Toshifumi Tsujiuchi

Isolation and localization of type IIb Na/Pi cotransporter in the developing rat lung.

Differential display analysis of rat lung at different developmental stages identified a fragment, HG80, which appeared on embryonic day 16.5 and thereafter. A full-length cDNA derived from a cDNA library of newborn rat lung probed with HG80 was the rat counterpart of sodium-dependent phosphate transporter type IIb and was designated rNaPi IIb. In situ hybridization showed that rNaPi IIb was expressed in type II alveolar cells, suggesting a role in the synthesis of surfactant in the alveoli. The time-dependent changes in localization of this gene in the developing lung and its possible use as a type II pneumocyte marker are discussed.

Early ductal lesions of pancreatic carcinogenesis in animals and humans

SummaryTwo cases of human early pancreatic duct adenocarcinoma were presented, and ductal lesions observed histologically were compared to those induced in hamsters using a rapid-production model of pancreatic carcinoma. In human cases, direct histologic evidence was obtained to suggest that cancerous changes arose from duct epithelial cell hyperplasia, because lesions of hyperplasia and carcinoma coexisted in continuity. In hamster serialkilling studies, it was suggested that carcinoma developed through atypical ductal hyperplasia.

Effects of 3‐Aminobenzamide on Induction of Multiorgan Carcinogenesis by N‐Nitrosobis(2‐hydroxypropyl)amine in Hamsters

The effects of an inhibitor of poly(ADP‐ribose)polymerase, 3‐aminobenzamide (ABA), on N‐nitrosobis(2‐hydroxypropyl)amine (BHP)‐induced pancreas, liver, gallbladder and lung carcinogenesis in Syrian golden hamsters were investigated. Animals were given either BHP alone, by subcutaneous injection at a dose of 500 mg/kg body weight, or in combination with an intraperitoneal injection of ABA 30 min after the BHP at a dose of 300 or 600 mgAg body weight once a week for 5 weeks, and then killed 35 weeks after the commencement of the experiment. ABA exerted inhibitory effects on pancreas and lung carcinogenesis induced by BHP, with mean numbers of lesions (including hyperplasias and carcinomas) being significantly decreased compared with the BHP‐alone group values, while no significant effect was observed on liver or gallbladder carcinogenesis. These results suggest that the effects of ABA on carcinogenesis depend on the target organ as well as the chemical carcinogen examined.

Effects of 3-aminobenzamide on the post-initiation phase of N-nitrosobis(2-oxopropyl)amine induced pancreatic carcinogenesis in Syrian hamsters

Effects of 3-aminobenzamide (ABA) on pancreatic carcinogenesis after initiation by N-nitrosobis(2-oxopropyl)amine (BOP) were investigated in Syrian hamsters. Animals were given BOP at a dose of 70 mg/kg body weight by subcutaneous injection and following a 2-week recovery period, were administered basal diet or basal diet containing 0.5, 0.75 and 1.5% ABA for 30 weeks. While the incidences of resultant pancreatic lesions, including hyperplasia, atypical hyperplasia and carcinoma, induced by BOP were not significantly influenced by ABA treatment, the mean numbers of those pancreatic lesions were significantly decreased in a dose-dependent way. The results therefore suggested the possible involvement of poly(ADP-ribosyl)ation in the post-initiation phase of pancreatic carcinogenesis in hamsters.

Effects of Novobiocin on the induction of γ-glutamyltranspeptidase positive foci in the liver of rats treated with diethylnitrosamine

Effects of novobiocin on the induction of gamma-glutamyltranspeptidase(GGT)-positive foci, an early lesion occurring during hepatocarcinogenesis, after diethylnitrosamine(DEN) initiation were investigated in Fischer 344 rats. Animals were given DEN at a dose of 20 mg/kg b. w. followed by novobiocin at doses of 50, 100 and 200 mg/kg b. w. The latter two doses, but not 50 mg/kg b. w., significantly inhibited the development of GGT-positive foci, providing evidence of the possible involvement of mono(ADP-ribosyl)ation in the initiation phase of hepatocarcinogenesis in rats.

Dose-response study of N-nitrosomethyl(2-hydroxypropyl)amine-induced nasal cavity carcinogenesis in rats.

Dose response to the carcinogenic activity of N-nitrosomethyl(2-hydroxypropyl)amine (MHP) was investigated for the nasal cavity of male Wistar rats. MHP dissolved in 0.9% saline was administered intraperitoneally once a week for 12 weeks at doses of 0, 4.4, 8.8 and 17.6 mg/kg body weight, and all surviving animals were sacrificed 26 weeks after the beginning of the experiment. Hyperplasias, papillomas and squamous cell carcinomas were induced. Hyperplasias could be divided into flat, protruding and downgrowth types and were observed in respiratory and squamous epithelial regions. Papillomas and squamous cell carcinomas developed in the respiratory region, and the incidence of the latter reached 83% in rats which received the highest dose of MHP. These results indicate that MHP shows its carcinogenic activity of the nasal cavity by the development of squamous cell carcinomas.

Induction of rat liver γ-glutamyltranspeptidase-positive foci by oral administration of 1-nitropyrene

In the present study, the question of whether the ubiquitous environmental pollutant, 1-nitropyrene (1-NP), can induce gamma-glutamyltranspeptidase (GGT)-positive foci, an early lesion occurring during hepatocarcinogenesis, when given orally to F344 rats was examined. Significant induction of GGT-positive foci was observed with all the doses of 1-NP (1000, 500, 250 and 100 mg/kg body wt) used in the present experiment after 6 repeated intragastric (i.g.) intubations when accompanied by partial hepatectomy (PH) performed midway, but not after a single i.g. 1000 mg/kg body wt intubation plus PH. The potential for induction of foci by 1-NP, however, was far less than that by benzo[a]pyrene (B[a]P). The results thus suggested a weak but substantial initiation activity for 1-NP in the rat liver when given orally, particularly with repeated doses.

Possible involvement of poly(ADP-ribosyl)ation in phenobarbital promotion activity in rat hepatocarcinogenesis

Poly(ADP-ribosyl)ation has been suggested to be involved in various biological processes, including DNA repair (Shall, 1984), cell differentiation (Farzaneh et al., 1982), cell proliferation (Menegazzi et aI., 1988) and malignant transformation (Borek et al., 1984). Previously, we reported that inhibitors of poly(ADP-ribose) polymerase enhanced liver carcinogenesis which was given in the initiation phase of diethylnitrosamine(DEN) (Takahashi et al., 1982;Takahashi et al., 1984). Recently, 12-O-tetradecanoylphorbol-I3-acetate(TPA), a mouse skin tumor promoter, was found to increase poly(ADPribosyl)ation of nuclear proteins in human monocytes, mouse fibloblasts and rat hepatocytes (Singh et al., 1985;Singh and Cerutti, 1985;Romano et al., 1988), and suggested the involvement of poly(ADP-ribosyl)ation on tumor promotion processes. In the present experiment, we studied the effects of inhibitors of poly(ADPribose)polymerase on the promotion by phenobarbital (PB) in liver carcinogenesis initiated by DEN in rats.

Delayed DNA synthesis induced by 3-aminobenzamide in partially hepatectomized liver of rats

The possibility of poly(ADP‐ribosyl)ation playing a role during liver regeneration induced by partial hepatectomy (PH) in vivo was examined. When rats were given an i.p. injection of 3‐antinobenzamide (ABA) at a dose of 600 mg/kg body weight 12 h after PH, the levels of DNA synthesis at 20 h after PH were significantly reduced. The time course of DNA synthesis in regenerating liver was significantly delayed in the ABA‐treated group. Enzymatic assay revealed the activity of poly‐(ADP‐ribose)polymerase (PADPRP) in controls to be increased in parallel with the increase of DNA synthesis induced by PH. This increase in PADPRP activity was delayed and very much weaker after ABA treatment. The results thus suggested that poly (AUP‐ribosyl)ation might play an important role in DNA synthesis during liver regeneration in vivo.

Lack of modifying effects of 6-mercaptopurine in a medium term bioassay system for liver carcinogenesis using male F344 rats

Carcinogenic and modification potential of 6-mercaptopurine (6-MP) was studied in a medium-term bioassay system for rat liver carcinogenesis. F344 male rats were initiated with a single dose (200 mg/kg body wt.) of diethylnitrosamine (DEN) i.p. and fed diets containing either 0.005% or 0.02% 6-MP with or without 0.05% phenobarbital (PB) for 6 weeks. Quantitative data revealed that 6-MP did not enhance the appearance of enzyme-altered preneoplastic foci and nodules even when administered at the highest dose (0.02%) despite showing an immunosuppressive effect and slight liver cell damage. Neither of the doses of 6-MP exerted any significant influence on the enhancing effect of PB when administered simultaneously in the medium-term-bioassay.