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K Imaida

Publications and source records attributed to K Imaida.

At least 19 recordsLinked to original sources
PubMed1996

Medium-term liver and multi-organ carcinogenesis bioassays for carcinogens and chemopreventive agents.

To bridge the gap between long-term carcinogenicity tests and short-term screening assays such as the Ames test, several types of medium-term bioassay for rapid detection of carcinogenic agents have been developed using male F344 rats. The liver model, in which diethylnitrosamine initiation and acceleration of carcinogenesis by partial hepatectomy are essential components, requires only 8 weeks of animal experimentation and a few weeks for quantitative analysis of hepatic preneoplastic lesions. Using the model, a total of 250 chemicals have been analyzed and the efficacy of the system for hapatocarcinogens has thereby been well established. Other models are so-called multi-organ bioassays for detection of carcinogenic agents in multiple organs within relatively short periods. Among these, the DMBDD bioassay with 5 known carcinogens as initiators has been found to be most applicable and has now been introduced for practical use. Data from these bioassays and several single organ carcinogenesis systems have demonstrated that carcinogenic and modifying effects of individual exogenous agents may markedly differ from organ to organ. Therefore, research into chemoprevention should be based on a whole body level analysis. The present medium-term systems are very useful for this purpose.

Animals↗
PubMed1996

Chemically induced lung and forestomach neoplasias in transgenic mice carry mutant forms of the human c-Ha-ras transgene.

Susceptibility to lung carcinogens and genetic changes in neoplastic lesions were investigated in transgenic mice carrying a human hybrid c-Ha-ras gene, encoding a prototype p21 gene product. Nine-week-old male and female transgenic mice and non-transgenic littermates were injected i.p. with 6-nitrochrysene (6NC) three times biweekly or administered urethane in their drinking water for 3 weeks. Control mice were given dimethylsulfoxide (DMSO), the solvent for 6NC, alone. The incidences of lung adenocarcinomas were four out of seven female (57%) transgenic mice treated with 6NC and three out of three males (100%) and three out of three females (100%) receiving urethane. No adenocarcinomas were observed in control animals or non-transgenic mice. Adenomas developed in all treated groups, but the incidence and multiplicity were higher in transgenic animals than in their non-transgenic counterparts. In the 6NC-treated group, forestomach papillomas and squamous cell carcinomas were also observed in both male (25 and 50%) and female (56 and 33%) transgenic mice. PCR-SSCP and DNA sequence analysis of these induced lesions revealed point mutations at codon 61 of transgenic human c-Has-ras, from CAG (Gln) to CTG (Leu) or CAG (Gln) to AAG (Lyn) in lung hyperplasias (two out of three), an adenoma (one out of two), adenocarcinomas (five out of seven) and forestomach squamous cell carcinomas (four out of five). Mutations were not observed in forestomach papillomas. No changes in mouse Ha-ras or Ki-ras were found in any lesions. Furthermore, p21 overexpression was not evident in lung or forestomach tumors on immunohistochemical analysis. These findings indicate a high sensitivity to lung carcinogens in transgenic mice carrying the human c-Ha-ras gene and that this might be effected by mutational activation.

Animals↗
PubMed1996

Direct effects of testosterone, dihydrotestosterone and estrogen on 3,2'-dimethyl-4-aminobiphenyl-induced prostate carcinogenesis in castrated F344 rats.

The present experiment was carried out to explore the effect of endogenous androgen on rat prostate carcinogenesis induced by 3,2'-dimethyl-4-aminobiphenyl (DMAB) and testosterone propionate (TP) or 5alpha-dihydrotestosterone (DHT) with or without ethinyl estradiol (EE). In order to eliminate the influence of endogenous androgen, F344 rats were orchiectomized just after initiation with the prostate carcinogen, DMAB, and then given TP, DHT, TP plus EE or DHT plus EE for 40 weeks. The results demonstrated that while administration of TP following DMAB treatment causes invasive carcinomas in the lateral and anterior prostate and seminal vesicles, DHT does not exhibit equivalent effects. Synergistic enhancement was also evident with TP plus EE, but not with DHT plus EE. The incidences of prostatic and seminal vesicle lesions in all groups of the present experiment, except for the group given castration without hormonal supplement, were equivalent to those previously found in non-castrated animals. Therefore, the present findings indicate that endogenous testosterone may not be required for promotion by TP/EE of DMAB-initiated prostate carcinogenesis and that it may not contribute to the actions of DHT.

Aminobiphenyl Compounds↗
PubMed1995

Chemoprevention by dehydroepiandrosterone and indomethacin in a rat multiorgan carcinogenesis model.

The chemopreventive efficacy of dehydroepiandrosterone (DHEA) and indomethacin (IM) alone or in combination was investigated in a rat multiorgan carcinogenesis model. These two chemicals were selected as chemopreventive agents with different functions. Animals were sequentially given five carcinogens with different organ target sites in the first 4-week initiation period. One week after its completion, the rats received 0.3% DHEA in the diet, 20 ppm IM in the drinking water, or 0.3% DHEA + 20 ppm IM until experimental week 28. DHEA enhanced hepatocarcinogenesis, but concurrent treatment with IM suppressed tumor development as compared to the DHEA group. DHEA inhibited tumor development in the thyroid, with a similar tendency observed for the small intestine. In addition, treatment with this hormone decreased occurrences of preneoplasias in the urinary bladder and seminal vesicles. Treatment with IM clearly suppressed development of preneoplasias or neoplasias in the lung and small and large intestines. In the urinary bladder, treatment with IM tended to decrease preneoplastic lesion development. Analysis of multiplicity of total tumors of any category revealed comparable values for DHEA and control groups, while the IM group showed a significant reduction. IM in combination with DHEA caused suppression as compared to DHEA alone. In a separate 8-week experiment, DHEA or IM were administered for 4 weeks after prior carcinogen application, and biochemical responses in the target organs were investigated. DHEA increased glucose-6-phosphate dehydrogenase levels in the liver but caused a decrease in the small intestine. In addition, DHEA decreased serum T4 but not T3. IM decreased prostaglandin E2 content in the small intestine. In conclusion, although DHEA or IM exert significant chemopreventive effects in multiorgans with the exception of the DHEA-treated liver case, treatment in combination did not result in amplification of their beneficial influence. Our results suggest the possible application of IM for chemoprevention in high-risk individuals, but the question of effects of DHEA in the liver must be answered before this hormone can be considered for use in humans.

Animals↗
PubMed1995

Ki-ras mutations with frequent normal allele loss versus absence of p53 mutations in rat prostate and seminal vesicle carcinomas induced with 3,2'-dimethyl-4-aminobiphenyl.

We have developed a prostate carcinogenesis model in Fischer 344 rats using 3,2'-dimethyl-4-aminobiphenyl (DMAB) as a carcinogen to examine various potential modifying factors. In this study, mutational changes in the ras and p53 genes were assessed in DMAB-induced rat prostate and seminal vesicle carcinomas by single-strand conformation polymorphism analysis and subsequent direct DNA sequencing. Eight of 22 prostate adenocarcinomas (three of nine (33.3%) from the ventral lobe and five of 13 (38.5%) from the dorsolateral lobe, including three transplantable tumors) and one of 11 seminal vesicle adenocarcinomas (9.1%) demonstrated point mutations in the Ki-ras gene. One prostate malignant fibrohistiocytoma examined was negative. Among the positive cases, five (three ventral prostate carcinomas and two transplantable tumors) also showed loss of the normal allele. In contrast, other than one mutation in the p53 gene in the malignant fibrohistiocytoma, there were no mutations in the Ha-ras or p53 genes. These results indicate that mutational activation of the Ki-ras gene, but not of the Ha-ras or p53 genes may play a mechanistic role in prostate and seminal vesicle carcinogenesis by DMAB and that a loss of the normal allele of the Ki-ras gene may also be involved in the process.

Adenocarcinoma↗
PubMed1995

Effect of ingestion of 20 pesticides in combination at acceptable daily intake levels on rat liver carcinogenesis.

Exposure of agricultural workers and the general population to pesticides is a major concern, and possible summation or synergistic effects deserves particular attention. In this study, however, combined dietary administration of 19 organophosphorus compounds and one organochlorine pesticide, each at acceptable daily intake (ADI) levels, did not enhance rat liver preneoplastic lesion development initiated by diethylnitrosamine. In contrast, a mixture of 100 times ADI significantly increased the number and area of lesions. The results thus provide direct support for the present safety factor approach to the quantitative hazard evaluation of pesticides.

Administration, Oral↗
PubMed1995

Rat strain differences in catechol carcinogenicity to the stomach.

The carcinogenic potential of catechol was compared in male Wistar, WKY, Lewis and SD strains of rats. Groups of 30 animals were treated with powdered diet containing 0.8% catechol for 104 wk and then examined histopathologically. Induction of glandular stomach adenocarcinomas occurred in 67, 73 and 77% of Wistar, Lewis and SD animals, respectively, but in only 10% of WKY rats. In addition, catechol induced forestomach papillomas in 20% (P < 0.05), and squamous cell carcinomas in 3% of SD rats. The results thus indicate that Wistar, Lewis and SD rats are much more susceptible than WKY rats to induction of glandular stomach adenocarcinomas by 0.8% catechol, and that this phenolic antioxidant also possesses weak carcinogenic activity for the SD rat forestomach.

Adenocarcinoma↗
PubMed1995

Analysis of the potential carcinogenicity of coffee and its related compounds in a medium-term liver bioassay of rats.

The potential carcinogenicity of coffee and related compounds was examined using a medium-term liver bioassay based on the induction of glutathione S-transferase placental form (GST-P)-positive foci in F344 rats. A total of 230 males were initially injected with diethylnitrosamine (200 mg/kg body weight, ip) or saline as controls and 2 wk later were fed on diet or drinking water supplemented as follows for 6 wk: 5% regular instant coffee; 5% decaffeinated instant coffee; freshly brewed coffee, 8 g in 140 ml water; 0.1% caffeine, 0.2% methylglyoxal, 0.2% glyoxal; or 0.3% theophylline in the drinking water (w/v); and 0.4% theobromine in the diet (w/w). All rats were subjected to two-thirds partial hepatectomy at wk 3 and killed at wk 8. The resultant values for GST-P-positive hepatic focus induction were slightly increased with methylglyoxal and decreased with glyoxal and theobromine compared with the corresponding controls. Although the increase in number of foci for methylglyoxal was statistically significant at P < 0.05, the value was within the historical control levels. Regular and decaffeinated instant coffee as well as fresh-brewed coffee, caffeine and theophylline exerted no effects on focus development. Thus, the coffee-related compounds examined demonstrated no obvious enhancing potential, and it is therefore concluded that coffee and its main constituents are not carcinogenic for the rat liver.

Administration, Oral↗
PubMed1995

Lack of carcinogenicity of pesticide mixtures administered in the diet at acceptable daily intake (ADI) dose levels in rats.

Carcinogenic effects of pesticide mixtures were examined with our medium-term carcinogenesis protocols using male F344 rats. In the 8-week liver model, combined dietary administration of 20 pesticides (19 organophosphorus compounds and 1 organochlorine), each at acceptable daily intake (ADI) levels, did not enhance rat liver preneoplastic lesion development initiated by diethylnitrosamine. In contrast, a mixture of 100 times ADI significantly increased the number and area of liver lesions. In the second experiment using a multi-organ carcinogenicity protocol of 28 weeks, mixtures of 40 pesticides (high volume compounds) and 20 pesticides (suspected carcinogens) added to the diet at their respective ADI levels did not enhance carcinogenesis in any organ initiated by 5 different known carcinogens in combination. These results provide support for the safety factor (usually 100) approach presently used for the quantitative hazard evaluation of pesticides.

Animals↗
PubMed1995

Urinary bladder carcinogenesis induced by melamine in F344 male rats: correlation between carcinogenicity and urolith formation.

Urinary bladder carcinogenesis associated with melamine treatment was examined with concomitant use of NaCl to allow assessment of the relationship between uroliths and lesion development. Analysis of the chemical composition of calculi was also performed. F344/DuCrj male rats received diets containing 3 or 1% melamine alone or in combination with either 10 or 5 % NaCl, or 10% NaCl alone for 36 weeks, and then diet without NaCl supplement for a further 4 weeks. The water intake, used as an index of urinary output, was increased by NaCl treatment. The incidences of bladder transitional cell carcinomas and papillomas were 90 and 55% in the group treated with 3% melamine alone; 0 and 15% in the group treated with 3% melamine and 10% NaCl; and 21 and 42% in group treated with 1% melamine alone; and zero in the other groups. Calculus formation resulting from melamine administration was suppressed dose-dependently by the simultaneous NaCl treatment, along with the occurrence of hyperplasia of the papilla in the kidneys. The main constituent of calculi were melamine itself and uric acid (total contents 61.1-81.2%), contained in equal molar ratio. The results indicate that melamine-induced proliferative lesions of the urinary tract of rats were directly due to the irritative stimulation of calculi, and not molecular interactions between melamine itself or its metabolites with the bladder epithelium.

Animals↗
PubMed1995

Carcinogenicity of nitropyrenes in the newborn female rat.

The carcinogenicities of 1-nitropyrene (1-NP), 4-nitropyrene (4-NP), 1,3-dinitropyrene (1,3-DNP), 1,6-dinitropyrene (1,6-DNP), 1,8-dinitropyrene (1,8-DNP), 3-hydroxy-1-nitropyrene (3-OH-1-NP) and a mixture of 6- and 8-hydroxy-1-nitropyrene (6/8-OH-1-NP) were investigated in newborn female rats. Newborn female CD rats were treated s.c. eight times at weekly intervals with a total dose of 6.3 mumol 1-NP,1,3-DNP,1,6-DNP or 1,8-DNP; control animals received only dimethylsulfoxide (DMSO). The experiment was terminated at 67 weeks. With the exception of 1,6-DNP- and 1,8-DNP-treated animals, which had average survival periods of 149 and 164 days respectively, the animals administered the other compounds did not show decreased survival. Malignant fibrous histiocytomas were observed in 12%, 100% and 100% of the rats treated with 1,3-, 1,6- and 1,8-DNP respectively. Leukemia was found in 20% and 22% of the animals treated with 1,6- and 1,8-DNP respectively. No control rats developed these tumors. Additionally, mammary tumors were induced in rats treated with 1-NP. Newborn female CD rats were similarly treated with 1-NP, 4-NP, 3-OH-1-NP, 6/8-OH-1-NP or DMSO and newborn female F344 rats were treated with 1-NP or DMSO. The experiment was terminated at 86 weeks, 1-NP and 4-NP produced mammary adenocarcinoma in CD rats. Although 1-NP did not produce mammary adenocarcinoma in F344 rats, it induced leukemia. 4-NP also induced malignant fibrous histiocytomas in CD rats. This study demonstrates that 4-NP is more carcinogenic than 1-NP and that CD rats are more susceptible than F344 rats to mammary carcinogenesis by 1-NP. Additionally, 1,6- and 1,8-DNP are more potent than 1-NP in inducing malignant fibrous histiocytomas and leukemia.

Animals↗
PubMed1995

Differences in cell proliferation and apoptosis between reversible and irreversible mucosal lesions associated with uracil-induced urolithiasis in N-butyl-N-(4-hydroxybutyl)nitrosamine-pretreated.

Differences between the reversible papillomatosis and preneoplastic lesions of the urinary bladder of rats were investigated in terms of cell proliferation and apoptosis after cessation of uracil administration. Animals were given N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 4 weeks and then uracil for 8 weeks in order to induce urinary bladder lesions. During this period and after cessation of treatment until week 20, subgroups of animals were killed to allow sequential assessment of cell kinetics and apoptosis. Labeling indices (LI) in papillomatosis showed a marked elevation after 2 weeks of uracil treatment with a rapid decline thereafter. In contrast, LI in dysplasias, papillomas and carcinomas gradually elevated during the uracil treatment. Cessation of the uracil stimulation resulted in a complete disappearance of labeled cells in areas of papillomatosis accompanied by significant appearance of apoptotic bodies in the epithelial cells and shrinkage of the lesions. In the focal dysplasias and papillomas, however, any reduction in LI was temporary and followed by a rapid reelevation. The number of apoptotic bodies were relatively few in neoplastic lesions. Thus, removal of growth-stimulating uracil-calculi resulted in return of hyperplastic epithelium to normal by a homeostatically controlled apoptotic mechanism. In contrast, preneoplasias and neoplasias demonstrated an autonomous growth ability.

Animals↗
PubMed1995

Site-specific effects of testosterone propionate on the prostate of rat pretreated with 3,2'-dimethyl-4-aminobiphenyl: dose-dependent induction of invasive carcinomas.

It has been shown that testosterone propionate (TP) strongly promotes induction of invasive carcinomas in previously initiated accessory sex organs. In this study, in order to clarify the dose-dependence of this promotion, TP was given at 3 different levels (high, medium or low doses) using different sizes (2, 1 and 0.5 cm long) of Silastic tube for 40 weeks after administration of 3,2'-dimethyl-4-aminobiphenyl to male F344 rats. The data showed development of invasive carcinomas in the dorso-lateral and anterior prostate and in the seminal vesicle to be dose-dependent with the high dose of TP being most effective for tumor induction. Average levels of serum testosterone were approximately 800, 600, 300 and 150 ng/dl in rats given the high to low doses and in control rats, respectively. Development of neoplastic lesions in the ventral prostate demonstrated an inverse dependence on the dose of TP. These findings, together with previous data, suggest that the tumor-promoting potential of TP on rat prostate is unlikely to be simply due to its androgenic action and other factors should also be considered.

Aminobiphenyl Compounds↗
PubMed1995

Enhancement of rat liver cell foci development by combined treatment with heterocyclic amines at low doses.

Potential synergism between 5 or 10 carcinogenic heterocyclic amines (Trp-P-1, Trp-P-2, Glu-P-1, Glu-P-2, IQ, MeIQ, MeIQx, MeA alpha C, A alpha C and PhIP) acting at low doses was examined in a medium-term liver bioassay system for carcinogens. Immunohistochemically-demonstrated glutathione S-transferase placental form (GST-P) positive foci were assessed as the endpoint marker lesions. Male F344 rats were initially given diethylnitrosamine (DEN, 200mg/kg, ip) and beginning 2 weeks later received heterocyclic amines individually or in combination for 6 weeks. All animals were subjected to partial hepatectomy at week 3 and killed at week 8. A clear dose response relationship was observed for all heterocyclic amines, except for the nonhepatocarcinogen PhIP, with the dose used in earlier carcinogenicity assays and 1/5, 1/10, 1/25 and 1/100 of these levels. Carcinogenicity could be predicted for all compounds at the highest dose or lower dose levels except for PhIP. With combined administration of 5 or 10 chemicals, foci induction significantly exceeded the sums of 5 or 10 individual data for the 1/5, 1/10 and 1/25 dose levels, but not for the 1/100 case. The findings are of particular significance since several heterocyclic amines and other carcinogenic agents might be simultaneously generated during cooking, although each at very low concentration.

Amines↗
PubMed1994

Duration dependent induction of invasive prostatic carcinomas with pharmacological dose of testosterone propionate in rats pretreated with 3,2'-dimethyl-4-aminobiphenyl and development of androgen-independent carcinomas after castration.

Male F344 rats were first treated with 3,2'-dimethyl-4-aminobiphenyl for 20 weeks in the presence of testicular androgens and then administered of a pharmacological dose of testosterone propionate (TP) for various periods (maximum 40 weeks). This resulted in development of invasive carcinomas in the dorso-lateral prostate as well as the seminal vesicles whose incidences were TP duration-dependent. However, in situ carcinomas of the ventral prostate were not affected by the TP treatment and atypical hyperplasias were clearly decreased. When animals were subjected to orchiectomy after 20-weeks-treatment with the TP, invasive adenocarcinomas were still subsequently noted in the dorso-lateral prostate and seminal vesicles, demonstrating a certain androgen-independence. The data indicate that, in spite of the necessity of high dose of TP for induction of invasive prostate carcinomas in the present experimental model, a proportion of the resulting tumors are hormone-independent.

Aminobiphenyl Compounds↗
PubMed1994

Effects of testosterone, dihydrotestosterone and estrogen on 3,2'-dimethyl-4-aminobiphenyl-induced rat prostate carcinogenesis.

Post-initiation effects of testosterone propionate (TP), alpha-dihydrotestosterone (DHT) and ethinyl estradiol (EE) on 3,2'-dimethyl-4-aminobiphenyl (DMAB)-prostate carcinogenesis in F344 rats have been investigated by administration of each hormone individually or either androgen in combination with EE. DMAB plus TP resulted in induction of invasive adenocarcinomas in the lateral and anterior prostate and seminal vesicles, as shown in a previous study, whereas DHT did not exhibit any positive modulation potential. Administration of EE together with TP produced increased carcinoma incidence in the lateral and anterior prostate, from 17 and 28% to 70% and 80%, respectively. Dorsal prostate tumors, all of the non-invasive in situ type, were also evident in 30% of animals receiving both TP and EE. Rats treated with DHT plus EE, however, did not develop tumors. Our experiment thus provides evidence that estrogen may play an important role in prostate carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene↗