Investigations on the carcinogenicity of fusarin C -- a mutagenic metabolite of Fusarium moniliforme

The cancer initiating potential of fusarin C, a mutagen producedby Fusarium moniliforme strain MRC 826 was investigated on mouseskin using 12-O-tetradecanoyl-phorbol-13-acetate as promoterand in rat liver using pheno-barbital as promoter. In neitherof these models did fusarin C act as a cancer initiator. Culturematerial of strain MRC 826, which previously was found to behepatocarcinogenic in rats, exhibited cancer promoting activityin rat liver using diethylnitrosamine (DEN) as initiator andthe induction of gamma glutamyltranspeptidase (GGT)-positivefoci as end-point. The culture material of this fungus couldalso induce the formation of GGT positive foci without DEN initiation.These results seem to indicate that fusarin C is not involvedin the hepatocarcinogenic activity of F. moniliforme strainMRC 826.     

Carcinogenicity of Fusarium moniliforme culture material in rats

Two isolates of Fusarium moniliforme from corn were used in a chronic study with groups of 30 inbred male BD IX rats fed a semipurified diet that was marginally adequate nutritionally. Group 1 served as the controls and received the semipurified diet containing 5% cornmeal, group 2 received 5% of strain MRC 1069 culture material that was nontoxic to rats, and group 3 received 0.5% of strain MRC 826 culture material that was highly toxic to rats. The amount of the mutagen fusarin C detected in the culture material of strains MRC 826 and MRC 1069 was 104 and 364 mg/kg, respectively. Survival up to 2 years was good in all groups. Pathologic examination showed that many rats in group 2 had mild ductular cell hyperplasia. Almost all rats in group 3 had neoplastic nodules, gamma-glutamyltransferase-positive foci, adenofibrosis, and esophageal basal cell hyperplasia. Whereas no tumors were induced in groups 1 and 2, the 21 long-term survivors in group 3 developed 8 cholangiocarcinomas, 2 hepatocellular carcinomas, 4 carcinomas of the forestomach epithelium, and 1 esophageal papilloma. Since neoplastic lesions were confined to rats in group 3 and the diet of these rats contained much less fusarin C than that of group 2, it is highly unlikely that fusarin C was responsible for the carcinogenicity of the MRC 826 culture material. It appears that the toxicity of F. moniliforme strains may be related to their carcinogenicity, but the chemical nature of the toxic and carcinogenic metabolite(s) produced by F. moniliforme MRC 826 remains unknown.     

Carcinogenicity and mechanism of action of fumonisin B1: a mycotoxin produced by Fusarium moniliforme (= F. verticillioides)

Fumonisins are fungal metabolites and suspected human carcinogens. They inhibit ceramide synthase in vitro, enhance tumor necrosis factor alpha (TNFalpha) production, and cause apoptosis. Fumonisin B1 (FB1) was fed to rats and mice for 2 years or, in separate studies, given to rats or mice for up to 4 weeks. Kidney tubule adenomas and carcinomas were found in male rats fed > or = 50 ppm, whereas liver adenomas and carcinomas were found in female mice fed > or = 50 ppm for 2 years. In the short-term studies, increases in tissue concentration of the ceramide synthase substrate sphinganine (Sa) and the Sa to sphingosine (So) ratio were correlated with apoptosis. Further, hepatotoxicity was ameliorated in mice lacking either the TNFR1 or the TNFR2 TNFalpha receptors. Thus, FB1 was carcinogenic to rodents and thefindings support the hypothesis that disrupted sphingolipid metabolism and TNFalpha play important roles in its mode of action.     

Studies on a new mutagen produced by fusarium moniliforme isolated in Linxian County

A new mutagen, Fusarin C has been recently isolated and identified from corn meal inoculated with Fusarium moniliforme, one of the most common fungus pollutant of corn in Linxian County, a high-risk area of esophageal cancer. Fusarin C significantly induced sister chromatid exchange (SCE), micronucleus increase, chromosome aberrations, and 6-thioguanine resistant mutants in V 79 cells in the presence of microsomal preparations. Fusarin C also induced 6-thioguanine resistant mutants in V 79 cells cocultured with primary rat liver cells. The toxic action of Fusarin C on V 79 cells was much stronger in the absence of the microsomal preparations. However, Fusarin C did not show, at the highest concentration, any significant mutagenic or chromosomal damage on V 79 cells without the addition of the metabolic activation system. The possible relationship between the consumption of corn contaminated with Fusarium moniliforme and the etiology of esophageal cancer is discussed.     

A mutagenic metabolite produced by Fusarium moniliforme isolated from Linxian county, China

Fusarin C, a fungal metabolite, was recently isolated and identifiedfrom corn meal inoculated with Fusarium moniliforme which wasone of the most common fungi associated with corn in Linxiancounty, a high-incidence area of esophageal cancer. In the presenceof S-9 mix, fusarin C significantly increased the number ofrevertants in Salmonella typhimurium TA 100, and induced SCE,micronudei, chromosome aberrations and 6-TG resistant mutantsin V79 cells. The toxic action of fusarin C on V79 cells wasmuch stronger in the absence of S-9 mix. However, fusarin Cdid not show, at the largest concentrations used, any significantmutagenic or clastogenic effect on the cells without the additionof S-9 mix. The possib;le relationship between the consumptionof corn contaminated with F. moniliforme and the cause of esophagealcancer was discus     

Carcinogenicity of chloroform

Carcinogenicity of chloroform for various dosage and route of administration was assessed in CBA X C57B1/6 mice in a chronic experiment (250 or 15 mg/kg body weight in vegetable oil, intra-esophageally via a probe; or 300; 30; 3; 0.3 or 0.03 mg/l in drinking water). Chloroform did not reveal its carcinogenic properties unless a dose of 250 mg/kg was given.     

Carcinogenicity of anticancer agents

Chemotherapeutic treatment for cancer has been successful in prolonging survival but it has also been demonstrated that survivors of cancer patients who had received chemotherapy with alkylating agents have an increased risk of second malignancies, mostly acute non-lymphatic leukemia. The purpose of this paper is to show practical problems pertaining to the development and clinical use of anticancer agents in terms of prevention of second cancers.     

Carcinogenicity of cytostatic triazenes

Introduction of the anticancer drug dacarbazine is the result of an attempt to design antagonists of purine biosynthesis. The mechanism of action of dacarbazine depends mainly on enzymatic transformation into as yet unknown reactive (electrophilic) intermediates. Recent studies have led to the identification and synthesis of 5-(3-hydroxymethyl-3-methyl)imidazole-4-carboxamide (HMTIC), a carbinolamine metabolite with methylating capacity. Although dacarbazine and related cytostatic triazenes are effective in the treatment of malignant melanoma and other human malignancies, dacarbazine has been demonstrated to be a carcinogen in laboratory rodents. Chronic administration of dacarbazine to rats of each sex induced predominantly thymic lymphosarcomas and mammary adenocarcinomas that were transplantable. Intraperitoneally injected 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC), a metabolite of dacarbazine, induced a high incidence of mammary adenofibromas and a low incidence of uterine leiomyosarcomas. Animals treated with 5-diazoimidazole-4-carboxamide developed a low incidence of thymic, stomach, bladder or mammary tumours. Animals receiving 5-aminoimidazole-4-carboxamide developed a variety of tumours. No secondary malignancy has been reported in humans after treatment with dacarbazine alone. Despite their adverse effects, dacarbazine and related cytostatic triazene derivatives are useful clinically since their haematological toxicity is relatively moderate. As a rule, they are not cross-resistant with nitrogen mustard alkylating agents. It is hoped that research and development of second-generation N-(1-hydroxyalkyl)triazene compounds will lead to improvements in their clinical efficacy.     

Carcinogenicity of bucetin in (C57BL/6 X C3H)F1 mice

The carcinogenicity of bucetin [(3-hydroxy-p-butyrophenetidide) CAS: 1083-57-4], an antipyretic analgesic drug, was examined in 300 (C57BL/6 X C3H)F1 mice. Groups of 50 mice of each sex were treated with 1.5 or 0.75% bucetin in their basal diet for 76 weeks and then fed a basal diet for 8 weeks. Control groups were given a basal diet for 84 weeks. In 10 of 46 (22%) male mice given the high dose of bucetin and in 6 of 45 (13%) given the low dose, renal cell tumors were induced. Dysplastic lesions of the proximal tubules were frequently seen in the males given bucetin in a dose-related fashion. Neither tumorous nor preneoplastic lesions developed in the kidneys of bucetin-treated female mice and control animals. Papilloma of the urinary bladder in 1 male mouse and papillary or nodular hyperplasia in 9 mice of both sexes were observed in groups given the high dose of bucetin.     

Carcinogenicity Testing of the Cosmetic Dye: D&C Red No. 36

D&C Red No. 36, a drug and cosmetic dye commonly used for coloring lipsticks, was evaluated for its carcinogenicpotential in male and female Wistar rats. This dye has been shown to exhibit mutagenic activity towards Salmonellatyphimurium TA 98 in the presence of S9 mix. In the present study, 50 male and 50 female rats in each group weregiven diets containing D&C Red No. 36 at 2 different concentrations, 1,000 ppm and 2,000 ppm, for 78 weeks andsacrificed at week 98.It was found that dye treatment had no significant effect on the survival of either male or female animals as wellas the body weight gain in males. However, body weight gain of treated females was slightly lower than that of thecontrol group. Histopathological assessment demonstrated a number of benign and malignant tumors to havedeveloped in various organs of both dye treated and control groups. In male rats, benign liver tumors were found atincidences of 16.7% and 18.8% of the low (1,000 ppm) and high (2,000 ppm) dose groups, respectively, similar to the20% for the control group. Malignant tumors of the thyroid gland were observed only in the low dose and controlgroups, at 4.2% and 2%, respectively. In the high dose group, the incidences of lung, liver, urinary bladder and softtissue cancers were 4.2%, 2.1%, 2.1% and 2.1%, respectively, only one soft tissue cancer being observed in a controlgroup animal. In females, benign tumors were observed in the liver and mammary glands. The incidences of livertumors in the low and high dose groups were 12.8% and 16%, respectively, and 6% in the control group. Values formammary gland tumors were 10.6%, 10%, and 18% respectively. Malignant tumors were also observed in variousother organs, including the uterus, lung, kidney, thyroid, thymus and salivary gland, but the incidences were verylow (about 2-4%) and in dye treated male and female rats were not statistically different from those in the controlanimals.The results of the present study thus demonstrated that D&C Red No. 36 at the concentrations of 1,000 ppm and2,000 ppm in the diet is not carcinogenic either to male or female Wistar rats. While the occurrence of benign livertumors in female rats may be related to dye treatment, the lack of any apparent dose-dependence or any statisticallysignificant difference from the control group (P = 0.06) suggests that this is unlikely.     

Carcinogenicity of methylated nitrosopiperidines.

The carcinogenicity of nitrosopiperidine and five methylated derivatives was compared by feeding them to rats at equimolar concentrations in drinking water, at the rate of 20 ml per day, 5 days a week. The maximum treatment time was 50 weeks. Nitrosopiperidine, 2-methyl-, 3-methyl- and 4-methyl-nitrosopiperidine induced tumors of the nasal turbinates or upper gastrointestinal tract in almost 100% of the animals. There was a significantly longer time to death from these tumors in the group treated with 2-methylnitrosopiperidine and a number of hepatocellular carcinomas appeared in this longer lived group. Very few tumors of these sites were seen in rats treated with 2,6-dimethyl- or 2,2,6,6-tetramethyl-nitrosopiperidine. It was concluded that blockage by methyl groups of one or more carbon atoms alpha to the nitroso function in nitrosopiperidine significantly reduces carcinogenic activity of the molecule.     

Carcinogenicity of catechol in F344 rats and B6C3F1 mice

Carcinogenicity of catechol, a naturally occurring and industrialchemical which has been shown to have strong cell proliferatingpotential on rat glandular stomach epithelium, was investigatedin male and female F344 rats and B6C3F₁ mice. Groups of 30 maleand female F344 rats and B6C3F₁ mice were treated with 0.8%catechol in powdered diet continuously for 104 weeks (rats)or 96 weeks (mice). At necropsy, neoplastic lesions were observedmainly in the glandular stomach of both species. Adenomas werefound in all rats and in the majority of mice: 29 out of 30(97%) in males and 21 out of 29 (72%) females. In addition 15out of 28 (54%) and 12 out of 28 (43%) of the male and femalerats respectively, had well differentiated adenocarcinomas.No adenocarcinomas were found in mice of either sex. In theforestomach epithelium, although significant increase in papillomadevelopment was not evident, incidences of squamous cell hyperplasiawere significantly increased in rats and mice of both sexes.In other organs examined, incidence and numbers of liver hyperplasticfoci per cm² liver section were significantly lower in malerats. Although the incidence was not different, the numbersof hyperplastic foci were also significantly reduced in femalerats. Thus the present experiment clearly demonstrated thatcatechol exerts carcinogenic activity in rodent glandular stomachepithelium.