J. R. Maisin

Bacq and Alexander Award lecture--chemical radioprotection: past, present, and future prospects.

PURPOSE To review and evaluate the development of effective radiation protectors. OUTLINE Sulphydryl radioprotectors are the best radioprotectors known today. Their use encounters two great difficulties: their toxicity and the short period during which they are active. The biological response modifiers (BRM), developed mainly in the 1990s, demonstrated some protective effects. They can also modulate radiation injury when given after irradiation. In parallel with the use of single radioprotectors, observations have been made in mice using combined treatments with BRM and other radioprotectors. Low-to-moderate doses of several radioprotective agents acting via different mechanisms markedly improved the degree of protection in rodents while maintaining toxicity within acceptable limits, but applications in man remain doubtful. CONCLUSIONS No radioprotective drug available today has all the requisite qualities to be an ideal radioprotector. Although combinations of radioprotective drugs acting via different mechanisms markedly improve the degree of protection and keep toxicity to acceptable levels in small rodents, attempts to use such treatments in large mammals have been less successful. It is thus questionable whether chemical protection has any prospects for the future.

Life-shortening and Disease Incidence in C57bi Mice After Single and Fractionated-gamma and High-energy Neutron Exposure

C57Bl Cnb mice were exposed to single or fractionated d(50)+Be neutrons or 137Cs gamma-ray exposure at 12 weeks of age and were followed for life-shortening and disease incidence. The data were analyzed by the Kaplan-Meier procedure using as criteria cause of death and possible cause of death. Individual groups were compared by a modified Wilcoxon test according to Hoel and Walburg, and entire sets of different doses from one radiation schedule were evaluated by the procedure of Peto and by the Cox proportional hazard model. No significant difference was found in life-shortening of C57Bl mice between a single gamma and neutron exposure. Gamma fractionation was clearly less effective in reducing survival time than a single exposure. On the contrary, fractionation of neutrons was slightly although not significantly more effective in reducing life span than a single exposure. Life-shortening appeared to be a linear function of dose in all groups studied. The data on causes of death show that malignant tumors, particularly leukemias including thymic lymphoma, and noncancerous late degenerative changes in lung were the principal cause of life-shortening after a high single gamma exposure. Exposure delivered in 8 fractions 3 h apart was more effective in causing leukemias and all carcinomas and sarcomas than one delivered in 10 fractions 24 h apart or in a single session. Following a single neutron exposure, leukemias and all carcinomas and sarcomas appeared to increase somewhat more rapidly with dose than after gamma irradiation. No significant difference in the incidence of leukemias and all carcinomas and sarcomas was noted between a single and a fractionated neutron exposure.

Reduction of short-term radiation lethality by biological response modifiers given alone or in association with other chemical protectors

The advantages gained by a combined treatment of different chemical protectors on short-term lethality of X-irradiated adult male mice have been studied. The following compounds were given alone or in a mixture of two or three compounds: 16,16-dimethyl PGE2 (PGE2), cysteine (Cys), glucan, glutathione (GSH), 5-hydroxytryptamine (5-HT), mercaptoproprionylglycine (MPG), or WR-2721. The survival of mice treated before X irradiation with the optimal dose of each radioprotector given separately shows that WR-2721 and 5-HT yield the best protection with dose reduction factors (DRFs) of 2.2 and 1.7, respectively. Cysteine, glucan, PGE2, MPG, and GSH, with DRFs of 1.4, 1.4, 1.2, 1.1, and 1.1, respectively, are less efficient radioprotectors. When PGE2 was combined with a low dose of WR-2721 (200 mg/kg), the protection increased in a synergistic way. The increase in protection offered by a combination of PGE2 with Cys, glucan, GSH, or 5-HT is less marked and the effect obtained is only additive. A synergistic action is also obtained with a combination of WR-2721 (200 mg/kg) and 5-HT (8 mg/kg) (DRF 2.7).

Chemical protection against the long-term effects of a single whole-body exposure of mice to ionizing radiation. I. Life shortening.

A systematic study has been made of the advantages gained by treatment with combined radiochemical protectors for long-term survival of mice exposed to a single dose of ionizing radiation. Our results demonstrate that mixtures of radioprotectors increase the degree of protection compared with that obtained with each substance given separately. The dose-effect curves for the long-term survival obtained for irradiated untreated mice and for mice treated with a mixture of radioprotectors are not parallel. Thus the dose-reduction factor (DRF) varies with the X-ray dose administered. The optimum DRF obtained for long-term survival of

Chemical Protection against Long-Term Effects of Whole-Body Exposure of Mice to Ionizing Radiation: III. The Effects of Fractionated Exposure to C57B1 Mice

{\rm BALB}/{\rm c}^{+}

Life shortening and disease incidence in BALB/c mice following a single d(50)-Be neutron or gamma exposure

mice (2.5) was very close to that obtained against acute effects of ionizing radiation (2.8).

The effects of a fractionated gamma irradiation on life shortening and disease incidence in BALB/c mice

Mice of the C57B1/Cnb strain were exposed to four fractionated doses delivered at weekly intervals (total doses from 4 × 50 to 4 × 375 R). One group of mice received a mixture of radioprotectors. T...

Life-Shortening and Disease Incidence in Mice after Exposure to γ Rays or High-Energy Neutrons@@@Life-Shortening and Disease Incidence in Mice after Exposure to g Rays or High-Energy Neutrons

Male BALB/c mice, 12 weeks old, were given a single exposure of either 137Cs gamma rays or d(50)-Be neutrons at a dose rate of 3 Gy/min. The animals were kept until death, and causes of death or possible causes of death were ascertained by autopsy and histology. The data were evaluated by competing risk methods. The survival time dose-effect curve for both types of exposure was linear and did not differ significantly (slopes: 55.8 +/- 4.0 days/Gy for neutrons and 46.2 +/- 4.3 days/Gy for gamma rays). The incidence of different diseases also was similar for both groups except that more carcinomas, sarcomas, and myeloid leukemias seemed to occur after neutron exposure and that nonstochastic lung and kidney diseases seemed to arise at lower doses.

Effect of X rays alone or combined with diethylnitrosamine on tumor induction in infant mouse liver.

BALB/c male mice (12 weeks old) were exposed to a single or fractionated exposure of 137Cs gamma rays. The fractionated dose was split into 10 equal doses delivered at an interval of 1 day. The causes and possible causes of spontaneous death were ascertained by autopsy and histological examination, and the data were treated by competing risk analysis. Life shortening followed a linear dose dependency and was about the same for fractionated (38.1 +/- 3.1 days/Gy) as for single (46.2 +/- 4.3 days/Gy) exposure. Death from tumor disease was enhanced and that from nonstochastic lung and kidney diseases was reduced after fractionated compared to single exposure.

Effect of X-rays Alone or Combined with Diethylnitrosamine on Cancer Induction in Mouse Liver

Male C57Bl/Cnb and BALB/c mice were exposed to single and fractionated d(50) + Be neutrons or 137Cs gamma rays at 12 weeks of age and were followed for life-shortening and disease incidence as ascertained by autopsy and histological examinations at the time of spontaneous death. Fractionation schedules used were 10 exposures at 24-h intervals and 8 exposures at 3-h intervals for gamma rays, and 8 exposures at 3-h intervals for neutrons. The data were analyzed by the Kaplan-Meier procedure using as criteria causes of death and possible causes of death. Individual groups were compared by a modified Wilcoxon test according to Hoel and Walburg (J. Natl. Cancer Inst. 49, 361-372 (1972)). No significant difference was found in C57Bl/Cnb and BALB/c male mice between a single gamma-ray exposure and a single neutron exposure. Gamma-ray fractionation was clearly less effective in reducing survival time than a single exposure. In contrast, fractionation of neutrons was slightly, although not significantly, more effective in reducing survival time than a single exposure. The relative biological effectiveness (RBE) for life-shortening for d(50)-Be neutrons compared to gamma rays is of the order of 1 to 2 for a single exposure to neutrons and between 2 and 3 for fractionated neutrons compared to a single exposure to gamma rays. Neutron irradiation caused somewhat more cancer than gamma irradiation, and the RBE for cancer induction may be higher, probably between 2 and 3 in the range of 1 to 3 Gy, although the present data do not allow a more precise assessment.