methylnitronitrosoguanidine and Urinary-Bladder-Neoplasms

The historical background of studies in Japan on chemical carcinogenesis from environmental sources is described from personal experience.

Topics: 4-Nitroquinoline-1-oxide; Animals; Biotransformation; Carcinogens; Cyanobacteria; Environmental Pollution; Food Additives; Food Handling; Furylfuramide; Health Policy; Humans; Indoles; Japan; Lyngbya Toxins; Methods; Methylnitronitrosoguanidine; Mutagenicity Tests; Oncogenes; Primary Prevention; Rats; Risk; Stereoisomerism; Stomach Neoplasms; Streptomyces; Structure-Activity Relationship; Urinary Bladder Neoplasms

Topics: Animals; Antioxidants; Ascorbic Acid; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Carcinogens; Colonic Neoplasms; Ethoxyquin; Glutathione Transferase; Mammary Neoplasms, Experimental; Methylnitronitrosoguanidine; Neoplasms, Experimental; Phenobarbital; Propyl Gallate; Rats; Rats, Inbred F344; Saccharin; Stomach Neoplasms; Substrate Specificity; Urinary Bladder Neoplasms

Topics: 9,10-Dimethyl-1,2-benzanthracene; Adenocarcinoma; Animals; Cricetinae; Disease Models, Animal; Dogs; Drug Interactions; Guinea Pigs; Haplorhini; Kidney Neoplasms; Liver Neoplasms; Liver Neoplasms, Experimental; Lung Neoplasms; Methylcholanthrene; Methylnitronitrosoguanidine; Mice; Neoplasms, Experimental; Rabbits; Rats; Stomach Neoplasms; Urinary Bladder Neoplasms

The present survey deals with requirements the experimental-oncological models used in morphogenetic investigations should meet. Data on ways of inducing tumours of various organs the most suited for such investigations are presented. The available at present literature comprises data on different variants of morphogenesis of tumours; in a number of cases malignant neoplasms can develop against the background of an unchanged structure without previous alterations. Because of a contradictory character of the literature reports on morphogenesis of tumours, further investigations into the morphodynamics of the process of cancerogenesis are needed; at present, this may be successfully implemented if adequate models of the majority of tumour diseases in man are available. These studies are of importance for better understanding of pathogenesis or tumour growth and for ascertaining the concept of precancer changes.

Topics: 2-Acetylaminofluorene; 9,10-Dimethyl-1,2-benzanthracene; Aflatoxins; Animals; Azoxymethane; Benzopyrenes; Brain Neoplasms; Carcinogens; Cricetinae; Dimethylhydrazines; Dogs; Esophageal Neoplasms; Ethionine; Ethylnitrosourea; Female; Hematopoietic System; Intestinal Neoplasms; Liver Neoplasms; Lung Neoplasms; Male; Mammary Neoplasms, Experimental; Methylnitronitrosoguanidine; Methylnitrosourea; Mice; Neoplasms, Experimental; Nitrosamines; Nitroso Compounds; Nitrosoguanidines; o-Aminoazotoluene; p-Dimethylaminoazobenzene; Precancerous Conditions; Rats; Skin Neoplasms; Stomach Neoplasms; Urinary Bladder Neoplasms

The relationships between environmental factors and the genetic abnormalities that drive carcinogenesis are supported by experimental and epidemiologic evidence but their molecular basis has not been fully elucidated. At the genomic level, most human cancers display either chromosomal (CIN) or microsatellite (MIN) instability. The molecular mechanisms through which normal cells acquire these forms of instability are largely unknown. The arylamine 4-aminobiphenyl (4-ABP) is a tobacco smoke constituent, an environmental contaminant, and a well-established carcinogen in humans. Among others, bladder, lung, colon, and breast cancers have been associated with 4-ABP. We have investigated the effects of 4-ABP and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) on genetically stable colorectal (HCT116) and bladder (RT112) cancer cells. Cells were treated with carcinogens to generate resistant clones that were then subjected to genetic analysis to assess whether they displayed either CIN or MIN. We found that 50% to 60% of cells treated with 4-ABP developed CIN but none developed MIN as confirmed by their ability to gain and lose chromosomes. In contrast, all MNNG-treated clones (12/12) developed MIN but none developed CIN as shown by the microsatellite assay. The mismatch repair protein expression analysis suggests that the acquired mechanism of MIN resistance in the HCT116 MNNG-treated cells is associated with the reduction or the complete loss of MLH1 expression. By providing a mechanistic link between exposure to a tobacco constituent and the development of CIN, our results contribute to a better understanding of the origins of genetic instability, one of the remaining unsolved problems in cancer research.

Topics: Adaptor Proteins, Signal Transducing; Aminobiphenyl Compounds; Carcinogens; Chromosomal Instability; Colorectal Neoplasms; DNA Mismatch Repair; Humans; Immunoblotting; In Situ Hybridization, Fluorescence; Methylnitronitrosoguanidine; Microsatellite Instability; MutL Protein Homolog 1; Nicotiana; Nuclear Proteins; Smoke; Tumor Cells, Cultured; Urinary Bladder Neoplasms

The concept of hormesis (i.e., low-dose stimulation/high-dose inhibition) has been shown to be widely generalizable with respect to chemical class, animal model, gender, and biological end point. The public health implication of this lack of linearity in the low-dose area of the dose-response curve raises the question of whether low doses of carcinogens will reduce cancer risk. Articles relating to the process of carcinogenesis (i.e., initiation, promotion, tumor development, and progression) were obtained from a recently developed chemical hormesis database and evaluated for their evidence of hormesis. Numerous examples in well-designed studies indicate that U- or J-shaped dose-response relationships exist with respect to various biomarkers of carcinogenesis in different animal models of both sexes. Examples of such J-shaped dose-response relationships in each stage of the process of carcinogenesis were selected for detailed toxicological examination. These results have important implications for both the hazard assessment of carcinogens and cancer risk assessment procedures.

Topics: Animals; Caffeic Acids; Carcinogenicity Tests; Carcinogens; Cell Division; Dioxins; DNA Ligases; Dose-Response Relationship, Drug; Environmental Pollutants; Female; Humans; Hyperplasia; Keratinocytes; Kidney; Liver; Lung Neoplasms; Male; Mercury; Methylnitronitrosoguanidine; Neoplasms, Radiation-Induced; Phenobarbital; Polychlorinated Dibenzodioxins; Rats; Rats, Sprague-Dawley; Risk Assessment; Saccharin; Stomach; Testicular Neoplasms; Urinary Bladder; Urinary Bladder Neoplasms

Dehydroepiandrosterone (DHEA) and its sulfate conjugate are the major circulating steroids in human plasma. Low levels of these adrenal steroids are associated with a number of human diseases including certain cancers. In animal studies, DHEA is chemopreventive toward both spontaneous and chemically induced cancers. A potential concern for long-term usage of DHEA in humans is the finding that DHEA is hepatocarcinogenic in rats. The human health risk has been thought to be minimal, however, as the mechanism of DHEA hepatocarcinogenesis is assumed to be due to its properties as a peroxisome proliferator, a class of compounds to which humans are relatively insensitive. Recently, we have found DHEA to be a potent promoter of aflatoxin B1-initiation as well as a complete hepatocarcinogen in the rainbow trout, a species which is also insensitive to peroxisome proliferators. In order to determine the initiator- and tissue-specificity of DHEA promotion, we examined the effects of DHEA on N-methyl-N'-nitro-nitrosoguanidine (MNNG)-initiated carcinogenesis. Trout fry were initiated by a bath exposure (30 min at 35 ppm) to MNNG and then fed DHEA at levels of 0, 55, 111, 222, 444, or 888 ppm for 7 months. DHEA increased liver tumor incidence, multiplicity, and size in a dose-dependent manner. The liver tumor incidence ranged from 0 in the MNNG-initiated controls to 99% in initiated trout fed 888 ppm DHEA. The latter represents a potential synergistic interaction in liver between MNNG and DHEA, as tumor incidence in sham-initiated trout fed this level of DHEA was 41%. The kidney tumor incidence was also enhanced two- and threefold over initiated controls by 111 and 888 ppm DHEA, respectively. In contrast, the total number of stomach and swim bladder tumors was reduced by DHEA treatment. This study demonstrates differential effects of DHEA on MNNG-initiated carcinogenesis in liver, kidney, stomach, and swim bladder.

Topics: Animals; Carcinogens; Dehydroepiandrosterone; Kidney Neoplasms; Liver Neoplasms, Experimental; Methylnitronitrosoguanidine; Neoplasms, Experimental; Oncorhynchus mykiss; Stomach Neoplasms; Urinary Bladder Neoplasms

The mutagenic potentials of the human bladder carcinogen 4-amino-biphenyl (ABP) and three of its proximate carcinogenic metabolites, N-hydroxy-4-aminobiphenyl (N-OH-ABP), N-hydroxy-4-acetylaminobiphenyl (N-OH-AABP) and N-acetoxy-4-acetylaminobiphenyl (N-OAc-AABP) were tested on a prime human target cell type for carcinogenesis, human uroepithelial cells (HUC). SV-HUC (PC), a near diploid, clonally derived, nontumorigenic SV40-immortalized human uroepithelial cell line that is transformable to tumorigenicity after exposure to ABP and its metabolites, was used for quantitative mutation assays. The end point used was the induction of mutations in the hypoxanthine-guanine phosphoribosyltransferase (HGPRT) locus, selected using 6-thioguanine resistance (TGr). A single, 24-h exposure of SV-HUC to ABP, N-OH-ABP, N-OH-AABP, or N-OAc-AABP caused a statistically significant, dose-dependent increase in mutation frequency resulting in a 2-30-fold increase in the number of TGr mutants in carcinogen-exposed groups compared to untreated controls. These chemicals were similarly mutagenic towards MC-T11, an SV-HUC-derived low grade tumor cell line that was also shown to be responsive to transformation (in a separate study) by ABP, N-OH-ABP, or N-OH-AABP as judged by the generation of higher grade tumors. In contrast, the mutagenic potencies of ABP and N-OH-ABP were lower when tested on a subclone of SV-HUC (BC) that is refractory to transformation by these chemicals. Thus, these data support a model of transformation in which ABP as well as its metabolites contribute to tumorigenic transformation and neoplastic progression of HUC by inducing mutations in susceptible target cell genes.

Topics: Aminobiphenyl Compounds; Cell Line, Transformed; Dimethyl Sulfoxide; Drug Resistance; Humans; Hypoxanthine Phosphoribosyltransferase; Methylnitronitrosoguanidine; Mutation; Simian virus 40; Thioguanine; Urinary Bladder Neoplasms

This paper describes factorial experiments designed to determine whether two carcinogens that act on different organ systems act synergistically to produce cancers in Fischer 344 rats. Four carcinogens, N-methyl-N'-nitrosoguanidine (MNNG), N-butanol-N-butylnitrosamine (NBBN), nitilotriacetic acid (NTA), and dipentylnitrosamine (DPN) were studied in pairwise combinations. Each of the six possible pairs was studied by means of a 4 X 4 factorial experiment, each agent being fed at zero and at three non-zero doses. Methods of analysis designed explicitly for this study were derived to study interaction. These methods were supplemented by standard statistical methods appropriate for single agent studies. Antagonism was demonstrated in some chemical mixtures containing NTA. Other chemical mixtures did not interact. Findings for male and female animals were generally, but not always, in agreement.

Topics: Animals; Butylhydroxybutylnitrosamine; Carcinogens; Cocarcinogenesis; Data Interpretation, Statistical; Drug Interactions; Female; Kidney Neoplasms; Liver Neoplasms, Experimental; Male; Methylnitronitrosoguanidine; Nitrilotriacetic Acid; Nitrosamines; Rats; Rats, Inbred F344; Sex Factors; Stomach Neoplasms; Urinary Bladder Neoplasms

A comparative analysis of T24 human bladder carcinoma cells and N-methyl-N'-nitro-N-nitrosoguanidine (MeNNG)-transformed derivatives (MeNNG-T24 cells) revealed the following: (i) The presence of an activated c-Ha-ras gene (in the absence of the normal allele) is insufficient to confer upon T24 cells a tumor-associated phenotype. (ii) MeNNG-transformed T24 cells not only acquire tumor-associated (in vitro) traits (growth in soft agar and rhodamine retention) but, are highly tumorigenic in nude mice. (iii) It is possible to render T24 cells tumorigenic by chemical transformation; therefore, the reason that T24 cells lack tumorigenicity is not because of possible incompatibilities between these cells and nude mice but, in fact, because T24 cells are not malignant. (iv) The loss of expression of a transformation-related Mr 67,000 phosphoprotein by MeNNG-T24 cells after explantation of these cells from nude mouse tumors to in vitro culture indicates that culture conditions can be responsible for rapid phenotypic conversion of human tumor cell lines.

Topics: Animals; Cell Transformation, Neoplastic; Humans; Methylnitronitrosoguanidine; Mice; Mice, Nude; Molecular Weight; Neoplasm Transplantation; Nucleic Acid Hybridization; Phenotype; Phosphoproteins; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); Proto-Oncogenes; RNA, Messenger; Tumor Cells, Cultured; Urinary Bladder Neoplasms

We have investigated whether the activation of endogenous ras genes is associated with the immortalization or malignant transformation of primary hamster epidermal cells by chemical carcinogens. We have also asked whether transfection of a cloned c-Ha-ras oncogene (pEJ) into a nontumorigenic cell line established from hamster epidermal cells by N-methyl-N'-nitro-N-nitrosoguanidine treatment can induce conversion to a malignant phenotype. DNA from the nontumorigenic epidermal cell line (H5-MNNG) and from two neoplastic cell lines transformed by benzo(a)pyrene was not capable of transforming NIH/3T3 cells. This result suggests that these cells do not contain an activated (mutated) ras gene. However, when H5-MNNG cells were cotransfected with pEJ and pSV2-gpt, a plasmid containing the dominant selectable marker gene Ecogpt, seven of nine clones of Ecogpt transformants formed carcinomas in nude mice and colonies in soft agar. Southern blot analysis of BamHl-digested genomic DNA from the Ecogpt-transformed clones indicated that rapid malignant transformation was associated with integration of a complete copy of the 6.6-kilobase fragment of pEJ containing the activated c-Ha-ras gene. Furthermore, DNA from the malignant clones transformed NIH/3T3 cells in a secondary transfection assay. These studies demonstrate that a mutated c-Ha-ras gene, under the transcriptional control of its normal cellular promoter, can rapidly transform a nontumorigenic epidermal cell line. This result suggests that activation of an endogenous c-ras gene can function as the final completing event in the progression of epithelial cells to the malignant phenotype. Thus, preneoplastic cell lines of both mesenchymal and epithelial origin have now been shown to be susceptible to malignant conversion by a single mutation in a c-Ha-ras proto-oncogene.

Topics: Animals; Carcinogens; Cell Line; Cell Transformation, Neoplastic; Cricetinae; Epidermis; Gene Expression Regulation; Humans; Methylnitronitrosoguanidine; Mutation; Oncogenes; Proto-Oncogene Mas; Proto-Oncogene Proteins; Transfection; Urinary Bladder Neoplasms

Dietary sodium chloride has been identified, both experimentally and epidemiologically, as a risk factor for gastric cancer. In order to elucidate the manner in which salt increases gastric tumor incidence in N-methyl-N'-nitro-N-nitrosoguanidine-treated animals, flow cytometric cell cycle analyses were performed on rats which had been treated with 1 ml of a solution of saturated NaCl by gavage and sacrificed 0, 1, 6, 12, 24, or 48 h after treatment. The gastric antra were excised, disaggregated, and stained with propidium iodide for cell cycle analysis. Results showed that there is a reduction in cell yield at early time points due to the toxicity of NaCl, followed by a net increase in the number of cells in the S phase of the cell cycle at 24 h. Treatment of rats with NaCl 24 h prior to a dose of 10 micrograms of 3H-labeled N-methyl-N'-nitro-N-nitrosoguanidine did not lead to an increase in alkylation of DNA isolated from mucosal cells. Therefore, the hypothesis that salt enhances gastric cancer risk from N-methyl-N'-nitro-N-nitrosoguanidine by disruption of the "mucosal barrier" leading to an increased effective dose to target cells is not supported by the results of these experiments. Several studies have shown that cells in S phase are the most susceptible to mutagenesis and that increasing the number of cycling cells in a target organ will increase tumor incidence (e.g., partial hepatectomy). Thus it is possible that NaCl increases gastric cancer risk through the mitogenesis which results from the damage caused to the mucosa by this agent.

Topics: Animals; Autoradiography; Cell Cycle; DNA; Flow Cytometry; Gastric Mucosa; Male; Methylation; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Risk; Sodium Chloride; Stomach Neoplasms; Urinary Bladder Neoplasms

The modifying effects of 3 antioxidants, sodium L-ascorbate (SA), ascorbic acid (AA) and sodium erythorbate (SE) on two-stage gastric carcinogenesis in F344 rats initiated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were investigated. Administration of 5% SE in the diet significantly decreased the incidence of dysplasia of the pylorus and, more marginally the incidence of papilloma of the forestomach, whereas administration of 5% and 1% SA and 5% AA in the diet was not associated with effect. These results suggest that SE exerts a weak inhibitory effect on gastric carcinogenesis.

Topics: Animals; Ascorbic Acid; Body Weight; Cocarcinogenesis; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred F344; Stomach Neoplasms; Urinary Bladder Neoplasms

The effect of vitamin A deficiency on the sensitivity of the colon to the carcinogenic effect of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), a direct-acting carcinogen, given intrarectally was studied in female Fischer rats. Animals maintained on Purina laboratory chow, semipurified vitamin A-free diet, or semipurified vitamine A-supplemented diet were given intrarectally 1.25, 0.63, or 0.31 mg MNNG 3 times weekly for 30 weeks and autopsied at the 45th week. The number of large bowel tumors per tumor-bearing rat was higher in animals receiving 1.25 mg MNNG compared to those given 0.63 or 0.31 mg. Vitamin A deficiency in rats given 1.25 mg MNNG significantly suppressed the large bowel tumor induction compared to rats fed adequate vitamin A. A high incidence of squamous cell papillomatosis of the urinary bladder was observed in rats fed vitamin A-free diet and given 1.25 mg MNNG. The present experiment suggests that the large intestine has a susceptibility that is different from that of the respiratory and urinary tracts to tumorigenic stimulation in vitamin A-deficient status.

Topics: Animals; Colonic Neoplasms; Female; Methylnitronitrosoguanidine; Neoplasms, Experimental; Nitrosoguanidines; Papilloma; Rats; Urinary Bladder Neoplasms; Vitamin A Deficiency