Inhibitory effects of freeze-dried milk fermented by selected Lactobacillus bulgaricus strains on carcinogenesis induced by 1,2-dimethylhydrazine in rats and by diethylnitrosamine in hamsters.

Fermented milk products might be used for cancer chemoprevention due to their putative anticarcinogenic and antitumor activities. The diet was supplemented with freeze-dried milk fermented by Lactobacillus bulgaricus strain LBB.B 144 (product FFM.B 144) added throughout the experiment at doses of 1.3 g and 2.5 g per rat, 5 times a week starting 3 weeks before the first carcinogen injection. This treatment significantly inhibited, by 26.2-28.6% and by 34.2%, the total intestinal carcinogenesis induced by 1,2-dimethylhydrazine (DMH, 21 mg/kg, s.c., once per week for 20 weeks) in male and female BD6 rats, respectively. FFM.B144 decreased the tumor incidence and multiplicity in large bowel, caecum, and duodenum. Protective effects were better expressed in female animals, with exception of that observed in duodenum. Supplementation of diet with freeze-dried milk fermented by Lactobacillus bulgaricus strain LBB.B5 (product FFM.B5) inhibited DMH-induced carcinogenesis only in the large bowel, but had no significant protective effect when all intestinal tumors were taken into account. However, both freeze-dried products favorably shifted the differentiation of large bowel tumors by increasing the proportion of benign and highly differentiated malignant tumors and decreasing in parallel the number of poorly differentiated carcinomas without influencing the tumor size. A lower number of cases with visible mesenterial metastasis was also observed in FFM-treated rats. In addition, both FFM.B 144 and FFM.B5 significantly inhibited, by 26-33%, the induction in the same rats of ear-duct tumors. FFM.B144 but not FFM.B5 was also effective in inhibiting the tracheal carcinogenesis induced in Syrian golden hamsters by diethylnitrosamine (DEN, 100 mg/kg, two s.c. injections), the protective effect being better expressed in female animals. The anticarcinogenic potential of some fermented milk products might be exploited in chemoprevention of cancer in humans.

The effect of beta-carotene on BP-induced respiratory tract tumors in hamsters.

The modifying effect of beta-carotene on benzo[a]pyrene (BP)-induced tumors of the respiratory tract was investigated in Syrian hamsters. Groups of hamsters were fed a semisynthetic diet supplemented with either no or 56 mg/kg beta-carotene. Respiratory tract tumors were induced by intratracheal instillation of BP attached to ferric oxide. The beta-carotene and vitamin A contents of the liver were increased in the high beta-carotene group, but the serum beta-carotene levels were very low when compared with those commonly observed in humans. beta-Carotene supplementation did not affect the tumor response of the respiratory tract. Neither the incidence and severity of preneoplastic changes were influenced. However, there was a statistically significant inverse relationship between serum retinol content and the presence of respiratory tract tumors in survivors, regardless of the dietary treatment.

Dietary selenium- and benzo[a]pyrene-induced respiratory tract tumours in hamsters.

The modifying effect of selenium as sodium selenite on chemically induced respiratory tract tumours was tested in Syrian golden hamsters. Groups of 40 hamsters per sex (controls 60 per sex) were fed the following semisynthetic diets: control diet (0.1 p.p.m. Se, low fat); high-Se diet (5 p.p.m.); high-fat diet (20% sunflower oil); or high-Se + high-fat diet. After an adaptation period of 30 days on the diets, respiratory tract tumours were induced by intratracheal instillation of benzo[a]pyrene attached to ferric oxide. The experimental period was 429 days for males and 374 days for females. Respiratory tract tumours included mainly epidermoid papillomas, epidermoid carcinomas and combined epidermoid and adenocarcinomas. Selenium included either in a low-fat or high-fat diet did not influence the tumour response in the respiratory tract or in other organs. Neither was there a correlation between the serum or liver Se levels in the presence of respiratory tract tumours. The tumour response in the respiratory tract and also in other organs was slightly respiratory tract and also in other organs was slightly enhanced by dietary fat.

Trace metals and neoplasia.

Numerous trace metals induce cancerous growths in various animal species in vivo and cause mutagenic or chromosomal transformations in cells-cultured cells in vitro. The most potent is probably nickel. The present review indicates that arsenic, cadmium, chromium, nickel and probably beryllium are associated with malignant neoplasms in humans. Inhalation of these metals during processing at refineries has lead to a greater incidence of pulmonary carcinoma as well as other forms of cancer. There is an inverse relationship between the amount of selenium in the environment and the death rate from cancer in humans. Evidence is presented in this review indicating that mutagenic metal ions alter the fidelity of DNA synthesis. This has been demonstrated with purified DNA polymerases using both synthetic and natural DNA templates in vitro, and by mutagenic or carcinogenic effects in vivo. The need for further studies of the molecular effects of metal ions on DNA replication, RNA transcription and translation is indicated by these results.

Cancer risk among oil refinery workers. A review of epidemiologic studies.

The possibility that excess cancers result from occupational exposures in oil refineries has generated a great deal of interest. Ecological studies and case-control studies in the general population have suggested a positive association between oil industry activity and cancer rates, with more direct evidence provided by studies of refinery employees. The eight investigations of cancer risks among refinery employees are critically reviewed. The methodological strengths and weaknesses of these studies are evaluated with an emphasis on the likely impact on the results. While the results are markedly inconsistent across studies, there is some suggestion of excess risks for melanoma and for brain, stomach, kidney, and pancreatic cancers. Problems with exposure characterization, latency, and potential confounding factors limit all of the studies that were reviewed.

Modifying effect of vitamin A on benzo[a]pyrene-induced respiratory tract tumours in hamsters.

Groups of 40 hamsters of each sex were fed natural ingredient diets containing 600, 4000 or 100 000 IU vitamin A/kg. After an adaptation period of 170 days on the diets, respiratory tract tumours were induced by intratracheal instillation of benzo[a]pyrene + ferric oxide suspended in saline. Mortality was statistically significantly increased in the high dose group as compared with the mid (control) and low dose group. Microscopy of the respiratory tract did not reveal any significant differences in tumour response between the various dose groups. However, the incidence of preneoplastic respiratory tract lesions was distinctly inversely correlated with the oral vitamin A dose. The serum retinol values were similar in the various dose groups, without any indication of a dose related increase. It was concluded that under the experimental conditions used vitamin A did not influence benzo[a]pyrene-induced respiratory tract cancer in hamsters.

Modifying effect of dietary fat on benzo[a]pyrene-induced respiratory tract tumours in hamsters.

Groups of 40 Syrian golden hamsters of both sexes were fed diets containing either 5% fat (control), 20% saturated fat (beef tallow) or 20% unsaturated fat (sunflower seed oil) from weaning and during the whole experimental period (up to 656 days). Respiratory tract tumours were induced by intratracheal instillation of benzo[a]pyrene attached to ferric oxide and suspended in saline. Mortality was slightly, but not statistically significantly higher in the high fat groups than in the low fat control group. Microscopic examination of the respiratory tract revealed an increased number of tumour bearing animals, an increased multiplicity of respiratory tract tumours and an increased total number of respiratory tract tumours in animals fed high fat diets. The tumour enhancing effect of fat was most pronounced in the high unsaturated fat group. Especially epidermoid papillomas, epidermoid carcinomas and combined epidermoid and adenocarcinomas contributed to the observed differences in tumour response amongst groups. It was concluded that dietary fat enhances benzo[a]pyrene-induced respiratory tract carcinogenesis in hamsters.

Ureido-ethyl-imidazolines active against autochtonous diethylnitrosamine-induced epidermoid, papillary and adenocarcinomatous tumors of the respiratory tract of Syrian hamsters and against human bronchogenic carcinomas in nu/nu mice.

The detection of a new class of tumor inhibiting substances is described. Employing a chemical reaction discovered several years ago, a series of imidazolinylureas were prepared. It was found that some compounds of this group were active against diethylnitrosamine (DENA)-induced tumours in hamsters. CGP 15720 A (1-[2-[2-(4-pyridyl)-2-imidazoline-1-yl]-ethyl]-3-(4-carboxy-phenyl)urea. Xb), the most active compound at present, was developed through a series of structural variations. CGP 15720 A inhibits significantly in oral or parenteral treatment with well tolerated doses (10-30 mg/kg) the progressive growth of autochthonous, DENA-induced papillary, epidermoid and adenocarcinomatous tumors of the respiratory system in Syrian hamsters and prolongs significantly the survival. The substance also inhibits significantly the growth of 2 poorly differentiated human epidermoid or anaplastic bronchogenic carcinomas in nu/nu Balb/c mice and prolongs the mean survival time. In these mice, the substance is also active against the rodent ascites tumors Ehrlich carcinoma, CrSa 180 and Yoshida Sa AH 66, although it is only marginally active or inactive against these tumors in normal mice or rats.-In the therapeutic trials, hamsters tolerated the highest dose administered for 4 weeks, 1000 mg/kg p.o., without signs or symptoms of toxicity.

Detection of chemical carcinogens by assay of unscheduled DNA synthesis in rat tracheal epithelium in short-term organ culture.

A short-term organ culture of rat tracheal epithelium was used to detect the ability of 53 chemicals to induce UDS. In this system all direct-acting compounds (ultimate or proximate carcinogens) tested induced UDS. Of 24 compounds requiring metabolism (procarcinogens), nine induced UDS, viz., 4NQO, AF-2, BP, DMN, DEN, and NP. Urethane, AAF, and 2,7-AAF induced very slight UDS. 3-Methyl-4NQO for which carcinogenicity data is incomplete as positive in our system. Among the cancer chemotherapeutic agents tested only mitomycin C induced UDS. MC and DMBA, which are known to induce cancer of respiratory organs in experimented animals, and DAB, aflatoxin B1 and Trp-P-1, which are strong carcinogens in the liver, did not induce UDS within 2 h. With the longer exposure (24 h), these carcinogens also failed to elicit UDS. All the carcinogens that induce UDS showed clear dose-dependent effects. No non-carcinogens tested induced UDS. These results suggested that this system should be useful for screening environmental chemicals suspected of damaging DNA of the respiratory organ on the basis of organotropic effects for UDS induction in cultured rat tracheal epithelium.

Carcinogenicity test of six nitrosamides and a nitrosocyanamide administered orally to rats.

Six nitrosamides [ethylnitrosourea (ENU), 2-hydroxyethylnitrosourea (HENU), carboxymethylnitrosourea, 1-nitroso-5,6-dihydrouracil (NDHU), 1-nitrosohydantoin, and N-methyl-N-nitrosobenzamide (MNB)] and ethylnitrosocyanamide (ENC) were administered chronically in sodium citrate-buffered drinking water to MRC Wistar rats. ENU induced tumors of the reticuloendothelial system (RES) (50% incidence), mammary glands, and large intestine. NDHU in drinking water produced hepatocellular carcinomas (96% incidence), but NDHU injected ip caused mostly tumors at the injection sites (54% incidence). HENU produced bone tumors (38% incidence) and RES tumors (28% incidence). ENC produced nasal cavity tumors (36% incidence). Papillomas and/or carcinomas of the forestomach, tongue, and pharynx were induced by most of the compounds, with the highest incidence in the forestomach (47% for MNB); these tumors were attributed to local action when the compounds were ingested. Carcinogenicity was not quantitatively correlated with direct mutagenicity for Salmonella typhimurium TA1535.

In vivo studies in Syrian golden hamsters: a transplacental bioassay of ten nitrosamines.

The carcinogenic effects of low doses of 10 nitrosamines were determined in pregnant Syrian golden hamsters and their offspring. Compounds studied included dimethylnitrosamine, di-n-propylnitrosamine, di-n-butylnitrosamine, nitrosopiperidine, nitrosohexamethyleneimine, 2-dydroxypropyl-propyl-nitrosamine, 2-oxopropyl-propyl-nitrosamine, methylpropylnitrosamine, di(2-hydroxypropyl) nitrosamine, and 4-hydroxybutyl-butyl-nitrosamine. Tumor incidences of all organ systems were almost always higher and latencies shorter in the mothers than in the offspring. Exceptions occurred in the respiratory system in which several compounds induced a low incidence of tumors in the offspring but none in the mothers. Fetal susceptibility appeared greatest toward the end of gestation. For purposes of bioassay, transplacental exposure was less efficient than conventional adult treatment.