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Patients treated with glucocorticoids may have an increased risk of skin cancer. Using data from the population-based North Jutland Prescription Database and the Danish Cancer Registry, we compared observed and expected numbers of cases of skin cancer and non-Hodgkin lymphoma among 59 043 individuals who received prescriptions for glucocorticoids, a common immunosuppressive therapy, during an 8-year period from January 1, 1989, through December 31, 1996. The overall risks for squamous cell carcinomas and basal cell carcinomas of the skin were increased, particularly among persons who had 15 or more prescriptions (standardized incidence ratio [SIR] for squamous cell carcinomas = 2.45, 95% confidence interval [CI] = 1.37 to 4.04; SIR for basal cell carcinomas = 1.52, 95% CI = 1.09 to 2.07). An elevated risk was also found for non-Hodgkin lymphoma among those with 10-14 prescriptions (SIR = 2.68, 95% CI = 1.16 to 5.29). Our data suggest that use of glucocorticoids may be a shared risk factor for certain skin cancers and lymphomas.

The Nutritional Prevention of Cancer Trial was a double-blind, randomized, placebo-controlled clinical trial designed to test whether selenium as selenized yeast (200 microg daily) could prevent nonmelanoma skin cancer among 1312 patients from the Eastern United States who had previously had this disease. Results from September 15, 1983, through December 31, 1993, showed no association between treatment and the incidence of basal and squamous cell carcinomas of the skin. This report summarizes the entire blinded treatment period, which ended on January 31, 1996. The association between treatment and time to first nonmelanoma skin cancer diagnosis and between treatment and time to multiple skin tumors overall and within subgroups, defined by baseline characteristics, was evaluated. Although results through the entire blinded period continued to show that selenium supplementation was not statistically significantly associated with the risk of basal cell carcinoma (hazard ratio [HR] = 1.09, 95% confidence interval [CI] = 0.94 to 1.26), selenium supplementation was associated with statistically significantly elevated risk of squamous cell carcinoma (HR = 1.25, 95% CI = 1.03 to 1.51) and of total nonmelanoma skin cancer (HR = 1.17, 95% CI = 1.02 to 1.34). Results from the Nutritional Prevention of Cancer Trial conducted among individuals at high risk of nonmelanoma skin cancer continue to demonstrate that selenium supplementation is ineffective at preventing basal cell carcinoma and that it increases the risk of squamous cell carcinoma and total nonmelanoma skin cancer.

Background/methods: The treatment of psoriasis with high-dose exposure to oral psoralen and ultraviolet-A light (i.e., PUVA) substantially increases the risk of cutaneous squamous cell cancer, but not of basal cell cancer, within a decade of beginning treatment. To assess the persistence of cancer risk among individuals treated with PUVA, including those who discontinued therapy long ago and those without substantial exposure to other carcinogens, we prospectively studied a cohort of 1380 patients with psoriasis who were first treated during the period from January 1, 1975, through October 1, 1976, and evaluated risk factors associated with the development of cutaneous squamous cell cancers and basal cell cancers after 1985., Results: From 1975 through 1996, 237 patients developed 1422 cutaneous squamous cell cancers. From 1986 through 1996, 135 (12.5%) of 1081 patients without a prior squamous cell cancer developed 593 such tumors. From 1975 through 1997, 247 patients developed 1042 basal cell cancers; these patients included 151 individuals with a first basal cell cancer after 1985. Among those without a squamous cell or a basal cell cancer in the first decade of the prospective study, a strong dose-related increase in the risk of squamous cell cancer was observed in the subsequent decade (adjusted relative risk [> or =337 treatments versus <100 treatments] = 8.6; 95% confidence interval = 4.9-15.2). Risk of basal cell cancer was substantially increased only in those patients exposed to very high levels of PUVA (> or =337 treatments)., Conclusions: High-dose exposure to PUVA is associated with a persistent, dose-related increase in the risk of squamous cell cancer, even among patients lacking substantial exposure to other carcinogens and among patients without substantial recent exposure to PUVA. Exposure to PUVA has far less effect on the risk of basal cell cancer. The use of PUVA for psoriasis should be weighed against the increased cancer risk.

An attempt was made to identify the substances chiefly responsible for the carcinogenicity of gasoline engine exhaust condensate. A carcinogen-specific bioassay was performed by a comparison of the carcinogenic effect of various fractions with that of a total sample of automobile exhaust condensate, tested in two or three different doses. The results were examined by Probit analysis. After implantation into the lungs of OM rats, the condensate emitted from a gasoline-driven automobile and the fraction of polycyclic aromatic compounds consisting of more than 3 rings induced lung carcinomas and sarcomas. The tumor incidence demonstrated a clear-cut dose-response relationship. The fraction of polycyclic aromatic hydrocarbons (PAH) consisting of more than 3 rings accounted for about 81% of the total carcinogenicity of automobile exhaust condensate. This fraction represented only 2.8% by weight of the condensate. The content of benzo[a]pyrene (CAS: 50-32-8; 0.483 mg/g condensate) accounted for 2.4% of the total carcinogenicity of automobile exhaust condensate. Regarding the minor effect of the PAH-free fraction (approximately equal to 87% by wt), no evidence of cocarcinogenic activity was observed, since the total condensate as well as the PAH fraction consisting of more than 3 rings applied proportionally caused about the same tumor incidence.

Male and female European hamsters (45 of each sex) recieved sc injections once weekly for life of N-nitrosoheptamethyleneimine (NHMI) at one-fifth the median lethal dose (LD50) (females: 44 mg/kg body wt; males: 66 mg/kg body wt), one-tenth the LD50 (females: 22 mg/kg body wt; males: 33 mg/kg body wt), or one-twentieth the LD50 (females: 11 mg/kg body wt; males: 16.5 mg/kg body wt). Survival times for both males and females were dependent on the dose of NHMI. Pulmonary neoplasms were induced in almost all the treated animals. They were histologically diagnosed as adenocarcinomas, squamous cell carcinomas, and mixed cell carcinomas. In addition, nasal cavity tumors developed in all hamsters of all treatment groups; these were papillomas, squamous cell carcinomas, and a few adenocarcinomas. Only 1 tumor of the larynx and 1 tumor of the trachea were observed. Several papillomas and a few carcinomas were also detected in the forestomach. The results were discussed with reference to previous findings in rats and Syrian golden hamsters.

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.

The carcinogenicity of 1-nitropyrene [(1-NP) CAS: 5522-43-0] and 1,6-dinitropyrene [(1,6-DNP) CAS: 42397-64-8] was examined by their direct injection in a beeswax-tricaprylin vehicle into the lung of male F344/DuCrj rats. Of 28 rats given 0.15 mg of 1,6-DNP, 21 (75%) developed squamous cell carcinomas, 2 (7%) developed undifferentiated carcinomas, and 2 (7%) had squamous metaplasias in the lung by 72 weeks. In 32 rats that received 1.5 mg of 1-NP, neither carcinoma nor squamous metaplasia was induced. In all 19 rats (100%) given 0.5 mg of 3-methylcholanthrene [(MCA) CAS: 56-49-5], squamous cell carcinomas were induced earlier than in rats treated with 1,6-DNP. In 1 of 31 rats (3%) given the beeswax-tricaprylin vehicle only, squamous metaplasia was induced. Distant metastases of induced tumors were observed in 4 rats treated with 1,6-DNP and in 1 rat receiving MCA. Two lung tumors induced by 1,6-DNP were successively transplanted into the same strain of rats for 3 generations.

Charles River-CD Sprague-Dawley rats in 4 equal groups of 240 each were exposed to 4,000, 400, 50, and 0 ppb of hexamethylphosphoramide (HMPA) vapor for 9 to 24 months. In an additional study, 4 equal groups of 200 rats were similarly exposed to 100, 50, 10, and 0 ppb HMPA vapor. Nasal tumors were first detected after approximately 7 months exposure at 4,000 and 400 ppb, after 9 months at 100 ppb, and 12 months at 50 ppb. No HMPA-related lesions were found at 10 ppb. Tumor incidence was 83% at 4,000 ppb exposure, 82% at 400 ppb, 38% at 100 ppb, and 20% at 50 ppb after 24 months of exposure. Most tumors developed from the squamous, respiratory epithelium and nasal gland both of which showed squamous metaplasia or dysplasia in the anterior nasal cavity. Exposure concentrations correlated with tumor induction and latency but not with tumor types. Of a total of 473 nasal tumors, epidermoid carcinoma was predominant (71.9%) followed by adenoid squamous carcinoma (15%), papilloma (8.2%), transitional (respiratory epithelial) carcinoma (1.9%), adenocarcinoma (1.3%), and undifferentiated tumor (1.1%), (mixed) pleomorphic tumor (0.4%), and adenomatous polyp (0.2%). Most tumors developed in the anterior nasal cavity (59.1%), then progressed to the posterior nasal cavity (40.9%). Only 0.4% of the tumors involved the posterior nasal cavity alone. Tumors invaded the nasal bone (47.5%) and brain (1.1%), or metastasized to the lung (1.5%) and cervical lymph nodes (1.1%). Malignancy of the epidermoid carcinoma was correlated to the cellular differentiation and degree of keratinization.

Groups of 50 6-week-old male F344 rats were given a powdered diet containing 0, 0.125, 0.25, 0.5, 1, or 2% butylated hydroxyanisole [(BHA) CAS: 25013-16-5] for 104 weeks. The highest dose--2% BHA--induced significant increase in the incidence of squamous cell carcinoma of the forestomach. Papillomas of the forestomach developed in 20 and 100% of the rats given diets containing 1 and 2% BHA, respectively. The incidence of epithelial hyperplasia of the forestomach increased with the increased BHA doses, to 100% incidence at the highest dose. Thus the incidences of proliferative and neoplastic lesions of the forestomach were dose dependent.

In an attempt to dissociate the chemotherapeutic from the carcinogenic properties of the antischistosomal and antitrypanosomal nitrovinylfuran trans-5-amino-3-[2-(5-nitro-2-furyl)vinyl]1,2,4-oxadiazole [(SQ18506) CAS: 28754-68-9; (E)-5-amino-3-(2-(5-nitro-2-furyl)vinyl)-1,2,4-oxadiazole], potential inhibitors of carcinogenesis were administered to female outbred CD-1 mice before and during exposure to SQ18506. The compounds tested were ascorbic acid, etretinate, butylated hydroxyanisole (BHA), cysteamine hydrochloride, cysteine hydrochloride, dimercaprol, disulfiram, 1,4-dithiothreitol, reduced glutathione, and spermidine phosphate. The primary types of tumors observed were squamous cell carcinomas of the stomach and thymic and nonthymic lymphomas. BHA reduced the incidence of malignant tumors to control levels, whereas cysteine hydrochloride, spermidine phosphate, and disulfiram reduced the incidence of chemically induced tumors by 42, 34, and 32%, respectively. Although cysteamine hydrochloride and disulfiram had no or only a modest effect on the overall incidence of tumors, the data suggested possible tissue-specific anticarcinogenic properties for these agents. Of the 8 antioxidants tested, only 1 had marked anticarcinogenic properties against SQ18506. These data indicate that antioxidant properties alone cannot account for the anticarcinogenic activity of the compounds tested. Coadministration of the anticarcinogen BHA with SQ18506 also blocked the chemotherapeutic effects of this agent on female CD-1 mice infected with Schistosoma mansoni.

The effect of histamine on induction of tumors in the forestomach and the glandular stomach after N-nitroso-N-methylnitroguanidine (MNNG) administration was studied in male inbred W rats. Animals were given 50 micrograms MNNG solution/ml orally for 25 weeks and then 4 mg histamine dihydrochloride sc per day in depot form. Administration of histamine in depot form after MNNG significantly increased the incidence of tumors in the forestomach, but it significantly decreased the incidence of adenocarcinomas in the glandular stomach. All of the tumors induced in the forestomach were of the squamous cell type, and 50% of them were squamous cell carcinomas. Histamine alone had no apparent carcinogenicity in rats.

Lung cancers were induced in inbred W rats by cadmium chloride aerosols. For 18 months, 120 male W rats were continuously exposed to cadmium chloride aerosols with cadmium (Cd) concentrations of 12.5, 25, and 50 micrograms/m3, respectively. For the same period of time, 41 rats were kept in filtered air; these rats served as the control group. The survivors were killed 13 months after the end of the inhalation experiments. Histopathologic examination revealed a dose-dependent incidence of primary lung carcinomas of the following types: adenocarcinomas, epidermoid (squamous cell) carcinomas, combined epidermoid carcinomas and adenocarcinomas, and mucoepidermoid carcinomas. The incidence of lung carcinomas was 71.4% in the group exposed to 50 micrograms Cd/m3, 52.6% in the group exposed to 25 micrograms Cd/m3, and 15.4% in the group exposed to 12.5 micrograms Cd/m3. None of the controls developed lung carcinomas. At the end of the experiment, the remaining Cd concentrations in the lungs were relatively high, almost at the same level as those in the livers.

The inhibitory effect of vitamin A alcohol (retinol) on the DNA synthesis and neoplastic cell growth of chemically induced carcinomas (squamous cell carcinomas in Swiss male albino mice and basal cell carcinomas in inbred SD rats) by 3-methylcholanthrene [(MCA) CAS: 56-49-5] was studied. A marked inhibition of squamous cell carcinomas and basal cell carcinomas was observed following a combined administration of MCA and vitamin A (retinol) compared to the finding for animals treated with MCA alone (P less than .001). DNA radioactivity and autoradiographic studies with the use of [3H]thymidine showed a marked inhibition of DNA synthesis (twofold to threefold) in the neoplastic cell nuclei following a concomitant administration of vitamin A (retinol) and MCA (12%) as compared to the DNA synthesis following administration of MCA alone (31%) (P less than .001). Electron microscopic and cytologic observations revealed an advanced cytolysis and disorganization of neoplastic cells with reduction of polysomes, tonofilaments, and lysosome populations and mitochondrial alterations following vitamin A and MCA administration as compared to characteristic squamous neoplastic cells and basal neoplastic cells following MCA treatment alone. In addition, scanning electron microscopy revealed advanced changes of cell surfaces with reduction of microvilli and disorganization of cytoarchitecture. The present findings demonstrate that vitamin A exerts its anticarcinogenic effect by inhibiting DNA synthesis, disrupting cell surfaces, and possibly interfering with MCA metabolism in epidermal cells.

The effect of the potent synthetic protease inhibitor [N,N-dimethylcarbamoylmethyl 4-(4-guanidinobenzoyloxy)-phenylacetate] methanesulfate (FOY-305) on skin carcinogenesis in ddY mice was examined over a total observation period of 105 days. Administration of 0.1% FOY-305 in the diet suppressed the incidence of carcinomas induced by repeated local application of the carcinogen 3-methylcholanthrene (MCA) (P less than .05) in mouse skin and delayed the time of appearance of the skin tumors (P less than .001). There was no significant difference in the number of tumors per tumor-bearing mouse and the size of the tumors between mice treated with MCA and mice treated with MCA plus FOY-305.

European hamsters were treated sc with 0.025 the median lethan dose of N-dibutylnitrosamine. The induced neoplasms of the urinary bladder (transitional cell carcinomas and squamous cell carcinomas) were examined electron microscopically. Their ultrastructure indicated these tumors to be different developmental stages of the same type of tumor rather than two fundamentally different types of neoplasm.

The intratumoral migration of tritiated thymidine ([3H]dThd)-labeled cells was recorded at various intervals (from 1 to 240 hr) in squamous invasive carcinomas of the cervix in 25 inbred C57Bl mice. Carcinomas were induced by local application of benzo[a]pyrene for 5 months. This treatment was discontinued 7 days before the animals were killed. Cells were labeled by a single ip injection of 6 muCi [3H]dThd/g body weight. The tumors were divided by the aid of an ocular scale into three equal compartments: a peripheral zone, an intermediate zone, and a central zone. Many densely (initially) labeled cells were present in the peripheral and intermediate zones 1-48 hours after the injection of isotope, but these cells decreased in number in the intermediate zone and had disappeared from the peripheral zone by 96 hours. Conversely, densely labeled cells were absent in the center of the tumor during the first 24 hours, but they were recorded in large numbers at 48 hours. It was concluded that in addition to already known mechanisms of cell migration in solid tumors (e.g., invasion of the surrounding normal tissue, intravascular migration, migration toward the center of individual tumor nests, and cell exfoliation), there is intratumoral migration of cells toward the center in cervical carcinomas in mice.

The effect of age on induction of carcinogenesis by N-butyl-N-(4-hydroxybutyl)nitrosamine [(BBN) CAS: 3817-11-6] in the urinary bladder epithelium was examined in 130 male and 130 female F344 rats. Rats of both sexes 6, 52, and 98 weeks old were given 0.025% BBN in their drinking water for 20 weeks. Then approximately half the rats were sacrificed, while the rest were maintained without further treatment for 10 weeks. Examination of the rats revealed an age-related increase in the induction of urinary bladder carcinoma, although the total intakes of BBN and urinary excretions of its proximate carcinogen were not age related. Rats treated with BBN at 98 weeks of age developed more squamous cell carcinomas and invasive carcinomas than the 2 younger groups. This study demonstrated an increased risk of urinary bladder carcinogenesis with age in animals.

Male weanling inbred SD rats were given ad libitum a nutritionally adequate semipurified diet and demineralized drinking water without or with 100 or 200 ppm tungsten (W) or 2 or 20 ppm molybdenum (Mo) added to the drinking water. The animals were gastrically intubated with a solution of N-nitrososarcosine ethyl ester (NSEE) from the 4th week twice weekly for 2-8 consecutive weeks. The addition of Mo at either the 2- or 20-ppm level significantly inhibited NSEE-induced esophageal and forestomach carcinogenesis. The 200 ppm W significantly countered the inhibitory effect of a low level of Mo naturally occurring in the diet.

In two simultaneous experiments (A and B), tracheal tissue from 25 young Syrian hamsters was implanted in their mothers' spleens. In A, after tracheas from 3-week-old untreated donor offspring were implanted into their mothers, the mothers received 18 mg diethylnitrosamine (DEN)/kg body weight, sc, twice weekly for 20 weeks. Thereafter, the implants were removed and transferred to the spleens of other untreated offspring that were then similarly treated with DEN for 20 weeks. In B, the procedure was similar except that the donor offspring were pretreated with DEN for 20 weeks, beginning at the age of 8 weeks. The average treatment time for the implants in experiment A was 65 weeks; in B, 44 weeks. In A, only four implants demonstrated a papilloma or a papillary polyp. In B, such neoplasms developed after a much shorter treatment time, and in three cases, squamous cell carcinomas with invasive growth in to the splenic pulp were formed.

The carcinogenic effects of diisopropanolinitrosamine (DIPN) were tested in Sprague-Dawley rats and were then compared with results produced earlier by the same substance in Syrian hamsters. In addition to the similarities, several differences were noted; for example, DIPN caused pancreatic tumors in all the hamsters, but only 1 pancreatic tumor was observed among the 150 rats. Administration of DIPN to rats led to the development of neoplasms in the nasal and paranasal cavities, lungs, thyroid gland, esophagus, liver, and kidneys. The highest tumor incidence in rats was in the nasal cavities. Almost all the pulmonary neoplasms were malignant and were usually squamous cell carcinomas. We found a 15.4-50% incidence of malignant tumors of the thyroid gland; we also noted that thyroid neoplasms occurred at almost the same rate (36.4-50%) in the groups given 1/5, 1/10, and 1/20 the median lethal dose.

Of 158 channel catfish (Ictalurus punctatus) exposed to N-methyl-N'-nitro-N-nitrosoguanidine [(MNNG) CAS:70-25-7] in water for 28 days, 2 developed disseminated lymphosarcoma. One fish was necropsied at 12 months and another at 18 months following exposure. Both fish had a massive neoplastic infiltration of the bilateral pairs of head and trunk kidneys from which the neoplastic cells appeared to originate. The neoplastic infiltration was also observed in the following: thymus, gills, oral mucosa, liver, skin, skeletal muscle of head-neck region, and to a lesser extent spleen and bone marrow. This is probably the first report of lymphosarcoma in channel catfish. Although the occurrence of lymphosarcoma in these 2 catfish appeared to be related to exposure to MNNG, the exact role MNNG played in the tumor formation was not determined.

This study evaluated the skin tumor-promoting activity of mezerein in SENCAR mice. The effect of initiation dose of 7,12-dimethylbenz(a)anthracene (DMBA) on tumor promotion by mezerein was examined. Excellent dose-response relationships were observed for initiation with DMBA at 0.2-20 micrograms per mouse with mezerein as a complete promoter. None of the mezerein-only promotion groups had papilloma responses similar to those of the corresponding groups receiving two-stage promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA) followed by mezerein, even when a 40-micrograms initiating dose of DMBA was used. The effect delaying promotion with mezerein for 10 weeks was also examined in mice initiated with either 0.2, 2, 20, or 40 micrograms of DMBA per mouse. The 10-week delay led to a slight increase in the number of papillomas per mouse in some but not all treatment groups. Again, none of the delayed-mezerein-treatment groups had papilloma responses similar to those of the corresponding two-stage promotion (TPA-mezerein) groups at any corresponding initiating dose of DMBA. Finally, the progression of papillomas to carcinomas during promotion with mezerein was examined in groups of mice initiated with either 2 or 20 micrograms of DMBA. Higher ratios of carcinomas to papillomas were observed in mice promoted with mezerein than in mice receiving TPA promotion or two-stage promotion (TPA-mezerein). However, the presence of two to four times more papillomas in some mezerein-treated groups did not lead to greater numbers of carcinomas than in the groups with fewer papillomas. The data do not support the idea that spontaneous stage I promotion can be induced by delaying mezerein treatment for 10 weeks. Furthermore, the data suggest that the higher ratio of carcinomas to papillomas observed with mezerein promotion may be a function of the lower tumor burdens obtained after promotion with this compound rather than a specific property of the chemical.

A method for the induction of carcinomas in a circumscribed region of the hamster trachea is reported. By means of a special catheter, a solution of N-nitroso-N-methylurea was applied twice a week to about a 6-mm length of the trachea 10- to 16-mm distal from teh vocal cords. Slight alteration of this catheter allowed sampling of cytologic specimens directly from the surface of the carcinogen0exposed epithelium. This procedure permitted the simple and accurate correlation of sequential histologic and cytologic changes observed during tumor development in the hamsters. Noninvasive dysplastic and metaplastic lesions were seen in animals killed after 5 and 10 weeks of carcinogen application. These epithelial changes could be readily correlated with abnormal exfoliated cells abundantly present in cytologic specimens from these animals. Exposure to carcinogen for 15 weeks induced a 100% tumor incidence exclusively at the application site. More than 75% of the malignancies appeared within 15-20 weeks after the start of carcinogen administration. Most tumors were epidermoid carcinomas but some anaplastic large-cell carcinomas were also observed. Cytologic specimens of tumor-bearing animals had many cells conclusive of malignancy. The new experimental system lends itself to study of the effect of topically applied anticarcinogenic or cocarcinogenic agents on different carcinogen-induced epithelial lesions whose regression or progression can be followed by exfoliative cytology.

Ninety-seven tumors induced in the anal region in female CBA and BALB/c mice by 1,2-dimethylhydrazine were examined histologically. Tumors originated mainly from the following sources: epidermis (papillomas and basal cell neoplasms), pilosebaceous complexes of the anal region (keratoacanthomas, cystic squamous cell tumors, and adenomas of the perianal sebaceous glands), and clitoral (preputial) glands (adenomas and adenoacanthomas). A subcutaneous location and late ulceration were characteristics of many tumors originating from the pilosebaceous complexes and clitoral glads. From 31 to 43% of all anal tumors were of sebaceous gland (perianal or clitoral) origin. Cystic squamous cell tumors were morphologically similar to type II keratoacanthomas of rodents. Squamous cell tumors of any origin finally became squamous carcinomas.

The inhibitory effect of fumaric acid (FA) on carcinogenesis by potassium 1-methyl-7-[2-(5-nitro-2-furyl)vinyl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (trans, NFN) was examined histologically with male ICR/JCL mice. NFN was fed to mice at a dose level of 0.012% in the diet for 14 weeks. These mice were then divided into 2 groups. One group was given a basal diet, and the other group was given a diet containing 1% FA in the subsequent 39 weeks. In the group of 30 mice fed NFN alone, squamous cell carcinomas were found in the stomachs of 7 mice, multiple papillomas in the stomachs of 13 mice, and multiple and large papillary adenocarcinomas in the lungs of 27 animals. The administration of FA suppressed the NFN-induced stomach and lung carcinogenesis. In the group of 32 mice fed NFN and FA, no stomach tumors developed except 1 early-stage of squamous cell carcinoma. In the lungs, only a small focus of mild atypical hyperplasia and a few early-stage adenocarcinomas were noted in 7 and 11 animals, respectively.

Albino rats (noninbred) were divided into 4 groups: 1) 56 control rats, 2) 40 rats fed 1 ml aspirin suspension (40 mg/ml) twice a week, 3) 20 rats given N-nitroso-N-methylnitroguanidine (MNNG) solution (250 micrograms/ml) to drink ad libitum, and 4) 40 rats given both aspirin and MNNG. In 18 months, there were no gastrointestinal tumors in groups 1 and 2, 8 cases of gastric tumors in group 3, and 37 cases of gastric tumors in group 4. Adenocarcinomas of the glandular stomach were found in 21 of 40 rats in group 4 but in only 4 of the 20 rats in group 3; the difference in incidence was significant. Histologic and electron microscopic examination of the epidermoid carcinomas and adenocarcinomas in group 4 showed no difference from such tumors induced by MNNG only. Hyperplasia of the forestomach mucosa and hyperplasia of the pyloric gland region of the glandular stomach in group 4 were more severe.

The weakly acidic fraction of cigarette smoke condensate was fractionated by preparative high-pressure liquid chromatography into major subfractions I-IV. Major subfractions II and III were fractionated further into subfractions A-J. Subfractions A-J were tested for cocarcinogenicity on the skin of noninbred Ha:ICR Swiss albino mice by application with 0.003% benzo[a]pyrene. Subfractions A-C and F-J showed significant cocarcinogenic activity; subfractions A, F, and H were the most active. Catechol was a major component of subfraction A and was also detected in subfractions B-D and F. Major components of the other subfractions included hydroquinone (B), coniferyl alcohol (C and H), hydroxyphenyl alcohols (D), alkyl-2-hydroxy-2-cyclopenten-1-ones (C, D, and F), hydroxyacetophenones (F), phenolic cyano compounds (F), and fatty acids (F). The results demonstrate the importance of catechol as a cocarcinogen in the weakly acidic fraction of cigarette smoke condensate and indicate the presence of other cocarcinogens.

Long-term administration of prolactin (PRL) markedly enhanced the induction of epidermal squamous cell carcinomas by a chemical carcinogen, 3-methylcholanthrene [(MCA) CAS: 56-49-5], in Swiss male albino mice. DNA radioactivity and quantitative estimation of autoradiographs with the use of [3H]thymidine revealed a significant increase in DNA content (twofold) and in the percentage of labeled neoplastic nuclei in mice treated with PRL plus MCA (48.50%) as compared to that in mice treated with MCA alone (23.50%). Ultrastructural and cytologic studies revealed the predominance of a trabecular-hepatoid type of epidermal carcinoma with advanced nuclear irregularities, glycogen granules, mirror-image cells, and phagolysosomes in PRL-MCA-treated carcinomas as compared to characteristic squamous neoplastic cells with enlarged nuclei, tonofilaments, and keratin formation in epidermal carcinomas following treatment with MCA alone. Scanning electron microscopy revealed the predominance of rounded cells covered by numerous thick microvilli and blebs with an intense stromal reaction following PRL-MCA administration as compared to characteristic polyhedral cells covered by small microvilli following treatment with MCA alone. These findings demonstrate that PRL is an important hormone in epidermal neoplastic cell growth and differentiation.

Disulfiram, diethyldithiocarbamate, and bis-(ethylxanthogen) inhibit symmetrical 1,2-dimethylhydrazine dihydrochloride (DMH)-induced neoplasia of the large bowel in female CF1 mice. These three compounds contain a carbon disulfide (CS2) moiety in their structure. In the present study, CS2 itself was found to inhibit DMH-induced neoplasia of the large bowel in female CF1 mice. Thus a relatively simple compound is now available for investigation of the mechanism of inhibition of DMH-induced neoplasia by a group of sulfur-containing inhibitors having common structural features.

The effects were studied of NaCl on the production of gastric carcinomas by N-methyl-N-nitro-N-nitrosoguanidine (MNNG) and by 4-nitroquinoline-1-oxide (NQO) in male Wistar rats. Nine groups of rats were treated as follows: Group 1 was given 50 mg MNNG/liter and 6 g NaCl solution/liter to drink and was fed a stock diet supplemented with 10% NaCl. Group 2 received 1 ml saturated NaCl once a week and 50 mg MNNG/liter to drink. Group 3 was treated with MNNG alone. Group 4 was given a solution of 1 mg NQO once a week and fed a stock diet supplemented with 10% NaCl. Group 5 received a solution of 1 mg NQO saturated with NaCl. Group 6 was given NQO alone. Groups 7 and 8 were given NaCl alone. Group 9 was untreated. Adenocarcinomas developed in the glandular stomach in group 2 at a significantly higher incidence than in group 3. Poorly differentiated adenocarcinomas of the glandular stomach were detected in only groups 1 and 2. One poorly differentiated adenocarcinoma metastasized to the lymph nodes. A high incidence of squamous cell carcinomas of the forestomach was found in groups 4 and 5. No malignant tumors were seen in groups 6-9. NaCl given alone had no apparent carcinogenicity in rats but, when administered with MNNG or NQO, it enhanced the carcinogenic effects of MNNG and NQO in the stomach.

The utility of gamma-glutamyl transpeptidase (GGT) was explored as a histochemical marker for chemical carcinogenesis in hamster buccal pouch mucosa. One or both buccal pouches of 18 noninbred male Syrian golden hamsters were treated topically with 0.5% 7,12-dimethylbenz[a]anthracene (DMBA) in mineral oil over 16 weeks to produce numerous epithelial lesions at various stages of neoplastic development. Both buccal pouches of 4 control animals were similarly treated with mineral oil alone. At the completion of the DMBA treatment, patchy GGT histochemical activity was detected in areas of dysplasia and in 35 of 106 papillomas and well-differentiated squamous cell carcinomas. GGT activity was not detectable in untreated pouches or pouches treated with mineral oil alone. In a separate experiment, Wholemounts of buccal pouch epithelium were used to detect and quantitate minute populations of GGT-stained cells induced in the epithelium by eight topical applications of DMBA over 4 weeks. With this technique, multiple discrete GGT-stained areas were visible in wholemounts prepared at 1 and 6 weeks after the final application of DMBA. The experimental results were consistent with the hypothesis that the early GGT-stained cell populations are preneoplastic in nature.

Butylated hydroxyanisole (BHA) was added at levels of 0.5 and 2.0% to the diet of inbred F344 rats for 2 years. The higher dose of BHA induced a significant increase in the incidence of papilloma and squamous cell carcinoma in both sexes. Both the higher and lower doses increased the incidences of hyperplasia of the forestomach, considered to be associated with neoplasias. The incidences of these neoplastic changes were dose-dependent. Neoplastic changes in other organs were not increased significantly by BHA. These results show that BHA is carcinogenic in the forestomach of F344 rats.

gamma-Glutamyltransferase (GGT), an enzyme not found in normal adult epidermis, was detected in most skin papillomas larger than 13 mm in diameter and in all squamous carcinomas induced by 7,12-dimethylbenz[a]anthracene initiation and 12-O-tetradecanoylphorbol 13-acetate promotion in noninbred Sencar mice. Furthermore, these GGT-positive lesions were also characterized by a marked decrease or absence of high-molecular-weight components of epidermal keratin. Since these characteristics are common to both carcinomas and large papillomas but are practically undetectable in normal epidermis and small papillomas, GGT activity and lack of high-molecular-weight keratin components seem to be good indicators of tumor progression, i.e., from papilloma to squamous carcinoma.

The neoplastic progression induced by intratracheal instillation of benzo[a]pyrene (BP) and magnesium oxide (MgO) was compared with that induced by intratracheal instillation of BP and ferric oxide (Fe2O3). BP and MgO produced squamous cell carcinomas and papillomas in the larynx with a latent period as shor as 9 weeks. They also induced many papillomas as well as squamous cell carcinomas and adenocarcinomas in the trachea and a papilloma, squamous cell carcinomas, adenocarcinomas, adenosquamous lesions, and peripheral adenomatoid lesions in the bronchi. They rarely caused tumors in other organs; only a few forestomach papillomas, one melanoma on the dorsal skin, and one ovarian carconoma were seen BP, with Fe2O3 as the carrier, induced a comparable number of histologically similar tumors; however, tumors developed more frequently in the main bronchi. Thus MgO strongly facilitated the tumor-inducing effects of BP, causing tumors in different areas of the respiratory tract, and was as effective as Fe2O3 as a carrier agent in the experimental induction of respiratory tumors.

In the standard model for hamster buccal pouch, using a 0.5% solution of 7,12-dimethylbenz[a]anthracene [(DMBA) CAS: 57-97-6], it was shown that vitamin E (alpha-tocopherol) inhibited carcinogenesis. With a less potent carcinogen (0.1% DMBA), vitamin E was shown to prevent tumor development. Eighty (total) male and female Syrian hamsters (Mesocricetus auratus) were divided into 4 equal groups. After 28 weeks, animals in group 2 that had left buccal pouches painted with 0.1% DMBA (in heavy mineral oil) three times/week and that had been given 10 mg DL-alpha-tocopherol on alternate days (i.e., two times/wk) showed no tumors there. However, the pouches of group 1 animals that had been similarly painted with DMBA but that had received no vitamin E demonstrated grossly and microscopically the presence of epidermoid carcinomas.

The rate of cell division during a 6-hour period was determined in cervical epithelia from 64 normal mice, 26 mice with cervical atypias, and 8 mice with invasive carcinomas. Cervical atypias and carcinomas were induced by local application of benzo[a]pyrene (BP), and mitosis was arrested with colchicine. Values for the ratio of dividing basal cells to total dividing cells and for the rates of basal cell division for the 6-hour period were both significantly greater in normal epithelia than in atypias, and these values for atypias were greater than those for invasive carcinomas. The differences were not estrous cycle-dependent. There was no evidence that the mechanism of host invasion by squamous tumor cells was due to an increased number of cells in mitoses. The occurrence of areas with mitotic activity suggested the existence of focally distributed and probably alternating, synchronous cell production in normal cervical epithelium. This property was apparently not altered by topical BP application or by carcinogenesis.

Hibernating European hamsters reacted differently to sc injections of N-nitrosodiethylamine (DEN) than did European hamsters that were not hibernating. Hibernating animals tolerated higher dose levels but developed fewer neoplasms. In contrast, hibernating males had more pulmonary tumors than did the respective nonhibernators. However, the hibernating females of the low dosage group developed fewer lung tumors. The survival times were longer for the male hibernators than for the male nonhibernators. The organ specificity of DEN, as well as the morphology and histogenesis of the neoplasms, showed no differences between the hibernating and nonhibernating groups.