Takao Sakata

Modification of N-methyl-N-nitrosourea initiated carcinogenesis in the rat by subsequent treatment with antioxidants, phenobarbital and ethinyl estradiol

The modifying effects of butylated hydroxyanisole (BHA), sodium L-ascorbate (SA), phenobarbital (PB) and ethinyl estradiol (EE) were studied by their administration to F344 rats subsequent to initiation with N-methyl-N-nitrosourea (MNU), a wide-spectrum carcinogen inducing tumors in many organs. Rats were initially given 4 doses of MNU (50 mg/kg) intraperitoneally within a 2-week period and then placed on a diet containing BHA (1%), SA (5%), PB (0.05%) or EE (0.001%) for 23 weeks prior to killing. Since the experiment was based on a whole body concept of carcinogenesis, all major organs were examined histologically and histochemically for any preneoplastic lesions. BHA enhanced forestomach and urinary bladder carcinogenesis as did SA also for the urinary bladder, whereas PB enhanced the induction of gamma-glutamyl transpeptidase positive (gamma-GT+) foci in the liver and also the incidence of thyroid carcinoma and forestomach carcinoma. In contrast, EE inhibited the induction of thyroid tumors, malignant lymphoma or leukemia. Thus these compounds, when given after initiation of many organs by a single carcinogen, exert an influence on the site of tumor development by, as yet unknown, organotropic modifying effects.

Effects of lntravesical instillation of antitumor chemotherapeutic agents on bladder carcinogenesis in rats treated with N-butyl-N-(4-hydroxybutyl)nitrosamine

The effects of intravesical instillation of Adriamycin (doxorubicin) (ADR), and mitomycin C (MMC), as inhibitors of development of rat bladder tumors, were examined in rats treated with N‐butyl‐N‐(4‐hydroxybuty1)nitrosamine (BBN). Intravesical instillation of ADR or MMC once a week for 12 weeks into rats pretreated with BBN for 4 weeks markedly enhanced development of bladder tumors. That is, one week after the end of intravesical instillation of these compounds the incidence of papillary or nodular hyperplasias, namely preneoplastic lesions, was significantly increased, and at the end of the experiment the incidence of not only papillary or nodular hyperplasias but also of papillomas and cancers was significantly increased. These results indicate that the intravesical instillation of ADR or MMC promotes two‐stage bladder carcinogenesis in rats.

Effect of quercetin on two-stage carcinogenesis of the rat urinary bladder

The initiating and promoting effects of quercetin on urinary bladder carcinogenesis in male F344 rats were examined histopathologically. No tumor or hyperplasia were observed in rats given 5.0% quercetin as initiator in the diet for 4 weeks followed by 0.001% N-butyl-N-(4-hydroxybutyl) nitrosamine (BHBN) for 29 weeks. Moreover, administration of 5.0% quercetin diet for 25 weeks after initiation with 0.01% BHBN for 4 weeks did not promote urinary bladder carcinogenesis. Furthermore, no lesions were detected in rats given 5.0% quercetin diet only. These results suggest that quercetin is not carcinogenic to rat urinary bladder.

Metabolism of 2- and 3-tert-butyl-4-hydroxyanisole (2- and 3-BHA) in the rat (I): Excretion of BHA in urine, feces and expired air and distribution of BHA in the main organs.

The mechanism of the carcinogenic or toxic action of BHA on rat forestomach was examined by studies on the excretion and tissue distribution of radioactivity in F344 male rats given tert-butyl- or methoxy-labelled 3-BHA orally. Within 2 days after a single oral dose of labelled BHA at 1 g/kg body wt, 87-96% of the 14C was excreted, mainly in the urine with smaller amounts in the feces and expired air. More 14C was found in the tissues of rats given the methoxy-labelled compounds. The distributions of 14C in the forestomach and the glandular stomach were similar. At 168 h after treatment, more 14C was found in the forestomach of rats given 2-BHA than in that of rats given 3-BHA. These results indicate that excretion of BHA is rapid, that 4-O-methyl demethylation may take place readily and that demethylated methyl group may become distributed non-specifically in tissues. The carcinogenic or toxic action of BHA on the forestomach does not seem to be due accumulation of BHA in the forestomach.

Modification potentials of ethyl alcohol and acetaldehyde on development of preneoplastic glutathione S-transferase P-form-positive liver cell foci initiated by diethylnitrosamine in the rat

The modification potentials of ethyl alcohol (EA) and acetaldehyde (AA) on development of immunohistochemical glutathione S-transferase (placental type)-positive (GST-P+) liver cell foci were examined in an in vivo short-term assay system. Rats were given a single intraperitoneal injection of diethylnitrosamine (DEN) and then various concentrations of EA (20, 10, 5%) or AA (5, 2.5%) in their drinking water from week 2 till termination in week 6. All rats were subjected to two-thirds partial hepatectomy in week 3. Animals given EA (20% and 10%) or AA showed significant decrease in liver and body weight. However, only EA caused significant dose-related inhibition of development of areas of foci (mm2/cm2), but AA had no effect on their development.

Primary Carcinomas of Urinary Bladder Diverticula

Two cases of carcinoma arising from the urinary bladder diverticulum were found at autopsy. Both patients had hematuria as a chief complaint and were found to have a tumor mass in the bladder on cystoscopic examination. However, owing to various difficulties the tumors could not be diagnosed before death. Autopsy revealed that the tumors in both cases had arisen within diverticula and had grown into the orifice of the diverticula giving the appearance of ordinary bladder tumors. Histological examination showed that in Case 1, two carcinomas, a keratinizing squamous cell carcinoma and a transitional cell carcinoma, had developed separately in a diverticulum. This may be the first case report of two cancers in a bladder diverticulum. There were no metastases in this case. Case 2 had an undifferentiated carcinoma with metastases to many organs including the lung, liver, and lymph nodes.