The mutagenic activity of the S-nitrosoglutathione/glutathione system in Salmonella typhimurium TA1535.

S-nitrosoglutathine (GSNO) and reduced glutathione (GSH) were tested for mutagenicity against strain Salmonella typhimurium TA1535 in the Ames Standard plate incorporation assay. Neither GSNO not GSH were mutagenic when tested alone. In combination, the GSNO/GSH system induced a positive mutagenic response that ranged from 3 to 20 x over background at concentrations of 10 to 50 micromol (micromol)per plate, respectively. This mutagenic response can be attributable to the generation nitric oxide, among the many other reactive products generated by the reaction of GSNO with GSH.

Induced Robertsonian fusions and tandem translocations in mammalian cell cultures.

Cultures of a cattle cell line and a Peromyscus eremicus cell line recovering from a pulse-treatment with mitomycin C, actinomycin D, 33258 Hoechst, and nitrosoguanidine exhibited translocations between chromosomes at the centromeric regions (Robertsonian fusions) as well as between centromere and telomere and between telomeres (tandem translocations). The frequency of Robertsonian fusions was found to be dose-dependent and duration-dependent with the mitomycin treatment. Biarmed chromosomes resulting from fusions may be monocentric or dicentric. Analyses of clones isolated from treated cells suggested that fused chromosomes may perpetuate in the cell populations.

Adenocarcinomas of the stomach induced in beagle dogs by oral administration of N-ethyl-N'-nitro-N-nitrosoguanidine.

Two 8-month-old and two 4-month-old male beagle dogs received 250 ml of 150 microgram/ml solution of N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) and 2% Tween 60 mixed with a pellet diet twice a day for 8 months as the same methods used for mongrel dogs in our first report [Juntendo Medical Jouranl 19, 579-583 (1973)]. Gastric carcinomas with distant lymph nodes metastases occurred in three beagle dogs except for one died from anesthesia at the endoscopy. Metastases to the liver were observed in two beagles. In the most long-lived beagles, peritonitis carcinomatosa with ascites and metastases to the liver, lungs, bones, and skin were found. Main gastric tumors were located at the subcardia in two dogs (elevated tumor in dog No. 6, ulcerated tumor in dog No. 8), but in dog No 7 at the angulus (ulcerated tumor). Histologically, carcinomas were composed of poorly differentiated adenocarcinoma, signet-ring cell carcinoma, tubular adenocarcinoma, and undifferentiated adenocarcinoma. In all of three dogs which developed adenocarcinoma of the stomach, Stewart's criteria were completely satisifed. Using our methods the target organ is limited only to the stomach, without any sarcomatous lesion of the intestines.

Tumor induction by a single subcutaneous injection of N-methyl-N'-nitro-N-nitrosoguanidine and its derivatives in newborn mice.

N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG), or its derivatives N-hexyl-N'-nitro-N-nitrosoguanidine (HNNG) and 1,6-bis(N'-nitro-N-nitrosoguanidinyl)-n-hexane (HxBNNG) were given to newborn ICR/JCL mice by a single subcutaneous injection in 1% gelatin suspension. In an acute toxicity study, the maximum tolerated dose of MNNG, HNNG or HxBNNG was 62 microgram/g, 555 microgram/g, or 500 microgram/g of body weight, respectively. In a chronic study, a single subcutaneous injection of MNNG to newborn mice at a dose of 62, 31, or 3 microgram/g of body weight induced tumors of the lung and hemangioendotheliomas in both sexes, and tumors of the liver in males. Other pathologic findings, such as deformities of the spine and alopecia of the skin, were frequently observed. The incidences of tumors in each group were clearly dose related. HNNG and HxBNNG were not tumorigenic within the observation period.

Effect of plastic bead on gastric carcinogenesis in rats treated with N-methyl-N'-nitro-N-nitrosoguanidine.

Experiments were made on induction of cancer of the glandular stomach of rats by a combination of oral administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and insertion of a plastic bead into the gastric lumen. The incidence of cancer with this combination of treatments was greater than by administration of MNNG alone. Fluoroscopic examination showed that barium sulfate remained in the stomach longer when a bead had been inserted into the gastric lumen. This indicates that after insertion of a bead, MNNG must have remained in the stomach longer, and so the period of exposure of the gastric mucosa to the carcinogen must have increased.

Large bowel carcinoma in strain-2 guinea pigs by intrarectal instillation of N-methyl-N'-nitro-n-nitrosoguanidine.

Intrarectal instillation of 0.5 ml of a 0.125% solution of N-methyl-N'-nitro-N-nitrosoguanidine twice weekly for 53 weeks to female inbred strain-2 guinea pigs induced multiple large bowel adenocarcinomas in 13 of 15 animals in 52 to 85 weeks. The lesions were plaque-shaped in small tumors and infiltrative or constrictive in large advanced tumors. The neoplasms showed histological features in varied grades of differentiation and invasiveness similar to those of human cases. These findings distinquished them from large bowel cancers chemically induced in rats and mice.

Cancer-related aspects of regeneration research: a review.

Tissue regeneration is simply the replacement of lost cells of a tissue by those remaining. Epimorphic regeneration involves dedifferentiation of many tissues and their organization into a blastema which eventually differentiates into the missing part, usually an appendage. A detailed comparison of the cell membrane changes occurring in epimorphic regeneration, tissue regeneration and cancer can contribute to greater understanding of the differences between normal and tumor cells. Further, there is evidence that epimorphic regeneration fields may in some instances suppress tuomr induction and control existing tumors. This influence may be mediated by bioelectric fields, which are ubiquitous in nature and appear to control many cellular events. Disruption of these bioelectric fields suppresses epimorphic regeneration and may lead to cancer in mammals, while applied electric fields alter regenerative events and cause tumor regression.

Cell kinetics of gastric carcinoma and other gastric lesions in rats by N-methyl-N'-nitro-N-nitrosoguanidine with or without Tween 60.

Male Wistar rats were divided into three groups for studying the chronic effect of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), in continuous dose of 50 mg/L in drinking water, or 50 mg/L MNNG and 0.4% Tween 60 in drinking water. From the 2nd to 50th week after the administration of MNNG, every 3 or 5 rats were sacrificed and autopsied after the intraperitoneal injection of 1 muCi 3-H-thymidine/g body weight at 2- or 3-week intervals. The resected stomachs were studied morphologically and autoradiographically. Six cases of experimental gastric cancer were produced that fulfilled Stewart's criteria. Autoradiographically, there was no significant different in the flash labeling index in the normal antral mucosa, in the non-pathologic antral mucosa, and in the cancerous lesion, but generation time and DNA synthesizing time of the cancerous lesion were 2 or 3 times longer than those of the glandular stomach of normal rats reported by Galjaard. They were also longer than those of the non-pathologic antral mucosa of rats treated with MNNG. These experiments results were discussed, comparing with cell kinetics of the gastrointestinal tracts in man.

Transplantable adenocarcinomas from color-rectal tumors induced by infusion of N-methyl-N'-nitro-N-nitrosoguanidine in ACI/N rats.

Two transplantable strains of adenocarcinoma were established from the carcinomas of the colon and rectum induced by infusion of N-methyl-N'-nitro-N-nitrosoguanidine in inbred ACI/N rats, The tumors are solid type, not converted to ascite form yet, either papillary or tubulo-papillary adenocarcinomas, and particularly grow slowly, showing 2 to 4 months of survival in animals transplanted subcutaneously. Besides histological resemblance of the tumors to human adenocarcinoma of the large intestine, marked mucin production in tumor was noted in one of these strains.