Emergence and prevention measures for multidrug resistant Pseudomonas aeruginosa in catheter-associated urinary tract infection in spinal cord injury patients.

OBJECTIVE: To evaluate measures for preventing multidrug resistant Pseudomonas aeruginosa (MDRP) in catheter-associated urinary tract infection (CAUTI) in spinal cord injury patients. SETTING: Spinal Cord Injury Unit of Hyogo Prefectural Hyogo Prefectural Rehabilitation Center, Kobe, Japan. METHODS: We defined MDRP as resistance to amikacin, imipenem and levofloxacin. We had eight cases of MDRP-causing CAUTI in hospitalized neurogenic bladder patients caused by spinal cord injury in 2 months. Pulse-field gel electrophoresis (PFGE) was performed for epidemiological studies. We assessed prevention measures against MDRP emergence from the 2nd month, such as surveillance of CAUTI and infection control, and evaluated the outcomes of these measures over a total of 8 months. RESULTS: Our PFGE results showed that these eight MDRP isolates could be considered as closely related strains. We concluded that this was an MDRP outbreak that was causing CAUTI. The isolated ratio of MDRP began to decrease over 4 months of surveillance and significantly decreased in the 4th quarter (7th and 8th months) compared with the 1st quarter (1st and 2nd months) (P=0.021) even though urinary tract device usage significantly increased over the same period (P<0.001). CONCLUSION: We experienced an outbreak of emergent MDRP causing CAUTI in neurogenic bladder patients with spinal cord injury. Our preventive measures for isolating the outbreak, including surveillance, may have led to the decrease we observed in the ratio of MDRP isolated.

Effects of prolonged water washing of tissue samples fixed in formalin on histological staining.

The effects of prolonged water washing after fixation for 48 h in 10% (v/v) phosphate-buffered neutral formalin on the quality of representative histological staining methods were evaluated using samples of liver, kidney, spleen and thymus collected from three male Crl:CD(SD)(IGS) rats and one male beagle dog. Because door-to-door courier services in Japan prohibit handling formalin, our goal was to confirm that formalin fixed wet tissue samples could be stored in tap water rather than formalin during transportation of the samples without decreasing the quality of their staining or immunohistochemistry. Each tissue sample was allocated randomly to one of three groups: 12 min, 3 days and 7 days of washing in running tap water; samples then were routinely embedded in paraffin and sectioned. The sections were stained with hematoxylin and eosin, periodic acid-Schiff, azan, and the TdT-mediated dUTP-biotin nick end labeling (TUNEL) method. Immunohistochemical staining for Factor VIII, ED-1 and CD3 also was assessed. Prolonged water washing for up to 7 days did not affect the morphology or stainability by standard histological methods, or the intensity and frequency of positive reactions using the TUNEL method. Only immunohistochemical staining of Factor VIII was altered in both the rat and dog sections after 7 days of water washing. The intensity of positive reactions of Factor VIII immunohistochemistry after 7 days water washing was still strong enough to detect microscopically. Therefore, prolonged water washing for up to 7 days after formalin fixation does not have seriously detrimental effects on the quality and characteristics of paraffin sections stained by various methods, including immunohistochemistry.

[Application of the lower partial sternotomy approach to patients who may need tracheostomy in the early period after cardiac surgery].

Recent good results of cardiovascular surgery have led to expansion of its indication to elderly patients and patients with serious complications. Such patients may have serious respiratory complications after cardiac surgery and need to undergo tracheostomy relatively early in the postoperative period. Although the full sternotomy approach is the standard in almost all cardiac surgeries, superficial and deep sternal infections are rather common after early tracheostomy in full sternotomy patients. The lower partial sternotomy approach is a safer and more useful procedure in patients who will need tracheostomy in the early period after cardiac surgery. We report on 2 patients who were successfully tracheostomized within a week after cardiac surgery, with a review of the literature.

Inhibitory effects of subcutaneous dexamethasone treatment on rat pulmonary toxicity of KW-2149, a new mitomycin C analogue.

An experimental model for pulmonary toxicity of KW-2149, a new mitomycin C analogue, was established and the inhibitory effects of dexamethasone (DM) were investigated. KW-2149 was given to male rats 3 or 5 times at weekly intervals by intravenous injection of 3.28 or 8.2 mg/kg. As a suitable model for pulmonary toxicity, the dose of 3.28 mg/kg per week for 3 weeks was selected, this causing exudative pleural effusion in all animals but no deaths. For preventing this toxicity, DM was injected subcutaneously 3 times every week at 0.5, 1.0, 2.5 or 5.0 mg/kg. The 0.5 mg/kg dose was sufficient to completely prevent development of pleural effusions. Combined DM treatment may be an effective chemotherapy for KW-2149 induced pulmonary toxicity.

Significant overexpression of metallothionein and cyclin D1 and apoptosis in the early process of rat urinary bladder carcinogenesis induced by treatment with N-butyl-N-(4-hydroxybutyl)nitrosamine or sodium L-ascorbate.

Effects of a genotoxic bladder carcinogen, N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) and a non-genotoxic bladder promoter, sodium L-ascorbate (Na-AsA), on protein expression, cell proliferation and apoptosis of the bladder epithelium with or without the influence of testicular castration were investigated. Male F344 rats were divided into six groups (groups 1-6). BBN was given with 0.05% drinking water to groups 1 and 4 for 8 weeks, groups 2 and 5 received diet with 5% Na-AsA. Then the animals were treated without any chemicals. Groups 3 and 6 were non-treated controls. Testicular castration was carried out 2 weeks before commencement of chemical treatment on groups 4-6. The total observation period was 18 weeks. Overexpression of cyclin D1 was induced by BBN but not Na-AsA and the degree of overexpression was higher in the order simple hyperplasia, papillary or nodular hyperplasia, papilloma and carcinoma. Metallothionein (MT) was also overexpressed in bladder epithelium treated with BBN but not Na-AsA, but was decreased in papillomas and never found in a carcinoma. Cyclin D1-positive cells were essentially MT-negative. Therefore, it is speculated that MT protects genes from insult by genotoxic carcinogens and its lack is associated with tumor development. Apoptotic cell death occurred during treatment with BBN and Na-AsA and after their withdrawal. Chromatin condensation of many G0/G(1) cells was particularly marked on flow cytometry analysis 1 week after cessation of treatment, this being considered as an early apoptotic change. Although testicular castration had no influence on the above events, it resulted in decreased tumor formation as compared with the case of similarly treated intact animals. Our data demonstrate that overexpression of MT and cyclin D1 is specific for treatment with a genotoxic carcinogen, and suggest that MT overexpression may play an important suppressive role in the early stages of rat urinary bladder carcinogenesis.

Inhibitory effects of repeated intravenous injections of dexamethasone on pulmonary toxicity of a new mitomycin C analogue, KW-2149, in a novel rat model.

An animal model for testing pulmonary toxicity of KW-2149, a new mitomycin C analogue, was developed (by intravenously injecting 3.28 mg/kg of the drug into male SD rats 3 times at weekly intervals), and exhibits pleural effusion from 1 week after the last injection. In this animal model, repeated intravenous injections of dexamethasone (DM), following any of three different schedules examined, were more or less effective of reducing the amount of effusion. The optimal results were obtained with 4 administrations a week (i.e. twice before and twice after KW-2149 treatment). The results of the present experiment suggest possible clinical application of DM in protecting patients from pulmonary toxicity of KW-2149.

Effects of n-tritriacontane-16,18-dione, curcumin, chlorphyllin, dihydroguaiaretic acid, tannic acid and phytic acid on the initiation stage in a rat multi-organ carcinogenesis model.

The modifying effects of the naturally occurring antioxidants n-tritriacontane-16,18-dione (TTAD), curcumin, dihydroguaiaretic acid (DHGA), chlorophyllin, tannic acid and phytic acid on the initiation stage in a rat multi-organ carcinogenesis model were examined in male F344 rats. Animals were initiated with two i.p. injections of 2,2'-dihydroxy-di-n-propylnitrosamine (DHPN), followed by two i.g. administrations of N-ethyl-N-hydroxyethylnitrosamine (EHEN), and then three s.c. injections of 3,2'-methyl-4-aminobiphenyl (DMAB) during the first 3 weeks. Starting 1 day before the first carcinogen application, groups of rats received diet containing one of the antioxidants (0.2% TTAD, the others at 1% each) until 1 week after the last carcinogen exposure. Surviving animals were killed and complete autopsies were performed at the end of week 36. Histological examination revealed no inhibitory effects in terms of the multiplicities and/or incidences of neoplastic lesions in any of the organs examined, other than a significant increase in seminal vesicle atypical hyperplasia observed in rats treated with tannic acid. Thus, the antioxidants, with the exception of tannic acid, did not show any modifying effects on the initiation stage in the present multi-organ carcinogenesis model and at the present dose levels applied.

Evaluation of cardiac function by echocardiography in dogs treated with doxorubicin.

Cardiac functions were evaluated by echocardiography in dogs treated with doxorubicin. The dogs were administered 1.5 mg/kg body-weight doxorubicin intravenously at intervals of 3 weeks. Two-dimensional echocardiography of several sections of the heart was taken and fractional shortenings of chordal and papillary muscle levels were measured from M-mode echocardiogram to assess the left ventricular contractile function. And color Doppler and pulse Doppler examinations of mitral flow velocity were performed. Concomitantly, electrocardiogram (ECG) was also examined. The animals with decreased cardiac function were euthanized and the hearts were examined histologically. Fractional shortening was reduced gradually in the dogs treated with doxorubicin. And mitral regurgitation during systolic phase and changes of mitral flow velocity during diastolic phase were also revealed in the dogs with severe reduction of fractional shortening. These changes might indicate the reduction of cardiac functions, both of contractility and diastolic filling functions. ECG abnormalities, which were small changes, revealed only in the dogs that had severe reduction of fractional shortening and mitral regurgitation. In histological examination, myocardial degeneration was observed. And, the degree of myocardial damage might be relative to alteration of fractional shortening. Thus, the result demonstrates that the early alteration of cardiac function induced with doxorubicin can be detected by echocardiography in dogs. The result also indicates that cardiac function predicted by fractional shortening measured from M-mode echocardiogram might be correlated with histological changes of myocardium.

Modification of N-butyl-N-(4-hydroxybutyl)nitrosamine-initiated urinary bladder carcinogenesis in rats by phytic acid and its salts.

The effects of dietary phytic acid and its salts on the promotion stage of two-stage urinary bladder carcinogenesis were examined. Male F344 rats were initiated by exposure to 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine in the drinking water for 4 wk, and then treated with basal diet containing a 2% supplement of phytic acid (PA), phytic acid dodecasodium salt (Na-PA), phytic acid dodecapotassium salt (K-PA), phytic acid hexamagnesium salt n-hydrate (Mg-PA) or no added chemical for 32 wk. Na-PA significantly increased the development of preneoplastic and neoplastic lesions of the urinary bladder. K-PA also brought about a tendency for increase in papillomas, whereas Mg-PA and PA were without effect. Both Na-PA and K-PA caused elevation of urinary pH, and Na+ or K+ concentration, respectively. These results confirm the promoting activity of the sodium salt of phytic acid for urinary bladder carcinogenesis and indicate modulation by urinary components, as demonstrated by increases in urinary pH, and Na+ concentration.

[Studies on aspoxicillin for its transfer to the skin].

To evaluate the usefulness of aspoxicillin (ASPC) in the field of plastic and reconstructive surgery, we examined its transfer to the skin. 1. After intravenous drip infusion of ASPC for 1 hour at a dose of 2 g in 13 adults and at 1 g in 2 children, the mean serum ASPC concentration 1 hour after termination of the infusion was 70.46 +/- 28.05 micrograms/ml. The mean concentration in the skin tissue 1 hour after infusion in 15 patients was 32.45 +/- 18.47 micrograms/g. The rate of transfer to the skin 1 hour after infusion in the 15 patients was 52.9 +/- 29.7%. 2. The ASPC concentrations in skin tissues and the rates of its transfer to the skin did not differ significantly between 5 patients with facial surgery and 10 with surgery in the trunk or limbs. 3. To prevent postoperative infections, ASPC was intravenously drip infused twice daily for 2 approximately 3 days after operation at a dose of 2 g in adults and 1 g in children. No postoperative infection occurred in any patient, suggesting the effectiveness of this drug. In addition, no side effects or abnormalities in clinical examination values were observed.

Induction and promotion of forestomach tumors by sodium nitrite in combination with ascorbic acid or sodium ascorbate in rats with or without N-methyl-N'-nitro-N-nitrosoguanidine pre-treatment.

In experiment I, short-term effects of combined treatment with anti-oxidants, sodium ascorbate (NaAsA) and sodium nitrite (NaNO2) on forestomach cell proliferation were examined in F344 male rats. Groups of 5 animals aged 6 weeks were treated for 4 weeks with 0.8% catechol, 0.8% hydroquinone, 1% tert-butyl-hydroquinone (TBHQ), 2% gallic acid or 2% pyrogallor alone or in combination with 0.3% NaNO2 in the drinking water and/or 1% NaAsA in the diet. The thicknesses of forestomach mucosa in rats treated with anti-oxidants and NaNO2 in combination were greater than those with antioxidant alone and additional NaAsA treatment further enhanced the thickening of mucosa. It was noteworthy that values for mucosae of animals treated with NaNO2 and NaAsA without anti-oxidant were similar to those for anti-oxidants. In experiment 2, effects of combined treatment with NaAsA or ascorbic acid (AsA) and NaNO2 on carcinogenesis were examined in F344 male rats with or without N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) pre-treatment. Groups of 20 or 15 rats, respectively, aged 6 weeks, were given a single intra-gastric administration of 150 mg/kg body weight of MNNG in DMSO:water = 1:1 or the vehicle alone by stomach tube. Starting 1 week later, they received supplements of 1% NaAsA or 1% AsA in the diet and 0.3% NaNO2 in drinking water in combination, each of the individual chemicals alone, or basal diet until the end of week 52. In MNNG-treated animals, incidences of forestomach papillomas and carcinomas were significantly enhanced in the NaNO2 alone group (84 and 47%, respectively) as compared with the basal diet group (30 and 10%), with further significant increase in carcinomas occurring with additional NaAsA (79%, p < 0.05) or AsA (85%, p < 0.05) treatment. In animals without MNNG, all animals in the NaNO2 group demonstrated mild hyperplasia, additional administration of NaAsA or AsA remarkably enhancing the grade of hyperplasia, and resulting in 53% and 20% incidences, respectively, of papillomas. Thus NaNO2 was demonstrated to exert promoter action for forestomach carcinogenesis, with NaAsA and AsA acting as co-promoters. The results strongly indicate that combined treatment with NaAsA or AsA and NaNO2 may induce forestomach carcinomas in the long term.

Effects of combined treatment with phenolic compounds and sodium nitrite on two-stage carcinogenesis and cell proliferation in the rat stomach.

The effects of combined treatment with NaNO2 and phenolic compounds on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) stomach carcinogenesis were investigated in F344 rats. In the first experiment, groups of 15-20 male rats were treated with an intragastric dose of 150 mg/kg body weight of MNNG, and starting 1 wk later, were given 2.0% butylated hydroxyanisole, 0.8% catechol, 2.0% 3-methoxycatechol or basal diet either alone or in combination with 0.2% NaNO2 in the drinking water until they were killed at week 52. All three antioxidants significantly enhanced forestomach carcinogenesis without any effect of additional NaNO2 treatment. However, in the absence of MNNG pretreatment, the grade of forestomach hyperplasia in the catechol and 3-methoxycatechol groups was significantly increased by the combined treatment with NaNO2. In a second experiment, the combined effects of various phenolic compounds and NaNO2 on cell proliferation in the upper digestive tract were examined. Groups of 5 rats were given one of 24 phenolic compounds or basal diet either alone or in combination with 0.3% NaNO2 for 4 weeks and then killed. Particularly strong enhancing effects in terms of thickness of the forestomach mucosa were seen with t-butylhydroquinone (TBHQ), catechol, gallic acid, 1,2,4-benzenetriol, dl-3-(3,4-dihydroxyphenyl)-alanine and hydroquinone in combination with NaNO2. In the glandular stomach, similar enhancing effects were evident in 11 cases, and in the esophagus with phenol, TBHQ and gallic acid. These results demonstrate that NaNO2 can augment cell proliferation induced in the stomach epithelium by various phenolic compounds.

Target organ specificity of cell proliferation induced by various carcinogens.

The target organ specificities of cell proliferation and histopathological lesion induction by 5 carcinogens having different target organs were evaluated using a multiorgan carcinogenesis bioassay. In Group 1, male F-344 rats aged 6 wk were sequentially treated with N-diethylnitrosamine (DEN, single 100-mg/kg ip injection, week 0), N-methyl-N-nitrosourea (MNU, 4 20-mg/kg ip injections, weeks 0-2), N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN, 0.05% in drinking water, weeks 0-2), N,N'-dimethylhydrazine (DMH, 4 40-mg/kg sc injections, weeks 2-4), and dihydroxy-di-N-propylnitrosamine (DHPN, 0.1% in drinking water, weeks 2-4) during the first 4 wk. In Groups 2-6, rats were treated with only one of the above initiators, applied as in Group 1. Group 7 served as the no-treatment control. Bromouracil deoxyriboside (BUdR) labeling indices (LI) were counted in various organs at weeks 2 and 4. Numbers and areas of glutathione S-transferase placental form positive (GST-P+) liver foci were measured at weeks 2, 4, and 28. Preneoplastic or neoplastic lesion development was assessed at week 28. With regard to specific elevation of cell proliferation in target organs, BUdR LIs in the urinary bladder, liver, and colon were, respectively, increased in the BBN alone, DEN alone, and DMH alone treated groups as well as in Group 1. However, LIs of thyroid, lung, and kidney were also elevated by several carcinogens not including these organs in their carcinogenic target specificity. On the other hand, morphological lesions and GST-P+ foci were limited to Group 1 and the target organs of the corresponding carcinogen-treated groups.(ABSTRACT TRUNCATED AT 250 WORDS)

3,2'-Dimethyl-4-aminobiphenyl-induced gallbladder carcinogenesis and effects of ethinyl estradiol in hamsters.

The effects of ethinyl estradiol (EE) on 3,2'-dimethyl-4-aminobiphenyl (DMAB)-induced carcinogenesis were examined in Syrian golden hamsters. DMAB was subcutaneously injected in corn oil at a concentration of 100 mg/kg once a week for 20 weeks and EE was administered in the diet at a dose of 0.75 ppm throughout the experiment. Some animals were killed at week 20 and all surviving ones were killed at week 50. Gallbladder tumors (adenomas and carcinomas) were induced in 6 of 15 hamsters (40%) in the DMAB + EE group and 5 of 14 (36%) in the DMAB alone group in males, and in 6 of 13 (46%) in the DMAB + EE group and 1 of 8 (13%) in the DMAB alone group in females at week 50. A clearer enhancing effect of EE on DMAB gallbladder carcinogenesis was observed for tumor multiplicity (No./animal) for both sexes; from 0.36 to 0.67 in males and from 0.14 to 0.62 in females. Thus, DMAB was demonstrated to be carcinogenic in the gallbladder of hamsters and EE enhanced this DMAB-induced gallbladder tumorigenesis.

Suppression of diethylnitrosamine-initiated preneoplastic foci development in the rat liver by combined administration of four antioxidants at low doses.

Potential synergism between 4 antioxidants acting at low doses on development of glutathione S-transferase placental form (GST-P)-positive liver cell foci was examined in male rats initially given diethylnitrosamine (200 mg/kg, i.p.). Beginning 2 weeks after the initiation, rats received the antioxidants, individually or in combination, in the diet for 6 weeks. All rats were subjected to two-thirds partial hepatectomy at week 3 and killed at week 8. The numbers and areas of GST-P-positive foci were significantly decreased by single treatment with butylated hydroxyanisole (BHA, 1%), tert-butylhydroquinone (TBHQ, 1%) and catechol (0.8%), but not with sesamol (0.5%). Combined treatments (BHA + TBHQ, catechol + sesamol, or all 4 chemicals) at a quarter of the above dose levels resulted in decrease in numbers and areas of foci to levels less than the sums of individual inhibition data obtained with the one-quarter levels. Although these combined effects were not statistically significant in the additive model, the results indicate possible synergistic suppression of carcinogenesis by low-dose combined treatment with anti-cancer agents and the usefulness of the present protocol for this type of analysis.

N-nitrosoheptamethyleneimine-induced pulmonary and esophageal carcinogenesis and effects of concomitant treatment with bleomycin in rats.

The combination effects of bleomycin with N-nitrosoheptamethyleneimine (NHMI) or dihydroxy-di-N-propylnitrosamine (DHPN) on pulmonary carcinogenesis were investigated. Male F344 rats were given NHMI (20 or 40 ppm) or DHPN (200 ppm) in the drinking water and intraperitoneally injected with bleomycin (1 mg/kg) once a week for 18 weeks and then killed at week 24. Many rats treated with NHMI died before the termination of the experiment due to toxicity or development of advanced esophageal carcinomas, considered to be the main cause of death. Detailed histological examination performed on rats killed at week 24 revealed no statistically significant effects of bleomycin on NHMI or DHPN induction of neoplastic lesions in the lung or esophagus, although pulmonary carcinomas were only found in two rats treated with NHMI plus bleomycin. Under the present experimental conditions, NHMI exerted stronger carcinogenic activity in the esophagus than in the lung, and no obvious modifying effects of simultaneously administered bleomycin were evident on NHMI- or DHPN-induced pulmonary carcinogenesis.

Effects of various bile acids and their sodium salts on development of pepsinogen-altered pyloric glands in rats.

Effects of dietary bile acids and their sodium salts on the development of pepsinogen-altered pyloric glands (PAPG) were examined in male WKY/N Crj rats initially given a single dose of 160 mg/kg body weight of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) by gastric intubation. From week 3 the animals were administered basal diet containing 0.5% supplements of cholic acid (CA), deoxycholic acid (DCA), chenodeoxycholic acid (CDCA) or their sodium salts (Na-C, Na-DC and Na-CDC), or 5% ascorbic acid (ASA) or its salt (Na-AS) for 18 weeks. The concentration of DCA and Na-DC was reduced to 0.3% from week 12. At week 20, animals were killed and the numbers of immunohistochemically-demonstrated PAPG were determined. Values were significantly higher with Na-C and Na-CDC than with the corresponding parent acids, and in the Na-C case PAPG development was greater than with MNNG alone. In addition, Na-CDC itself induced the numbers of PAPG significantly. These results suggest that bile salts are possible intrinsic promoters of gastric carcinogenesis. They were without effect, however, on forestomach lesions.

Synergistic enhancement of glutathione S-transferase placental form-positive hepatic foci development in diethylnitrosamine-treated rats by combined administration of five heterocyclic amines at low doses.

Potential synergism among 5 heterocyclic amines at low doses in the induction of glutathione S-transferase placental form (GST-P)-positive liver cell foci was examined in an 8-week experiment using male rats initially given diethylnitrosamine (200 mg/kg, ip). The heterocyclic amines applied were 3-amino-1-methyl-5H-pyrido[4,3-b]indole (500 ppm), 2-amino-6-methyldipyrido[1,2-a:3',2'-d]-imidazole (500 ppm), 2-amino-3-methyl-9H-pyrido[2,3-b]indole (800 ppm), 2-amino-9H-pyrido[2,3-b]indole (800 ppm), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP, 400 ppm). Separate groups received each chemical at the dose used in earlier carcinogenicity assays (above doses), at 1/5 or 1/25 of these, or all 5 chemicals together, each at the 1/5 or 1/25 levels. The numbers and areas of GST-P-positive foci were significantly increased with all chemicals, except for PhIP, at the highest dose, the results being consistent with the reported liver carcinogenicity. In the combined treatment at the 1/5 dose levels, synergistic enhancement occurred; the numbers and areas of foci were significantly increased above the sums of individual data. However, this was not the case for the 1/25 dose groups. Although the synergism between pyrolysis products in liver carcinogenesis depended on the dose and combination of chemicals, the findings, together with those from a previous experiment using 5 different heterocyclic amines, are of particular significance since several heterocyclic amines might be simultaneously generated during cooking of foodstuffs.

Modifying effects of the naturally occurring antioxidants gamma-oryzanol, phytic acid, tannic acid and n-tritriacontane-16, 18-dione in a rat wide-spectrum organ carcinogenesis model.

The modifying effects of the naturally occurring antioxidants gamma-oryzanol, phytic acid, tannic acid and n-tritriacontane-16, 18-dione (TTAD) were investigated in a rat wide-spectrum organ carcinogenesis model. Animals were initiated with two i.p. injections of 1000 mg/kg body wt 2,2'-dihydroxy-di-n-propylnitrosamine (DHPN) followed by two i.g. administrations of 1500 mg/kg body wt N-ethyl-N-hydroxy-ethylnitrosamine (EHEN), and then three s.c. injections of 75 mg/kg body wt 3,2'-dimethyl-4-aminobiphenyl (DMAB) during the first 3 weeks. Starting 1 week after the last injection, groups of rats received diet containing 1% gamma-oryzanol, 2% phytic acid, 0.2% TTAD or 1% tannic acid or basal diet alone for 32 weeks. Animals were then killed and complete autopsy was performed at the end of week 36. Histological examination revealed enhancement of lung carcinogenesis by gamma-oryzanol, and the incidence of urinary bladder papillomas to be increased by phytic acid. On the other hand, TTAD inhibited hepatic and pancreatic carcinogenesis. Phytic acid and tannic acid were marginally effective in inhibiting hepatic and colon carcinogenesis respectively. The results thus indicated that naturally occurring antioxidants each exert specific modifying effects depending on the organ site and indicate that wide-spectrum carcinogenesis models are useful for defining complex influences.

Effects of butylated hydroxyanisole pretreatment on low dose N-methyl-N'-nitro-N-nitrosoguanidine- or N,N-dibutylnitrosamine-induced rat forestomach or esophageal carcinogenesis.

The effects of butylated hydroxyanisole (BHA) pretreatment on subsequent low dose N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or N,N-dibutylnitrosamine (DBN) treatment on forestomach or esophageal carcinogenesis were investigated in male F344 rats. Groups of animals were pretreated with 2% BHA or basal diet alone for 24 weeks and then were given 20 mg/kg body wt MNNG once every 2 weeks, 0.025% DBN in drinking water continuously or basal diet alone for the subsequent 24 weeks. Further groups of rats were similarly treated with BHA or basal diet alone for 24 weeks, placed on basal diet for the next 24 weeks and then treated with MNNG, DBN or basal diet alone for the subsequent 24 weeks. Animals were killed 48 or 72 weeks after the beginning of the experiment. Histopathological examination showed that the incidence of forestomach tumors was not significantly affected by the BHA pretreatment in the MNNG-treated groups. On the other hand, the incidence of esophageal squamous cell carcinomas was lower in the group pretreated with BHA followed by DBN than in that treated with basal diet followed by DBN (48 week experiment). There was no significant difference in esophageal tumor incidence in the 72 week experiment. The results thus indicate that continuous treatment with 2% BHA for 24 weeks does not exert initiating activity on forestomach and esophageal epithelia.