Comparison of the Acute Toxicity of N-nitrosocimetidine with Three Structurally Related Carcinogens in the Rat*

ABSTRACT The acute toxicity of N-nitrosocimetidine, the nitrosated derivative of the histamine H,-receptor blocking agent cimetidine, was compared with the toxicities of three structurally related nitroso compounds known to be potent carcinogens, namely N-methyl-N'-nitro-N-nitrosoguanidine, N-methyl-N-nitrosourea, and N-methyl-N-nitrosourethane, and also with the parent drug cimetidine. The acute toxicity of each compound was investigated in 6-week-old female Fischer-344 rats by estimating the median lcthal doses via three different routes of administration. and by assessing the scquencc of histopathological alterations induced. According to median lethalities, all three known carcinogens were substantially more toxic than nitrosocimetidine whether administered by the intravenous, intraperitoneal, or oral routes. The widest margin of difference was represented by orally administered N-methyl-N-nitrosourca, the median lethal dose being 59 times greater than oral N-nitrosocimetidinc. By this method, thc acute toxicities of N-nitrosocimetidine and the parent drug cimetidine were virtually identical for each of the three routes of administration. Sequential histological assessment indicated that the three known carcinogens induced specific pathological alterations mainly in organs which were also known to be targets for their carcinogenic activity. In contrast, no tissue lesions of a spccific nature wcrc associated with N-nitrosocimctidinc or cimetidine in this study. The comparable results with N-nitrosocimetidine and the parent drug provide biological support for previously obtained biochemical data which suggested that N-nitrosocimetidine is rapidly denitrosated to cimetidine in the rat

Defective repair of radiation-induced DNA damage is complemented by a CHORI-230-65K18 BAC clone on rat chromosome 4

AbstractThe Long Evans cinnamon (LEC) rat is highly susceptible to X-irradiation due to defective DNA repair and is thus a model for hepatocellular carcinogenesis. We constructed a bacterial artificial chromosome (BAC) contig of rat chromosome 4 completely covering the region associated with radiation susceptibility. We used transient and stable transfections to demonstrate that defective DNA repair in LEC cells is fully complemented by a 200-kb BAC, CHORI-230-65K18. Further analysis showed that the region associated with radiation susceptibility is located in a 128,543-bp region of 65K18 that includes the known gene Rpn1. However, neither knockdown nor overexpression of Rpn1 indicated that this gene is associated with radiation susceptibility. We also mapped three ESTs (TC523872, TC533727, and CB607546) in the 128,543-bp region, suggesting that 65K18 contains an unknown gene associated with X-ray susceptibility in the LEC rat

Neutron Biological Effects Research at NIRS

The fifth Japan-France Workshop on Radiobiology and Medical Imagin

OK-432 reduces mortality and bacterial translocation in irradiated and granulocyte-colony stimulating factor (G-CSF)-treated mice.

Bacterial translocation/Acute radiation syndrome/Endotoxin/G-CSF/OK-432 Acute radiation induces bacterial translocation from the gut,followed by systemic infection and sepsis. In order to reduce the mortality after acute whole body irradiation, it is essential to control bacterialtranslocation. In this study, we established a bacterial translocation assay as a sensitive method to detect minor mucosal injury by radiation. By utilizing this assay, we evaluated the adverse effects, if any, of hematopoietic reagents on the mucosal integrity in the respiratory and gastro-intestinal tracts. Bacterial translocation to the liver and spleen occurred after whole-body irradiation if the dose exceeded 6 Gy. The administration of G-CSF unexpectedly increased the bacterial translocation in 8 Gy-irradiated mice. The pharmaceutical preparation oflow-virulent Streptococcus pyogenes, OK-432, significantly reduced the endotoxin levels in peripheral blood without any reduction of bacterialtranslocation. A combined treatment with G-CSF and OK-432 decreased bacterial translocation and prevented death. This result indicates that the early administration of G-CSF has an adverse effect on bacterial translocation, and that a combined treatment of G-CSF and OK-432 attenuates the adverse effect of G-CSF and improves the survival rate after acute irradiation

Tumor induction in mice locally irradiated with carbon ions:a retrospective analysis

Tumor induction in mice legs that were locally irradiated with carbon ions was compared to tumor induction by gamma rays after single and fractionated irradiation. A total of 250 tumors were induced in 1104 mice that received carbon-ion doses of 5 through 65 Gy. A total of 77 tumors were induced in 371 mice that received gamma-ray doses of 45 through 95 Gy. Of carbon-ion induced 91 tumors histologically examined, 97 percent was malignant, and sarcomas such as malignant fibrous histiocytoma (47%) and fibrosarcoma (32%) were most frequently observed. Malignant fibrous histiocytoma was also the most frequently observed tumor (12 out of 20 tumors; 60%) after gamma-ray irradiation, followed by carcinomas (25%) such as adenocarcinoma and squamous cell carcinoma. Neither dose fractionation nor linear energy transfer affected tumor induction for carbon ions and gamma rays. Dose responses were linear for carbon ions and gamma rays, and showed no saturation up to 65 Gy of carbon ions and 95 Gy of gamma rays. Relative biological effectiveness of carbon ions was 2.2 for tumor induction and 1.9 for early skin reaction. We conclude that risk of secondary tumor induction by carbon-ion radiotherapy would not be seriously higher than anticipated