Inhibitory effects of non-steroidal anti-inflammatory drugs, piroxicam and indomethacin on 4-nitroquinoline 1-oxide-induced tongue carcinogenesis in male ACI/N rats

The effects of the non-steroidal anti-inflammatory drugs (NSAIDs), piroxicam and indomethacin on 4-nitroquinoline 1-oxide-(4-NQO)-induced tongue carcinogenesis in male ACI/N rats were examined. Rats were given 4-NQO (10 ppm) in the drinking water for 12 weeks and followed by either diet containing 150 ppm piroxicam or the drinking water containing 10 ppm indomethacin for 24 weeks. The incidence of tongue neoplasms (squamous cell papilloma and carcinoma) in rats given 4-NQO plus piroxicam (4/13, 31%) and those given 4-NQO plus indomethacin (3/13, 23%) were significantly lower than that of animals given 4-NQO alone (12/17, 71%) (P less than 0.05 and P less than 0.005). Rats given piroxicam or indomethacin alone had no neoplasms in the tongue. Thus, piroxicam and indomethacin significantly inhibited the development of tongue neoplasms in male ACI/N rats.     

The synergistic effect of 1-hydroxyanthraquinone on methylazoxymethanol acetate-induced carcinogenesis in rats.

The synergistic potential of 1-hydroxyanthraquinone (1-HA) on methylazoxymethanol (MAM) acetate-induced carcinogenesis was investigated in rats. A total of 154 inbred ACI/N rats (73 males and 81 females), six weeks old at the start of the experiment, were divided into four groups: group 1 was given i.p. injections of MAM acetate (25 mg/kg body wt), once per week for 2 weeks and then fed the diet containing 1% 1-HA for 42 weeks; group 2 received MAM acetate and was kept on the basal diet alone; group 3 was given 1-HA containing diet alone as for group 1; group 4 was treated as a control. At the termination of the experiment, the carcinogenic effect of MAM acetate and 1-HA in the large bowel or liver exceeded the sum of effects when given alone, indicating that the two chemicals act synergistically in the carcinogenesis of these organs.     

Effects of butylated hydroxyanisole, butylated hydroxytoluene, and NaCl on gastric carcinogenesis initiated with N-methyl-N'-nitro-N-nitrosoguanidine in F344 rats

Promoting activities of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and NaCl and of combinations of these antioxidants with NaCl on gastric carcinogenesis initiated by N-methyl-N'-nitro-N-nitrosoguanidine [(MNNG) (CAS: 70-25-7; 1-methyl-3-nitro-1-nitrosoguanidine] were investigated in male inbred F344 rats. Animals, 6-week old, were given an intragastric administration of MNNG at 150 mg/kg body weight by gastric tube and 1 week later were placed on a diet containing BHA (0.5%), BHT (1.0%), NaCl (5.0%), BHA (0.5%) plus NaCl (5%), or BHT (1.0%) plus NaCl (5.0%) for 51 weeks. Control rats received no further treatment after MNNG administration. A single intragastric application of MNNG to rats induced multiple epithelial tumors of the forestomach and a few epithelial tumors of the glandular stomach after 52 weeks. Squamous cell carcinomas of the forestomach were seen in 2 of 18 effective rats (11.1%) in the control groups, and the incidences in the groups receiving the subsequent treatment were 45.0% with BHA, 15.8% with BHT, 30% with NaCl, 70% with BHA plus NaCl, and 52.9% with BHT plus NaCl. Differences in the incidences of squamous cell carcinoma between the controls and groups given BHA, BHA plus NaCl, and BHT plus NaCl were statistically significant. NaCl given alone after MNNG administration also significantly increased the incidence of papillomas in the forestomach. Incidences of glandular stomach tumors, adenomas and carcinomas were not affected by any of the subsequent treatments. No tumors of the stomach developed in the groups given BHA, BHT, and NaCl without MNNG pretreatment. Thus the present experiment revealed that BHA and NaCl but not BHT exert promoting activity on MNNG-induced forestomach carcinogenesis in rats and that, when BHA and BHT were given with NaCl, promotion was more marked, suggesting a synergistic effect on tumor promotion.     

Inhibition of azoxymethane-induced neoplasia of the large bowel by 3-hydroxy-3,7,11-trimethyl-1,6,10-dodecatriene (nerolidol)

The inhibitory capacities of four terpenes on azoxymethane (AOM)-induced neoplasia of the large bowel and duodenum was studied in male F344 rats. A complete course of AOM administrations was given and 3 days later the rats were fed a semipurified diet containing 5 mg/g of the test compounds, i.e. 3-hydroxy-3,7,11-trimethyl-1,6,10-dodecatriene (nerolidol), beta-citronellol, (+/-)-linalool and (1R,2S,5R)-(-)-menthol or a corresponding control diet. The experiment was terminated 22 weeks after the last dose of AOM. Under these conditions, nerolidol showed an inhibitory effect on carcinogenesis of the large bowel. The number of rats bearing large bowel neoplasms (adenomas) was reduced from 82% in the controls to 33% in rats fed nerolidol and the number of tumors/rat from 1.5 in the controls to 0.7 in the nerolidol group. A reduction in adenocarcinomas of the duodenum was found but the data are not statistically significant. The effects of nerolidol are of interest in terms of the identification of a new inhibitor of carcinogenesis of the large bowel. The chemical structure of nerolidol suggests the possibility that the compound might have an impact on protein prenylation or some other aspect of the mevalonate pathway, but this remains to be established.     

Cell kinetic analysis of the mucosal epithelium and assay of ornithine decarboxylase activity during the process of 1-hydroxyanthraquinone-induced large bowel carcinogenesis in rats.

Cell kinetics and activity of ornithine decarboxylase (ODC) were studied during the process of 1-hydroxyanthraquinone (1-HA)-induced intestinal carcinogenesis in rats. Starting at 6 weeks of age, a total of 37 male ACI/N rats were divided into two groups and treated as follows: group I (18 rats) received diet containing 1% 1-HA for 12 months; group II (19 rats) was given the basal diet alone. Sub-groups of 5-7 rats were sequentially killed at 4, 8 and 12 months for evaluation of the length, cell numbers and 5-bromo-2'-deoxyuridine (BrDU) labeling indices of large bowel crypts together with ODC activity. All kinetic and ODC data indicated increased DNA synthesis and proliferation at all time points. Morphological observation of the intestines also revealed melanosis, crypt abscesses and erosion, becoming more pronounced with length of exposure to the anthraquinone. The data thus suggest that cell proliferation in the crypts of the cecum or colon is important for 1-HA-induced intestinal carcinogenesis.     

N-Nitroso-N-methylurea initiation in multiple tissues for organ-specific tumor promotion in rats by phenobarbital

Effects of phenobarbital [(PB) CAS: 50-06-6], a systemic tumor promoter, on carcinogenesis initiated by the broad-spectrum carcinogen N-nitroso-N-methylurea [(NMU) CAS: 684-93-5] were investigated in F344/NCr rats. Single and divided doses of NMU were evaluated for this purpose in 4-week-old rats of both sexes. Rats received iv injections of either 0.2 mmol NMU/kg (body wt) once or 0.05 mmol NMU/kg (body wt) for 4 weeks (1 injection/wk), followed by or concurrently with PB (0.05% in drinking water) that was continued until the termination of the experiment. Half the rats were killed at 52 weeks and survivors at 80 weeks. At 52 weeks, PB given subsequent to NMU or concurrently with divided doses of NMU significantly enhanced the incidence of thyroid follicular tumors only in male rats. This sex difference in thyroid tumorigenesis was somewhat less pronounced in animals killed at 80 weeks. Only 1 liver cell adenoma occurred in males and none in females given NMU alone. PB given concurrently with divided doses of NMU enhanced the yield of hepatocellular foci/cm2 but had no significant effect on hepatic tumor development. Subsequent exposure to PB, however, significantly promoted hepatocarcinogenesis in rats of both sexes given NMU in divided doses; 50% of males and 40% of females given NMU (0.05 mmol/kg, administered four times) followed by PB had hepatocellular adenomas and carcinomas by 80 weeks. PB did not affect the incidence of any other kind of neoplasms seen in NMU-initiated or control rats. These lesions included squamous cell neoplasms of the skin, oropharynx, and forestomach; nonsquamous epithelial tumors of mammary gland, pituitary body, intestinal mucosa, and urinary bladder; tumors of the central and peripheral nervous system; and mesenchymal tumors of the kidney. A sequence of multiple low doses of NMU appeared to be a convenient and useful systemic, multitissue, tumor-initiation regimen for systematic investigation of organ-specific tumor promotion in rats.     

A new medium-term rat colon bioassay applying neoplastic lesions as endpoints for detection of carcinogenesis modifiers-validation with known modifiers

We have established a medium-term colorectal carcinogenesis rat model initiated with 1,2-dimethylhydrazine (DMH) followed by dextran sodium sulfate (DSS) treatment, featuring induction of neoplastic lesions within 10 weeks. In the present study, we examined its ability to detect modification of colon lesion development with 10- or 20-week experimental periods. F344 male rats were given three subcutaneous injections of DMH (40 mg/kg b.w.) in a week followed by free access to drinking water containing 1% DSS for a week. One week after this regimen, basal diet alone, basal diet containing 0.04% nimesulide or 2% lactoferrin as known inhibitors, 0.3% deoxycholic acid (DCA) as a promoter or 1.5% 1-hydroxyanthraquinone (1-HA) as a carcinogen were supplied. At week 10, the incidence and multiplicity of combined adenomas and adenocarcinomas were significantly (P < 0.05 or 0.01) decreased by nimesulide and lactoferrin, and values for adenomas were significantly (P < 0.01) increased in the 1-HA group. There was no clear change in the DCA group. At week 20, multiplicity and volume of the tumors were significantly (P < 0.01 or 0.05) decreased by nimesulide, but no effect was now evident with lactoferrin. Multiplicity and volume of tumors were significantly (P < 0.01) increased in 1-HA group and a similar tendency was apparent (P = 0.08) with DCA. It is concluded that this system offers a useful tool for detection of colorectal carcinogenesis modifiers within 10-20 weeks, pending further studies for verification employing other model chemicals.     

Strain comparison of systemic N-nitrosohexamethyleneimine carcinogenesis in BALB/c, SENCAR and CD-1 mice

SENCAR mice have been selectively bred for hypersusceptibility to 2-stage chemical skin carcinogenesis. In this study the relative susceptibilities of SENCAR, BALB/c and CD-1 mice to systemic carcinogenesis by N-nitrosohexamethyleneimine (NHEX) were examined. NHEX was administered twice weekly (1 mg/mouse) in corn oil by gavage for 30 weeks. NHEX caused primarily liver and lung tumors in all 3 strains of mice. Hemangiosarcomas (but not other liver tumors) were more common in CD-1 mice than BALB/c or SENCAR mice. Lung tumors (adenomas and adenocarcinomas) and forestomach tumors (squamous carcinomas) were more common in SENCAR mice than BALB/c or CD-1 mice. Survival was better in SENCAR mice dosed with NHEX than in the other 2 strains. These results indicate that SENCAR mice are not unusually sensitive to liver carcinogenesis by NHEX, but are relatively sensitive to tumorigenesis in 2 epithelial tissues, lung and forestomach.     

Prostaglandin E2 counteracts the inhibition by indomethacin of rat colon ornithine decarboxylase induction by deoxycholic acid

The mechanism whereby bile acids promote colon tumor development was studied. Bile acids increase intestinal ornithine decarboxylase (ODC), an effect that is suppressed by indomethacin, an inhibitor of prostaglandin (PG) synthesis. Male Sprague-Dawley rats were pretreated with 0.002% indomethacin solution in drinking water for 3 days, then given a single intrarectal instillation of 20 mg of deoxycholate and/or 1 mg of PGE2. Four hours later, the rats were killed, and the ODC activity was measured in the mucosa of the distal large bowel. ODC was significantly lower in rats given indomethacin plus deoxycholate than in those given deoxycholate alone, but it was significantly higher in rats treated with indomethacin and PGE2 plus deoxycholate. Without deoxycholate, indomethacin plus PGE2 did not elevate ODC compared with indomethacin alone or no treatment. Indomethacin reduced the colonic mucosal PG level. Thus, PGE2 mediates the deoxycholate-induced colonic mucosal ODC activity, and overcomes the inhibition of this enzyme activity by indomethacin. It is concluded that the anti-promoting effect of indomethacin in colon carcinogenesis, previously demonstrated, may result from the indomethacin inhibition of PG synthesis.     

Neoplasms in strains of splenectomized mice after a single 7,12-dimethylbenz[alpha]anthracene treatment.

The effects of splenectomy on carcinogenesis by a single 10-mg dose of 7,12-dimethylbenz[alpha]anthracene (DMBA) given in olive oil by gavage was tested on BTOs, C57BL/60s, C3H/HeOs, and BALB/cOs mice. The splenectomy, performed a week before the DMBA was given, did not affect physical status or the incidence of acute toxic death of animals. DMBA-treated animals developed neoplasms at a significantly higher rate than did untreated mice. Splenectomy did not influence the overall incidence of neoplasms. Observed tumors in DMBA-treated groups were those of skin, forestomach, colon, liver, lung, adrenal, ovary, breast, hematopoietic-lymphoreticular system, and vascular system, depending on the strain. Types of DMBA-treated neoplasms were affected by prior splenectomy, depending on the strain: Splenectomy inhibited lung adenomas in BALB/cOs females and hepatomas in C57BL/60s females; splenectomy enhanced skin neoplasms in C57BL/60s and squamous cell carcinoma of the forestomach in BTOs males. The most significant change was in the incidence of the group of lymphomas. Myelogenous leukemia was increased in DMBA-treated groups of all strains, but splenectomy inhibited the development of this type of lymphoma.     

Carcinogenicity of naturally occurring 1-hydroxyanthraquinone in rats: induction of large bowel, liver and stomach neoplasms

The carcinogenic potential of 1-hydroxyanthraquinone (HA), anaturally occurring compound, was examined. A total of 60 maleACI/IN rats, 1.5 months old at the commencement were dividedinto two groups. Group 1 (30 rats) were fed the diet containingHA at a concentration of 1% throughout the experIment (480 days).Group 2(30 rats) served as the control given a basal diet alone.Twenty-five of 29 effective animals in group 1 developed adenomasor adenocarcinomas in the cecum or upper portion of the colon,the mean number of large bowel tumors/tumor bearing rat being2.3. In addition to these intestinal tumors, liver neoplasms(neoplastic nodules and hepatocellular carcinomas) were observedin 12 rats and benign stomach tumors were obtained in five animals;no rats of group 2 demonstrating development of any of thesetumor types. The incidences of the large bowel, liver and stomachneoplasms in group 1 were all significant as compared with group2 (P < 2 x 10^–13, P < 5 x 10^–5 and P <3 x 10^–2 respectively) clearly indicating that HA is carcinogenicin rats.     

Tumorigenic action of streptozotocin on the pancreas and kidney in male Wistar rats.

Pancreatic islet cell tumors were induced in 38 of 44 male Wistar rats (86%), which survived 9 to 14 months following the various treatment schedules. A single i.v. injection of streptozotocin alone, 30, 40, 50, or 65 mg/kg of body weight produced adenomas of pancreatic islet cells in 8 of 9 (89%), 6 of 7 (86%), 2 of 4 (50%), and 1 of 2 rats (50%), respectively. The neoplasms were seen in all of the 8 rats given a single i.p. injection of picolinamide, 250 mg/kg of body weight, 15 min before a single i.v. injection of streptozotocin, 65 mg/kg of body weight. Among the 14 rats given a single i.p. injection of nicotinamide, 500 mg/kg of body weight, 15 min before a single i.v. injection of streptozotocin, 65 mg/kg of body weight, 13 rats (95%) developed pancreatic islet cell tumors. Renal tumors were seen in only 3 rats treated with streptozotocin and nicotinamide. None of rats used in this study developed hepatic tumors. This study demonstrates that steptozotocin, even in a dose of 30 mg/kg of body weight, has an exceedingly marked tumorigenic action on the rat pancreas, while it has little effect on the kidney and no effect on the liver.     

Modification of N-methyl-N-nitrosourea initiated carcinogenesis in the rat by subsequent treatment with antioxidants, phenobarbital and ethinyl estradiol

The modifying effects of butylated hydroxyanisole (BHA), sodium L-ascorbate (SA), phenobarbital (PB) and ethinyl estradiol (EE) were studied by their administration to F344 rats subsequent to initiation with N-methyl-N-nitrosourea (MNU), a wide-spectrum carcinogen inducing tumors in many organs. Rats were initially given 4 doses of MNU (50 mg/kg) intraperitoneally within a 2-week period and then placed on a diet containing BHA (1%), SA (5%), PB (0.05%) or EE (0.001%) for 23 weeks prior to killing. Since the experiment was based on a whole body concept of carcinogenesis, all major organs were examined histologically and histochemically for any preneoplastic lesions. BHA enhanced forestomach and urinary bladder carcinogenesis as did SA also for the urinary bladder, whereas PB enhanced the induction of gamma-glutamyl transpeptidase positive (gamma-GT+) foci in the liver and also the incidence of thyroid carcinoma and forestomach carcinoma. In contrast, EE inhibited the induction of thyroid tumors, malignant lymphoma or leukemia. Thus these compounds, when given after initiation of many organs by a single carcinogen, exert an influence on the site of tumor development by, as yet unknown, organotropic modifying effects.     

Forestomach carcinoma and hepatoma induced in mice and rats by N-3-methylbutyl-N-1-methylacetonylnitrosamine (MAMBNA)

MAMBNA is a new N-nitroso compound isolated from Fusarium moniliforme-inoculated corn meal. In the present studies the carcinogenicity of MAMBNA is shown by the induction of forestomach carcinomas and liver tumors in mice and rats following the gastric intubation of this compound. Among 42 mice of Kunming (KM) stock treated with MAMBNA (10-20 mg/week), 22 showed epithelial hyperplasia of the esophagus, 29 papillomas and 4 squamous carcinomas in the forestomach, and there were 6 liver adenomas and 3 hepatomas. One mouse had forestomach carcinoma and carcinoma in the liver. Most tumors developed in mice receiving the treatment for 136-317 days, with a total dose of 210-670 mg (Table 1). No tumor was found in 12 controls observed for 239-357 days. In the experiment with 29 Wistar strain rats, administration of MAMBNA (20-120 mg/week) resulted in 11 epithelial hyperplasias in the lower esophagus, 14 atypical hyperplasias and papillomas, and 11 squamous carcinomas in the forestomach. The earliest forestomach carcinoma appeared in a rat treated for 454 days, receiving 4480 mg of MAMBNA, and the other 10 carcinomas occurred in animals treated for 518-640 days. Hyperplasia of liver cells was noted in 4 rats and liver adenoma in 7 and hepatocellular carcinoma in 8. Most hepatomas developed in rats treated for 480-640 days, and 5 rats had both forestomach carcinoma and hepatoma (Table 2). In 11 untreated rats observed for 411-644 days only one forestomach papilloma was noted.     

Effects of NaCl, Tween 60 and a low dose of N-ethyl-N' -nitro-N-nitrosoguanidine on gastric carcinogenesis of rat given a single dose of N-methyl-N' -nitro-N-nitrosoguanidine

Effects of NaCI, Tween 60 and N-ethyl-N' -nitro-N-nitrosoguanidine(ENNG) on gastric carcinogenesis were investigated in male Wistarrats. Animals received a single dose of N-methyl-N' -nitro-N-nitrosoguanidlne(MNNG) at 250 mg/ kg body weight by gastric tube followed oneweek later by either 10% NaCI in their diet, twice-weekly applicationsof 1 ml of saturated NaCI solution by gastric tube, 1.0% Tween60 in their drinking water or 0.0005% ENNG in their drinkingwater. One group of rats were given MNNG 24 h after a singleapplication of 1 ml of saturated NaCI solution to investigatethe effect of NaCI on initiation. A single dose of MNNG to ratsresulted in development of multiple epithelial tumors in theforestomach and no epithelial tumors in the glandular stomachafter 52 weeks. There were no differences in tumor incidencesof the forestomach and glandular stomach between experimentalgroups which were given a subsequent treatment with NaCI orTween 60 and the control group with MNNG alone. ENNG significantlyenhanced the tumor induction in the glandular stomach, whileENNG alone did not induce any tumors in the stomach. The NaCItreatment prior to MNNG administration also increased tumordevelopment in the glandular stomach but not in the forestomach.     

Promoting effects of combined antioxidant and sodium nitrite treatment on forestomach carcinogenesis in rats after initiation with N-methyl-N'-nitro-N-nitrosoguanidine

The effects of sodium nitrite (NaNO2), in combination with one of three antioxidants, tert-butylhydroquinone (TBHQ), alpha-tocopherol (alpha-Toc) and propyl gallate (PG), on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) stomach carcinogenesis were investigated in F344 rats. Groups of 15 male rats were treated with an intragastric dose of 150 mg/kg body weight of MNNG, and starting 1 week later, were treated with 0.5% TBHQ, 1% alpha-Toc, 1% PG or basal diet with or without 0.2% NaNO2 in their drinking water until they were killed at the end of week 36. Macroscopically, in MNNG-treated animals, combined administration of alpha-Toc or PG with NaNO2 significantly increased the areas and numbers of forestomach nodules as compared with the respective antioxidant alone values. Microscopically, in MNNG-treated animals, treatment with TBHQ significantly increased the incidence and multiplicity of forestomach papillomas as compared with basal diet alone value. Combined administration of alpha-Toc with NaNO2 significantly raised the multiplicity of forestomach papillomas, with a tendency to elevation in the incidence as compared with the group given alpha-Toc alone. Incidences of forestomach moderate and/or severe hyperplasias were significantly higher in the TBHQ or PG plus NaNO2 groups than in the single compound groups. In rats without MNNG treatment, combined treatment of antioxidants with NaNO2 significantly increased the incidences of mild or moderate hyperplasia. In the glandular stomach, although the incidence of atypical hyperplasia showed a non-significant tendency for decrease with TBHQ treatment, additional administration of NaNO2 caused significant increase. These results indicate that co-administration of NaNO2 with alpha-Toc, TBHQ or PG and particularly the first, promotes forestomach carcinogenesis. Concurrent alpha-Toc, TBHQ or PG treatment with NaNO2 is likely to induce forestomach tumors in the long term.     

Spontaneous tumors and common diseases in two colonies of Syrian hamsters. II. Respiratory tract and digestive system.

Spontaneous respiratory tract neoplasms in Syrian hamsters occurred in almost equal frequencies in two colonies: 3% in the Eppley Colony (EC) and 3.6% in the Hannover Colony (HC). Neoplasms were in the nasal cavity, trachea, and lungs, and most were benign; however, 2 adenocarcinomas of the nasal cavity (EC) and 1 adenocarcinoma of the larynx (HC) were found. The incidence of digestive tract tumors showed a more marked difference than that of the respiratory tract: 7% in the EC and 23% in the HC. Digestive tract tumors accounted for 15 and 41% of all tumors in the EC and HC, respectively. All EC digestive tract neoplasms were benign and occurred mostly in males; 19 (83%) were forestomach papillomas and the remaining 4 )17%) were liver hemangioendotheliomas (2) and pancreatic duct adenomas (2). In the HC, almost 50% of the digestive tract neoplasms were malignant and most frequent in females. These tumours include 19(42%) intestinal adenocarcinomas, 18(40%) liver neoplasms (hemangioendotheliomas, cholangiomas, cholangiocarcinomas), 5 (13%) forestomach papillomas, and 2 (4%) gallbladder polyps. The morphology of these neoplasms was reported.     

Induction of hepatocellular carcinoma and highly metastatic squamous cell carcinomas in the forestomach of mice by feeding 2-amino-3, 4-dimethylimidazo[4, 5-f]quinoline

2-Amino-3, 4-dimethylimidazo[4, 5-f]quinoline (MelQ), a potentmutagen which was Isolated from grilled sardines, was testedfor carcinogenicity in CDF1 mice. Mice were given diet containing0.04 or 0.01% MelQ for 91 weeks. The incidences of liver tumors(hepatocellular carcinomas and hepatocellular adenomas) in femalemice given 0.04 and 0.01% MelQ were significantly higher thanthose in controls. The incidences of forestomach tumors (squamouscell carcinomas and papil-lomas) were also significantly higherin both sexes of mice given MelQ. About 40% of the squamouscell carcinomas that developed in mice given diet containing0.04% MelQ meta-stasized to the liver.     

Influence of caffeic acid and other o-dihydroxybenzene derivatives on N-methyl-N'-nitro-N-nitrosoguanidine-initiated rat forestomach carcinogenesis.

Promotion effects of the o-dihydroxybenzene derivatives, protocatechuic acid (PCA), dopamine hydrochloride (DAH), dl-dopa and caffeic acid on forestomach and glandular stomach carcinogenesis were investigated in rats pretreated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Groups of 20 male F344 rats were given a single intragastric administration of 150 mg/kg body wt MNNG and starting 1 week later than received diet containing 1.5% PCA, 1.5% DAH, 1.5% dl-dopa or 1% caffeic acid or basal diet alone for 51 weeks and then killed. Other groups of 10-15 rats were given PCA, DAH, dl-dopa or basal diet alone without the MNNG pretreatment. On histological assessment, the incidences of forestomach papillomas and squamous cell carcinomas were significantly enhanced in the group treated with caffeic acid (95 and 100%) as compared with the control values (35 and 10%). Although the incidence was not different, the number of papillomas per rat in the group given DAH (0.79 +/- 0.79) was also significantly increased (0.35 +/- 0.49). PCA and dl-dopa treatments did not modify the development of neoplastic lesions in the forestomach epithelium to any significant extent. None of the four chemicals enhanced glandular stomach carcinogenesis. The results thus demonstrated that whereas caffeic acid and DAH respectively, exert strong and weak promotion activity for rat forestomach carcinogenesis this promotion potential is not shared by all dihydroxybenzene derivatives. An influence of substituents in the para position in addition to the o-dihydroxy moiety is indicated.     

Co-carcinogenic Effect of Retinyl Acetate on Forestomach Carcinogenesis of Male F344 Rats Induced with Butylated Hydroxyanisole

The potential modifying effect of retinyl acetate (RA) on butylated hydroxyanisole (BHA)-induced rat forestomach tumorigenesis was examined. Male F344 rats, 5 weeks of age, were maintained on diet containing 1% or 2% BHA by weight and simultaneously on drinking water supplemented with RA at various concentrations (w/v) for 52 weeks. In groups given 2% BHA, although marked hyperplastic changes of the forestomach epithelium were observed in all animals, co-administration of 0.25% RA significantly (P<0.05) increased the incidence of forestomach tumors (squamous cell papilloma and carcinoma) to 60% (9/15, 2 rats with carcinoma) from 15% (3/20, one rat with carcinoma) in the group given RA-free water. In rats given 1% BHA, RA co-administered at a dose of 0.05, 0.1, 0.2 or 0.25% showed a dose-dependent enhancing effect on the development of the BHA-induced epithelial hyperplasia. Tumors, all papillomas, were induced in 3 rats (17%) with 0.25% RA and in one rat (10%) with 0.05% RA co-administration. RA alone did not induce hyperplastic changes in the forestomach. These findings indicate that RA acted as a co-carcinogen in the BHA forestomach carcinogenesis of the rat.