytes may also confer thyroidal protection against radioiodine exposure.Biokinetic models for radioiodine mostly describe exchanges between compartments by first order kinetics. This leads to correct predictions only for low (radio)iodide concentrations. These models are not suited to describe the kinetics of iodine if administered at the dosages recommended for thyroid blocking and moreover does not permit to simulate either the protective competition mechanism at the membrane or the Wolff-Chaikoff effect. Models adapted for this purpose must be used. Such models may use a mathematical relation between the serum iodide concentration and a relative uptake suppression or a dependent rate constant determining total thyroidal radioiodine accumulation. Alternatively, the thyroidal uptake rate constant may be modeled as a function of the total iodine content of the gland relative to a saturation amount. Newer models integrate a carrier-mechanism described by Michalis-Menten kinetics in the membrane and in analogy to enzyme kinetics apply the rate law for monomolecular irreversible enzyme reactions with competing substrates to model the competition mechanism. An additional total iodide uptake block, independent on competition but limited in time, is used to simulate the Wolff-Chaikoff effect. CONCLUSION: The selection of the best model depends on the issue to be studied. Most models cannot quantify the relative contributions of the competition mechanism at the membrane and the Wolff-Chaikoff effect. This makes it impossible or exceedingly difficult to simulate prolonged radioiodine exposure and the effect of repetitive administrations of stable iodine. The newer thyroid blocking models with a separate modeling of competition and Wolff-Chaikoff effect allow better quantitative mechanistic insights and offer the possibility to simulate complex radioiodine exposure scenarios and various protective dosage schemes of stable iodine relatively easily. Moreover, they permit to study the protective effects of other competitors at the membrane carrier site, like e.g. perchlorate, and to draw conclusions on their protective efficacy in comparison to stable iodine.

Ascorbic acid-2 glucoside mitigates intestinal damage during pelvic radiotherapy in a rat bladder tumor model.

PURPOSE: Ascorbic acid is a strong antioxidant and has potent radioprotective effects on radiation injuries. Ascorbic acid 2-glucoside (AA2G) is a stabilized derivative of ascorbic acid and rapidly hydrolyzed into ascorbic acid and glucose. Since there is the possibility that AA2G treatment interferes with the antitumor activity of radiotherapy, we investigated the effect of AA2G treatment during radiotherapy on acute radiation enteritis and antitumor activity of radiotherapy in rats. MATERIALS AND METHODS: AY-27 rat bladder tumor cells were used to induce bladder tumors in rats. Two weeks after inoculation rats received fractionated pelvic radiotherapy in eight fractions for 4 weeks totaling 40 Gy. During radiotherapy, one group of rats received per os AA2G (ascorbic acid: 250 mg/kg/day) and its bolus engulfment (ascorbic acid: 250 mg/kg) 8 h before each X-irradiation fraction. Seven days after the last X-irradiation, we studied histology, DNA double strand break (DSB) damage (by 53BP1 foci staining), and the M1/M2 macrophage response by immunohistochemistry of paraffin-fixed bladder and intestinal tissues. RESULTS: AA2G treatment reduced the intestinal damage (shortening of villi) but did not reduce antitumor effectiveness of radiotherapy against bladder tumors. Like the controls, AA2G-treated rats showed no residual tumor lesions in the bladder after X-irradiation. Both AA2G-treated and control groups showed similar persistent DSB damage (53BP1 foci) both in bladders and ilea seven days after radiotherapy. Radiotherapy tended to reduce CD163+ M2 macrophages, which are considered as an anti-inflammatory subtype favoring tissue repair, in the bladders. X-irradiation also reduced the occurrence of M2 macrophages in the ilea. AA2G treatment significantly increased CD163+/CD68+ macrophage ratio in the ilea of rats after pelvic irradiation in comparison to the sham irradiated control rats. AA2G treatment increased, albeit not significantly, the CD163+/CD68+ macrophage ratio in the irradiated bladders relative to the control irradiated rats. On the other hand, bladders and ilea of the irradiated rats with and without AA2G treatment showed similar frequencies of CD68+ macrophages. CONCLUSIONS: AA2G treatment mitigated radiation-induced intestinal damage without reducing antitumor activity after fractionated pelvic radiotherapy against bladder tumors in rats. The beneficial effect of AA2G treatment seems to promote a restoration of the M2 answer as well as tissue remodeling and wound healing. Similar residual DNA damage in bladders and ilea seven days post-irradiation is consistent with tumor control in both groups.