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The individual effects of desferrioxamine B (DFOA), Na3Ca diethylenetriaminepentaacetic acid (DTPA), Na-salicylate, DL-penicillamine, and 2-aminoethylisothiouronium bromide hydrobromide, as well as the effect of mixed-ligand treatment on the retention and elimination of 95Nb in mice have been examined. It was found that 95Nb could easily be mobilized by a single dose of DFOA, but the best result was obtained with the DFOA and DTPA combination. Mixed-ligand treatment did not change the deposition characteristics and translocation kinetics of 95Nb.

The ability of thiol and non-thiol radioprotectors to induce hypoxia was determined using the binding of [3H]misonidazole by bone marrow cells as a measure of hypoxia. When administered at maximally radioprotective doses, four drugs (WR-2721, cysteamine, 5-hydroxytryptamine, and 16,16-dimethyl prostaglandin E2) significantly increased the amount of [3H]misonidazole bound by marrow cells, while no significant increase in binding was observed with three other agents (endotoxin, AET, superoxide dimutase). Doses of WR-2721 previously shown to provide suboptimal radioprotection did not significantly increase 3H-misonidazole binding. These results suggest that the physiological effects of some radioprotectors, that is, their ability to induce marrow hypoxia, may contribute to their efficacy in vivo.

Rat females were exposed to a single 4.0-Gy gamma-ray dose and treated postradiation with a mixture of ATP-AET-mexamine at daily doses of 24, 12, and 3 mg/kg body wt, respectively, in drinking water throughout the period of their survival. With the radiation dose used, life shortening appeared primarily attributable to nonstochastic effects. The mixture of chemical protectors failed to show modification of long-term radiation effects with regard to either life span or tumor incidence.

The purpose of this paper was to determine whether or not a radioprotective agent which binds to DNA and inhibits DNA damage could also provide protection against radiation-induced micronuclei. Male mice were injected intraperitoneally with such an agent, 2-aminoethylisothiouronium bromide hydrobromide (AET), or its solvent 15 min prior to a single 10-min exposure to 60Co gamma rays delivered at various dose rates. Animals were killed 24 hr after irradiation and examined for the frequency of polychromatic erythrocytes containing micronuclei. The results showed a significant dose response to the irradiation for both treatments and a significant reduction in the frequency of micronucleated cells in the mice receiving the radioprotective agent.

A chemical mixture containing 25 Amoles of MEA, 7 pmoles of AET, and 2 micromoles of 5-HT was found to be of significant value in protecting mice against repeated exposures of 800 R, 1100 R, or 1400 R given at intervals of 28 days. Dose-reduction factors of 2.17, 2.18, 1.95, 2.14, and 1.58 were obtained for the first five exposures. Following the first exposure there was no chemical mortality. The beneficial value of this mixture, however, was limited by the incidence of chemical toxicity which was more prevalent in mice with higher cumulative doses of radiation.

Studies on the distribution and metabolism of the radiation-protective agents 2-mercaptoethylguanidine (MEG) and bis(2-guanidoethyl) disulfide (GED) in mice have shown that, after administration of either agent, the major chemical forms found in the tissues at the time when the animal is protected are proteinbound agent and free GED (1). Moreover, the tissue concentrations of these two chemical forms are the only ones that correlate with protection in the animals studied at 20 minutes (protected) and 120 minutes (no longer protected) after intraperitoneal administration of the protective agents. These results suggest that further studies on the mechanism of protection by MEG and GED be directed at the mechanism of action of protein-bound agent and free GED. Most of the protein-bound agent in MEGor GED-treated animals is MEG in mixed disulfide linkage with protein sulfhydryl groups. This form readily results from the reaction

The distribution and chemical forms of 2-mercaptoethylguanidine (MEG) and bis(2-guanidoethyl) disulfide (GED) in the various tissues or 8- to 10-week- old C57Bl male mice 30 min after an oral radiation protective dose of 400 mg of MEG-S35 and GED-S35/kg were studied. At 30 min after oral administration of MEG or GED, a significant amount of protective agent remained in the gastrointestinal tract. This accounts for some of the differences in LD50(30) values for equal doses of protective agent by oral and intraperitoneal routes. MEG was absorbed from the intestines more rapidly than GED, and protective forms appeared in the tissues in higher concentration after MEG administration. This explains the better protection provided by oral MEG as compared with oral GED at 30 min. The difference in absorption rates of MEG and GED may be useful in controlling the speed of onset and duration of protection by these agents in mice.

The pharmacological properties of nine compounds formed by substitutions either in the AET or in the APT molecule were studied in cats. None of the compounds elicited the chemoreflex characteristic of the parent compounds. In general, substitutions in the APT and AET molecules attenuated gut responses, amplified ganglionic block, ing activity (particularly in AET analogs), and resulted in compounds with some degree of neuromuscular depressant activity.

Litters of 8- to 10-day-old nestling rats were protected against whole-body x-irradiation by cysteamine, AET, and deep hypothermia, singly, and by a combination of cysteamine pretreatment and deep hypothermia. The different treatments were randomized among littermates to minimize animal variation. A comparison of the ${\rm LD}_{50(30)}$ values obtained for the different treatments gave a dose-reduction factor of 3.3 for the combined treatment, which was significantly greater than the factor for hypothermia alone, 2.6, or that for cysteamine alone, 1.4. Cysteamine therefore provided additional protection in the fully hypoxic (hypothermic) animal. Judged from the histological appearance of the gonads of the surviving male nestling rats, killed 30 days after irradiation, hypothermia afforded some protection to the germinal epithelium. Cysteamine, although injected when the testes were abdominal, had no demonstrable protective effect.

The sedimentation characteristics of mitochondria from livers of mice treated with various radioprotective aminothiols were measured by techniques of density-gradient and zonal centrifugation. Trea...

A high incidence of glomerulosclerosis has been noted in rodents surviving more than 1 year after mid-lethal whole-body irradiation (1-4). This experiment was a study of X-ray-induced glomerulosclerosis in mice as influenced by such factors as radiation exposures (300 to 1200 R), part of body irradiated (whole body, lumbar exposure, or lumbar area shielded), age at time of exposure (10 weeks or 1 year), and administration of the radioprotective chemical S,2-aminoethylisothiouronium Br. HBr (AET). Information is also included on other delayed effects of radiation, including life shortening, neoplasm incidence, nonneoplastic effects, and graying of the hair.

The distribution and chemical nature of the protective agent in the various tissues of 8- to 10-week-old C57BL/6J male mice given a protective dose of MEG-S/sup 35/ and GEDS/sup 35/ were studied. Results were obtained at 20 minutes after an intraperitoneal (i.p.) injection of 140 and 280 mg of MEG per kilogram and at 20, 60, and 120 min after an i.p, injection of 140 mg of GED per kilogram. Protein-bound S/sup 35/, GED, taurocyamine, guanidoethanesulfinic acid, MEG, and sulfate were identified in the serum, tissues, and excreta. Several unknown compounds were also observed. Concentrations of protein-bound S/ sup 35/ and GED decreased at 120 minutes after GED administration and correlated best with protection of the mice. All products increased in the tissues at the higher dose of MEG. Some differences in the concentrations of products were noted on comparison of MEG with GED-treated animals. The relation of the results to the mechanisms of action of MEG and GED is discussed. (auth)

HASEGAWA, A. T., AND WANG, RICHARD I. H. Attentuation of Increased Vascular Permeability and Toxicity of a Radioprotective Chemical Mixture by Chlorpromazine in Mice. Radiat. Res. 45, 364-372, (1971). The toxicity of a chemical mixture containing 5-hydroxytryptamine (5-HT), 2-aminoethylisothiouronium (AET), and 2-mercaptoethylamine (MEA) was studied in normal and irradiated mice. Toxicity was manifested by severe motor depression, respiratory difficulty, cyanosis, and death. Mortality from acute chemical toxicity was more prevalent in irradiated mice than in normal mice. An increase in the diffusion of Evans blue and a concomitant increase in hematocrit were observed after administration of either 5-HT or the mixture. Neither AET nor MEA produced any significant changes. Pretreatment with chlorpromazine (CPZ) reduced the magnitude of the rise in hematocrit which followed the administration of the mixture and prevented death from chemical toxicity during multiple radiation exposures. CPZ also reduced slightly the radio

Female mice ( ${\rm LAF}_{1}{\rm J}$ ) were treated at age 14 weeks to 250, 500, or 880 rads of x-irradiation. Several of the groups were injected with AET just prior to irradiation, and some groups were transfused with isogenic marrow cells after exposure to 880 rads. The mice were then observed for periods up to 140 weeks for gross signs of neoplasms or illness, at which time they were sacrificed. It was found that the lymphoma incidence decreased from normal levels after exposure to the higher radiation doses, but that AET tended to inhibit this "therapeutic" radiation effect. On the other hand, the incidence of hepatomas and nonlymphatic malignancies increased with doses up to 500 rads. This carcinogenic radiation effect was inhibited by AET injection. In the mice exposed to 880 rads and restored with marrow cells, none showed these lesions in contrast to those which were treated with AET. While the results are not definitive, they do indicate that x-radiation acts primarily as a ca...

Mongrel dogs were subjected to intermittent exposures of 265 or 200 m of whole-body x irradiation. Prior to each radiation insult, experimental animals were given AET, PAPP, or a combination of the two drugs. In the group that received 265-r exposures, dogs given both AET and PAPP tolerated an average of 3268 r per dog; those given AET and PAPP singly had averages of 1413 and 1506 r, respectively. Controls tolerated an average of 707 r each. In the animals subjected to 200 r intermittently, the average accumulated doses were 3550 r for the drug combimation, 2000 r for AET, 2066 r for PAPP, and 866 r for the controls. (auth)