Carcinogenic effects of sequential administration of two nitrosamines in Fischer 344 rats

The carcinogenic effects of sequential treatment of female F344 rats with two nitrosamines were studied. The animals received either methylethylnitrosamine (NMEA), a strong liver carcinogen, N-nitrosomethylaniline (NMA), a moderately strong esophageal carcinogen, or N-nitrosopyrrolidine, (NPyr), a weaker liver carcinogen. The sequentially treated groups were given NMEA followed by NMA and vice versa, NPyr followed by NMEA and vice versa. The dose and duration for each chemical in the sequentially treated groups were identical for the individual treatments. The animals were allowed to die or were killed when moribund. The animals surviving longer than 110 weeks were sacrificed. The NMEA-NPyr and NPyr-NMEA groups had a tumor spectrum characteristic for NMEA alone (a mixture of hepatic carcinomas and sarcomas with extensive metastases to the lungs). The survival was reduced in the NMEA-NPyr group compared to the NMEA alone group. The time to death of the NMA-NMEA group was not affected by the NMA treatment, but many of the animals had esophageal neoplasms. The NMEA-NMA group survival was reduced when compared to the NMEA alone group but the tumor spectrum was dominated by NMEA. The data indicate that when the target organ is the same, the effect of two nitrosamines is additive with the stronger carcinogen dominating the tumor spectrum. When the target organs are different, the initial exposure influences the tumor spectrum, although the treatment with the second nitrosamine enhances the tumorigenicity of the initial nitrosamine.     

Carcinogenic effect of N-nitrosotriethylurea in single administration to female rats

N-Nitrosotriethylurea (NTEU) was administered once into thestomach or intravenously to outbred female rats. The rats givenNTEU by oral administration developed malignant tumours of themammary gland, uterus and liver. The rats exposed to NTEU byi.v. administration developed tumours of the mammary gland andovaries. NTEU accelerated the appearance of tumours which arenormally characteristic of the rat stock used (tumours of thepituitary, thyroid, adrenal cortex, fibroadenoma of the mammarygland, endometrial polyps).     

The effect of 4-substitution on the carcinogenicity of nitrosopiperidine

Nitrosopiperidine and three derivatives substituted in the 4-positionwere fed to female F 344 rats in drinking water at equimolarconcentration. The substituents were phenyl, cyclohexyl andtertiary-butyl. Like nitrosopiperidine, the t-butyl- and phenyl-derivativesinduced tumors of the upper gastrointestinal tract (esophagus,forestomach and tongue), but the animals given nitrosopiperidinedied earlier and after a smaller total dose. The rats given4-phenylnitrosopiperidine also had a high incidence of tumorsof the liver, both hepatocellular carcinomas and angiosarcomas.These tumors were absent from untreated animals of this strain.In contrast, no induced tumors were observed in rats treatedwith 4-cyclohexylnitrosopiperidine.     

Carcinogenic effect of N-nitrosobis (2-oxopropyl)amine in newborn rats

N-nitrosobis(2-oxopropyl)amine (BOP) was administered twiceweekly for a total of 11 doses to 2-day-old Fischer F-344 ratsof both sexes to ascertain the spectrum of tissues sensitiveto its carcinogenic effects. At 26 weeks, the following incidenceof neoplasms were encountered in male and females, respectively;hepatocellular carcinoma (53 and 46%); nephroblastoma (21 and11%); and in males gonodal stromal tumors of testis (68%). Althoughacidophilic and basophilic acinar cell foci were encounteredin pancreas, these were few in number and microscopic. Thesefindings indicate that in newborn Fischer rats, hepatocytes,epithelial and mesenchymal cells of the kidney, and mesenchymalcells of testis are more sensitive to BOP than those of exocrinepancreas.     

Carcinogenic effect of nitrosoalkylureas and nitrosoalkylcarbamates in Syrian hamsters

Three nitrosoalkylureas, two nitrosotrialkylureas, and three nitrosoalkylcarbamates were given to Syrian golden hamsters by gavage at approximately equimolar doses. Measured by the time to death with tumors as an index, nitrosoethylurea was the most potent carcinogen, followed by nitroso-2-hydroxyethylurea, which was less effective in males than in females. The least effective compounds, by this measure, were nitrosooxazolidone and nitroso-5-methyloxazolidone. The remaining compounds, nitroso-N-ethylurethan, nitroso-2-hydroxypropylurea, nitrosomethyldiethylurea, and nitrosotriethylurea appeared to be of similar potency. All of the compounds induced papillomas or carcinomas of the nonglandular stomach in high incidence, except in the groups given nitrosohydroxyethylurea or nitrosooxazolidone; exceptionally, only 35% of the latter group had tumors, compared with 70% or more in the other groups. All of the nitrosoalkylureas induced a high incidence of hemangiosarcomas of the spleen, but the nitrosoalkylcarbamates did not. The quite uniform response of the hamster to these compounds contrasts with the great variety of organs and cell types in which they induce tumors in the rat.     

Carcinogenic effect of the simultaneous administration of five heterocyclic amines to F344 rats

F344 rats were given five mutagenic and carcinogenic heterocyclic amines, i.e., 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2), 2-aminodipyrido[1,2-a:3',2'-d]imidazole (Glu-P-2), 2-amino-9H-pyrido[2,3-b]indole (AaC), and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), mixed together in the diet each at one-fifth of the concentration used in the previous single-compound carcinogenesis experiment. Liver, colon and Zymbal gland tumors in both sexes, skin tumors in males and clitoral gland tumors in females were induced at significantly higher incidences than in control groups. Among them, the incidences of liver tumors in both sexes, skin tumors in males and clitoral gland tumors in females were significantly higher than those expected from the simple assumptions that the incidence of tumors induced by each compound would be one-fifth of that in the corresponding previous experiment and that the combined effect of the five chemicals would be additive.     

Carcinogenic activity in rats of combined treatment with cyclophosphamide,methotrexate and 5-fluorouracil

A total of 240 outbred Sprague-Dawley rats were treated with 3 different doses of the cyclophosphamide-methotrexate-5-fluorouracil (CMF) regimen adopted from clinical chemotherapy studies in breast cancer patients. Eighty untreated rats served as controls. Individual and total doses of the drugs applied were lower than corresponding doses used in human adjuvant therapy protocols compared on a mg/m² basis. Lifelong observation of the animals demonstrated a strong doserelated carcinogenic response to the tested scheme. Main target organs of treatment-related neoplasms were the nervous system, the hematopoietic and lymphatic tissue, the urinary bladder, and the suprarenal gland. It is concluded that the CMF drug combination evokes carcinogenic responses in several organ systems in the rat and should be regarded as representing a carcinogenic risk to humans. Uncritical clinical use of the three-drug protocol should be avoided.     

Carcinogenicity of aflatoxicol in Fischer 344 rats

Aflatoxicol (AFL), a metabolite of aflatoxin B1 (AFB1), is formed in vitro by liver preparations from several species including humans. A positive correlation appears to exist between the sensitivity of a species to AFB1 and the species ability to metabolize AFB1 to AFL. Conversion of AFB1 to AFL is, therefore, a questionable detoxification step. The carcinogenicity of a diastereoisomeric mixture of AFL, prepared chemically from AFB1, was compared to AFB1 by tumor incidences being determined in 4 groups of 20 weanling male F344 rats fed either a negative control diet with no aflatoxin, a positive 50-ppb AFB1 control diet, a 50-ppb AFL diet, or a 200-ppb AFL diet for 1 year and then killed at the end of the 2d year. The respective hepatocellular carcinoma incidences were 0, 40, 20, and 70%, demonstrating that AFL is carcinogenic in the rat. The data show that a diastereoisomeric mixture of AFL is one-half as carcinogenic as AFB1, and the dose response appeared nearly linear in that a fourfold increase in dose produced a 3.5-fold increase in tumor incidence. The data did not establish unequivocally that AFL is a proximate carcinogen, but metabolism of AFB1 to AFL should not be considered an efficient detoxification reaction.     

Carcinogenic action of quinoxaline 1,4-dioxide in rats.

Quinoxaline 1,4-dioxide was fed to 400 rats at levels of 10 mg or 1 mg/kg body weight for 18 months. It produced a high incidence of nasal and liver tumors only in the group fed 10 mg/kg. Of diverse histologies, the nasal tumors included anaplastic carcinomas, adenocarcinomas, squamous cell carcinomas, neuroepitheliomas, basal cell carcinomas, and a single fibrosarcoma. The nasal epithelium not involved in the neoplastic process showed dysplasia and hyperplasia.     

Carcinogenesis of nitrosomethylundecylamine in Fischer rats.

Nitrosomethylundecylamine was synthesized and administered to Fischer rats by gavage in olive oil solution, at a dose of 46 mg/animal/week for 30 weeks. There were high incidences of hepatocellular carcinomas and cholangiocarcinomas in the liver and of squamous cell carcinomas and alveolar cell adenocarcinomas in the lung. In contrast with the activity of the next higher homolog, nitrosomethyldodecylamine, no bladder tumors were induced.     

Carcinogenic effect of N-bis(2-hydroxypropyl)nitrosamine by a single administration in rats.

The carcinogenic effect of a single intraperitoneal injection of N-bis)2-hydroxypropyl)nitrosamine (BHP) was studied in male Wistar rats. Lung tumors (adenomas and adenocarcinomas) had the highest incidence (100%). Fewer neoplasms were induced in the thyroid (adenomas and adenocarcinomas, 36%), kidney (renal cell carcinomas, 8%), and the sigmoid colon (adenomas and adenocarcinomas, 9%). No pancreatic neoplasms were found.     

Carcinogenic effects of N-ethyl-N-hydroxyethylnitrosamine and its metabolites in rats and mice.

N-ethyl-N-hydroxyethylnitrosamine (EHEN), a member of the nitrosamine class of carcinogens induces renal cancer. However, since very little is known about the metabolic products of EHEN and their effects, these were investigated in rats and mice. EHEN, N-ethyl-N-formylmethylnitrosamine (EFMN) and N-ethyl-N-carboxymethyl-nitrosamine (ECMN) were administered in the drinking water for 2 weeks and the animals were then maintained until sacrifice at week 32. The urine of the rats was collected over the 2-week exposure period and analyzed by HPLC. The results showed that EHEN but not EFMN or ECMN induces tumors in the kidneys of rats. In mice the lungs were targeted not only by the parent compound but also by both metabolites. The findings suggest that the kidney is the most susceptible organ to EHEN effects in the rat while the lung is the most susceptible organ in mice. These results are consistent with inter-species variation in the metabolism of xenobiotics.