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The nuclear matrix proteins (NMPs) consist of common and tissue-specific nuclear proteins, which can be altered by extracellular environments such as radiation, chemicals and virus infection. Thus, NMP profiles were analyzed in diethylnitrosamine (DEN)-treated rat liver. Male F344 rats (6 weeks old) were treated continuously with DEN (40 ppm) in drinking water. All animals were sacrificed at 10, 20 or 30 weeks during the experiment. The profiles of NMPs and cytoskeletal proteins (CSPs) progressively changed in their number and amount in DEN-treated rats. Four peptides increased in their relative amounts, while three decreased in the 10- and 20-week groups. Many NMPs were detected in DEN-induced hepatocellular carcinomas. These results suggest that the alteration of the NMPs may be involved in DEN-induced hepatocarcinogenesis.

To evaluate the induction of preneoplastic hepatic foci in relation to natural killer cell (NK) activity, we sequentially analyzed glutathione S-transferase placental form positive (GST-P+) hepatocytes and NK activity during diethylnitrosamine (DEN) and phenobarbital (PB)-induced hepatocarcinogenesis in Sprague-Dawley rats. Previous studies have shown that NK activity can modulate the carcinogenic process induced by chemical carcinogens. Newborn females were initially given a single intraperitoneal injection of 15 mg DEN/kg and three weeks later, they were treated with 500 ppm phenobarbital (PB). From week 3, PB was administered in drinking water for 9 weeks. Interim and terminal sacrifices were performed at weeks 12, 15 and 30. GST-P+ hepatocytes increased with age in DEN-treated rats, especially in the population of more than two GST-P+ hepatocytes. The NK activity of DEN-treated rats did not significantly differ from that of control rats until week 12, but it progressively decreased from week 15 to 30. These results indicate that changes of NK activity inversely correlated with the induction of preneoplastic hepatic foci. This strong correlation of decreased NK activity with enhanced induction of GST-P+ foci suggests that NK activity is important in the early progression of hepatocarcinogenesis in rats.

Our previous data suggested that in Sprague-Dawley (SD) rats, a short-term in vivo radiation carcinogenesis model can be established using glutathione S-transferase placental form (GST-P) positive hepatic foci induced by diethylnitrosamine (DEN) after gamma radiation. In the present study, differences between species, strain and sexes in susceptibility to radiation or radiation combined with DEN were examined. Newborn Fischer 344 (F344) and SD rats, and N:GP(S) mice were irradiated with whole body single 3Gy of gamma rays with or without intraperitoneally-injected DEN (15 mg/kg body weight) within 1 h of irradiation. Three weeks later, 0.05% phenobarbital was given in drinking water as a promoter, and at week 21 after birth, all animals were sacrificed. In both the radiation alone and radiation combined with DEN groups, F344 rats were more susceptible than SD rats to the induction of GST-P+ foci. In F344 rats, no significant difference in foci induction was seen between the sexes in both radiation alone and radiation combined with DEN groups, but in SD rats, female rats were more susceptible than males. In the case of mice, lung tumor incidence was examined, and in the radiation alone group, no differences between the sexes were seen; in the radiation combined with DEN group, however, females were more susceptible than males. These results suggested that susceptibility to radiation carcinogenesis could be potentiated by chemical carcinogens and showed wide variation between species, strains and sexes, of experimental animals.

Dimethylitaconate (DMI) is one of phase II enzyme inducers suggesting a candidate for a tumor inhibitor. We tested the modifying effect of DMI on post-initiation stage of MNU induced gastric carcinogenesis in male Fischer 344 rats. Groups I and II administered N-methylnitrosourea (MNU) at a concentration of 100 ppm in the drinking water for 15 weeks. Group II was treated 0.5% DMI in the drinking water for 37 weeks after the MNU treatment. Groups III and IV were DMI alone and untreated control, respectively. DMI-treated animals showed hyperplastic changes in gastric epithelium and the incidence was 40% in the DMI alone group. MNU combined with DMI significantly increased the adenoma incidence compared with MNU alone group (P < 0.05). The concomitant administration of DMI showed a significant increase of adenocarcinoma incidence, which was 95% (P < 0.005) compared with MNU alone group (11.8%). The replicative DNA synthesis and the labelling index of bromodeoxyuridine, which are the indicators of proliferating activity, were increased in the stomach of DMI-treated rats compared with untreated control (P < 0.001 and P < 0.005, respectively). These results suggested that DMI has potent promoting potential in the post-initiation stage of gastric carcinogenesis of rats and its mechanisms are probably involved in the induction of cell proliferation including replicative DNA synthesis.

The oncogenic potential of adriamycin was studied in both sexes of Sprague-Dawley rats. Single i.v. injection of 10 or 2 mg and repeated injections of 2 mg of adriamycin/kg body wt within 2 weeks were performed on rats, 50 days old at the commencement. All surviving animals were killed at 52 weeks of the experiment. Multiple mammary tumors, mostly fibroadenomas, were observed in 30 and 41% of the females given single low (2 mg/kg) or repeated doses (5 X 2 mg/kg) respectively. These incidences were significantly higher than those for the corresponding control group (8%). Two male rats in the low dose group also developed mammary tumors. Both sexes receiving the single high dose (10 mg/kg) injection demonstrated early mortality due to marked toxicity. The mortality of five repeated-treatment group was lower than a single high-dose group. Renal cell tumors were evident in five rats of the single, low dose groups and dysplastic foci of renal tubular epithelium occurred in the groups given a single low or repeated doses of adriamycin. Thus the present experiment provides preliminary indication of carcinogenic potential of this chemotherapeutic agent for both kidney and mammary gland of Sprague-Dawley rats and further investigations are necessary to evaluate the carcinogenic risk of adriamycin treatment.

The carcinogenic potential of tetramethylthiuram disulfide (thiram) was examined in F344 rats. Groups of 50 male and 50 female rats were given thiram in their diet at concentrations of 0.1% and 0.05% for 104 weeks. Similar numbers of male and female rats received the basal diet throughout the experiment. All surviving rats were sacrificed at week 112. The rats given the chemical at 0.1% showed reduced body weight gain, especially in females, and liver dysfunction in biochemical examination of blood in males. Histopathologically, however, no significant lesions or tumor induction attributable to the treatment were observed in any tissue except for dose-dependent reduction of spontaneous leukemia in both sexes and slightly reduced incidences of pituitary and thyroid adenomas in females. Under the present experimental conditions, thiram was not carcinogenic in F344 rats.

The effects of a single intragastric application of dibutyltin dichloride (DT), at a dose of 30 mg/kg body weight, on N-nitrosobis(2-oxopropyl)amine (BOP)-induced pancreatic carcinogenesis were studied in female Syrian golden hamsters. DT, which has been shown to selectively induce bile duct injury, was administered either 1 week before or after BOP initiation. BOP was injected subcutaneously once a week for 5 weeks at a dose of 10 mg/kg body weight. Controls were injected with BOP alone or given DT without carcinogen. Animals sacrificed at the end of the 25-week experimental period showed a significant inhibitory effect of DT on pancreatic carcinoma induction when DT was given before BOP treatment, although no such influence was evident with DT treatment following BOP exposure. These results indicate that the bile duct and more especially common bile-duct injury induced by DT may be relevant to the inhibition of the initiation stage of BOP-induced pancreatic carcinoma development in Syrian hamsters.