Toxin from Fusarium moniliforme: Effects on Plants and Animals.

A mycotoxin-producing strain of Fusarium moniliforme was isolated from southern leaf blight-damaged corn seed. A water-soluble toxin, subsequently purified from the fungus, had an oral median lethal dose of 4.0 milligrams per kilogram in 1-day-old cockerels. The toxin also produced plant growth-regulating and phytotoxic effects on plant systems. Physical and chemical data presented for the toxin suggest a structurally new toxin. The trivial name "moniliformin" has been assigned to the toxin.

Carcinogenesis studies of cresols in rats and mice.

Cresols, monomethyl derivatives of phenol, are high production chemicals with potential for human exposure. The three isomeric forms of cresol are used individually or in mixtures as disinfectants, preservatives, and solvents or as intermediates in the production of antioxidants, fragrances, herbicides, insecticides, dyes, and explosives. Carcinogenesis studies were conducted in groups of 50 male F344/N rats and 50 female B6C3F1 mice exposed to a 60:40 mixture of m- and p-cresols (m-/p-cresol) in feed. Rats and mice were fed diets containing 0, 1500, 5000, or 15,000 ppm and 0, 1000, 3000, or 10,000 ppm, respectively. Survival of each exposed group was similar to that of their respective control group. Mean body weight gains were depressed in rats exposed to 15,000 ppm and in mice exposed to 3000 ppm and higher. A decrease of 25% over that of controls for the final mean body weight in mice exposed to 10,000 ppm appeared to be associated with lack of palatability of the feed. A marginally increased incidence of renal tubule adenoma was observed in the 15,000-ppm-exposed rats. The increased incidence was not statistically significant, but did exceed the range of historical controls. No increased incidence of hyperplasia of the renal tubules was observed; however, a significantly increased incidence of hyperplasia of the transitional epithelium associated with an increased incidence of nephropathy was observed at the high exposure concentration. The only significantly increased incidence of a neoplastic lesion related to cresol exposure observed in these studies was that of squamous cell papilloma in the forestomach of 10,000-ppm-exposed mice. A definitive association with irritation at the site-of-contact could not be made because of limited evidence of injury to the gastric mucosa at the time of necropsy. However, given the minimal chemical-related neoplastic response in these studies, it was concluded that there was no clear evidence of carcinogenicity in male rats or female mice exposed to the cresol mixture.

Carcinogenesis studies of benzophenone in rats and mice.

Benzophenone, an aryl ketone, is used primarily as a photoinitiator and fragrance enhancer. Groups of 50 male and 50 female F344 rats and B6C3 F1 mice were fed diets containing 0, 312, 625, and 1250 ppm benzophenone for 105 weeks. Survival of males exposed to 1250 ppm benzophenone was significantly less than that of controls. There was a positive trend in the incidence of renal tubule adenoma in male rats; these neoplasms were accompanied by significantly increased incidences of renal tubule hyperplasia. Increased incidences of mononuclear cell leukemia were observed in male rats exposed to 312 or 625 ppm benzophenone and in female rats exposed to 625 ppm benzophenone. Liver lesions observed included significantly increased incidences of hepatocytic centrilobular hypertrophy in all exposed groups of rats. In mice, survival of all exposed groups was generally similar to that of the control groups. In male mice, there were significantly increased incidences of hepatocellular adenoma in the 625 and 1250 ppm groups. In female mice, the incidences of hepatocellular adenoma in the 625 and 1250 ppm groups were higher than expected after adjusting for the lower body weights in these groups. The incidences of kidney nephropathy in exposed groups of female mice, as well as the severity of nephropathy in exposed groups of males, were significantly increased. The incidences of metaplasia of the olfactory epithelium were significantly increased in 1250 ppm mice. Rare histiocytic sarcomas were observed in female rats and mice in the 625 and 1250 ppm groups. Under the conditions of these 2-year studies, there was some evidence of carcinogenic activity of benzophenone in male F344/N rats based on increased incidences of renal tubule adenoma. There was equivocal evidence of carcinogenic activity of benzophenone in female F344/N rats based on the marginal increased incidences of mononuclear cell leukemia and histiocytic sarcoma. There was some evidence of carcinogenic activity of benzophenone in male B6C3F(1) mice based on increased incidences of hepatocellular neoplasms, primarily adenoma. There was some evidence of carcinogenic activity of benzophenone in female B6C3F(1) mice based on increased incidences of histiocytic sarcoma; the incidences of hepatocellular adenoma in female B6C3F(1) mice may have been related to benzophenone exposure.

Mammary carcinogenesis in rats in relation to age at time of N-nitroso-N-methylurea administration.

The effects on mammary carcinogenesis when N-nitroso-N-methylurea (NMU) is administered to rats of different ages were studied. Female outbred Sprague-Dawley rats received two iv injections of NMU (5 mg/100 g body wt/injection) 1 week apart beginning at either 35, 50, 80, 140, or 200 days of age. Animals were killed 6 months after the initial NMU injection, and all mammary tumors were histologically classified. The percent incidence of mammary carcinomas for each age group was as follows: 100%, 35 days old; 94%, 80 days old; 59%, 80 days old; 30%, 140 days old; and 22%, 200 days old. Rats receiving NMU at a young age also exhibited a greater number of carcinomas per rat with latent periods that were in general shorter than those of rats treated at later ages. Since NMU does not require metabolic activation, the observed decrease in chemically induced mammary tumors in aging rats appears to be primarily due to changes occurring within the mammary gland.

N-nitroso-N-methylurea-induced mammary carcinogenesis: effect of pregnancy on preneoplastic cells.

The effect of pregnancy and lactation on mammary cancers induced with N-nitroso-N-methylurea (NMU) was determined in female outbred Sprague-Dawley rats. The animals received 5 mg NMU/100 g body weight at 50 days of age and were divided into the following groups: virgin, pregnancy (beginning 10 days after NMU administration), pregnancy and lactation (beginning 10 days after NMU), and pregnancy and lactation (beginning 82 days after NMU). The time of appearance of the first palpable cancers was shorter in rats undergoing an early pregnancy. Few cancers, however, were detected from rats after pregnancy or pregnancy and lactation was completed, and a decrease in cancer incidence from virgin rats was observed in these animals at termination of the study. Since NMU is a direct-acting carcinogen with a short half-life, no effect of pregnancy on carcinogen metabolism or binding could have occurred. Preneoplastic cells present before pregnancy appeared to have been either altered (such that their latent period was increased) or destroyed by the hormones associated with pregnancy.

Tumor induction relationships in development of transplantable cancers of the colon in mice for chemotherapy assays, with a note on carcinogen structure.

In an effort to establish an animal colon tumor model suitable for biological and chemotherapy studies, 82 colon tumors were induced and transplanted in four different inbred strains of mice. Four colon tumors survived the first transplant and are now in serial passage. All are suitable for chemotherapy trials. Two tumors are highly metastatic, and at least one of these is known to be suitable for surgery-chemotherapy adjuvant studies. The effective colon carcinogens contained a (see article) molecular similarity.

Evaluation of vitamin A analogs in modulating epithelial differentiation of 13-day chick embryo metatarsal skin explants.

Seventeen vitamin A compounds were evaluated in organ culture for activity in altering epithelial differentiation of metatarsal skin explants from 13-day-old chick embryos. The explants keratinized in 6 to 8 days and, when cultured in the presence of beta-retinoic acid (RA), inhibition of keratinization occurred and a mucous metaplasia developed. A cyclopentenyl analog of retinoic acid was approximately 10-fold more effective than RA in producing mucous metaplasia. Six other analogs exhibited about the same activity as RA: trimethylmethoxyphenyl analog of retinoic acids, alpha-retinoic acid, 13-cis-retinoic acid, methyl retinoate, ethyl retinoate, and N-ethylretinamide. The following 5 vitamin A compounds were about one-fourth as effective as RA: the trimethylmethoxyphenyl analog of ethylretinamide, the phenyl analog of retinoic acid, the trimethylmethoxyphenyl analog of ethyl retinoate, beta-retinyl acetate, and retinol. The furyl analog of retinoic acid and N,N-diethylretinamide were approximately one-tenth and one-fifteenth less effective than RA in inhibiting keratinization. The analog, alpha-retinyl acetate, was about one-hundredth as effective as RA and the pyridyl analog of retinoic acid (2.5 X 10(-5) M) did not inhibit keratinization. Since the property of altering epithelial differentiation may be a fundamental requirement for the prophylaxis and/or treatment of malignant epithelial lesions, this system can be used to determine whether the new synthetic analogs of vitamin A are active in modulating epithelial differentiation.

Induction and chemotherapeutic response of two transplantable ductal adenocarcinomas of the pancreas in C57BL/6 mice.

Following implant of cotton thread-carrying 3-methyl-cholanthrene into the pancreas tissue of 90 C57BL/6 and 60 BALB/c mice, 13 developed ductal adenocarcinomas. Two of these tumors, both of C57BL/6 origin (Panc 02 and 03), were established in serial s.c. transplant. Panc 02 was treated with 37 different anticancer drugs representing all of the chemical and functional classes of clinically useful anticancer agents including alkylating agents, antimetabolites, agents that bind to or cause scission of DNA, and others that inhibit mitosis or inhibit protein synthesis. When drug treatment was started within 3 to 4 days after tumor implant, Panc 02 showed only limited response to treatment with two nitrosoureas, [N'-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-N-(2-chloroethyl)-N- nitrosourea, monohydrochloride and N-(2-chloroethyl)-N'-(2,6-dioxo-3-piperdinyl)-N-nitrosourea)], and N-phosphonacetyl-L-aspartate. Drug response of Panc 03 was determined only with Adriamycin, 5-fluorouracil, cyclophosphamide, cis-(SP-4-2)-diamminedichloroplatinum, or N,N'-bis(2-chloroethyl)-N-nitrosourea. When drug treatment was started 3 days after tumor implant, high cure rates were obtained with Adriamycin treatment, and limited therapeutic responses were seen to treatment with cis-diamminedichloroplatinum or cyclophosphamide. A comparison of the biological characteristics and drug responsiveness of Panc 02 and Panc 03 with those of a number of other transplantable tumors of mice is reported.

Effect of retinoids on the differentiation of chick embryo metatarsal skin explants.

Twelve retinoids were evaluated in organ culture for activity in modulating epithelial differentiation of metatarsal skin explants from 13-day chick embryos. The epithelium differentiated into a squamous, keratinizing epidermis; but, in the presence of active retinoids, keratinization was inhibited, and a mucous metaplasia developed. The methyl-keto and 1-methoxyethyl cyclopentenyl analogs of retinoic acid were about tenfold more effective than retinoic acid in altering epithelial differentiation. The dichlorophenyl analog exhibited about the same activity as retinoic acid. The following analogs were one-half to one-third as effective as retinoic acid in inhibiting keratinization: the chlorotrimethylphenyl analog of retinoic acid and the 13-cis, 10-fluoro analog of trimethylmethoxyphenyl methyl retinoate. The other 7 retinoids were essentially not active at the concentration tested (1.4--2.0 x 10(-5) M). The activity of synthetic retinoids in altering epithelial differentiation may be related to their ability to affect or treat epithelial lesions provided that modification of the retinoid molecule can enhance its activity and decrease toxicity.