Beef Tallow, but Not Perilla or Corn Oil, Promotion of Rat Prostate and Intestinal Carcinogenesis by 3,2-Dimethyl-4-aminobiphenyl

The modifying effects of three kinds of fat (corn oil, beef tallow or perilla oil, each at 20% in the diet) on F344 rat prostate carcinogenesis induced by 3,2-dimethyl-4-aminobiphenyl (DMAB) were investigated. Non-invasive carcinomas of the ventral prostate were induced by DMAB alone and invasive carcinomas of the other prostate lobes and seminal vesicles by DMAB and testosterone propionate (TP). Eight groups of F344 rats were initiated with 50 mg/kg body weight of DMAB at 2-week intervals for the first 20 weeks, four also receiving TP, extended until week 60. The animals received basal chow powder diet or one of three high fat diets throughout the experiment (60 weeks). One further group served as a non-carcinogen-treated control maintained on basal chow powder diet. Beef tallow significantly increased the development of ventral prostate carcinomas with DMAB alone (from 15 to 45%, P<0.05), while perilla oil reduced the incidence of prostatic intraepithelial neoplasia (PIN) in the ventral lobe of rats given DMAB + TP (from 70 to 10%, P<0.01), but not in those given DMAB alone. No other effects of high fats were observed regarding PIN or invasive cancers of the dorsolateral and anterior prostate or seminal vesicles. A satellite experiment demonstrated that all high fat diets for 4 weeks increased the 5-bromo-2-deoxyuridine (BrdU) labeling index of prostate epithelial cells, suggesting that a high fat intake, irrespective of the fatty acid composition, may accelerate cell kinetics in the prostate. Of the three high fat diets, beef tallow was also found to increase intestinal carcinogenesis. Thus, the present data revealed carcinogenesis in the prostate and intestine to be promoted by beef tallow.     

Beef tallow, but not perilla or corn oil, promotion of rat prostate and intestinal carcinogenesis by 3,2'-dimethyl-4-aminobiphenyl.

The modifying effects of three kinds of fat (corn oil, beef tallow or perilla oil, each at 20% in the diet) on F344 rat prostate carcinogenesis induced by 3,2'-dimethyl-4-aminobiphenyl (DMAB) were investigated. Non-invasive carcinomas of the ventral prostate were induced by DMAB alone and invasive carcinomas of the other prostate lobes and seminal vesicles by DMAB and testosterone propionate (TP). Eight groups of F344 rats were initiated with 50 mg / kg body weight of DMAB at 2-week intervals for the first 20 weeks, four also receiving TP, extended until week 60. The animals received basal chow powder diet or one of three high fat diets throughout the experiment (60 weeks). One further group served as a non-carcinogen-treated control maintained on basal chow powder diet. Beef tallow significantly increased the development of ventral prostate carcinomas with DMAB alone (from 15 to 45%, P < 0.05), while perilla oil reduced the incidence of prostatic intraepithelial neoplasia (PIN) in the ventral lobe of rats given DMA + TP (from 70 to 10%, P < 0.01), but not in those given DMAB alone. No other effects of high fats were observed regarding PIN or invasive cancers of the dorsolateral and anterior prostate or seminal vesicles. A satellite experiment demonstrated that all high fat diets for 4 weeks increased the 5-bromo-2-deoxyuridine (BrdU) labeling index of prostate epithelial cells, suggesting that a high fat intake, irrespective of the fatty acid composition, may accelerate cell kinetics in the prostate. Of the three high fat diets, beef tallow was also found to increase intestinal carcinogenesis. Thus, the present data revealed carcinogenesis in the prostate and intestine to be promoted by beef tallow.     

Lack of tumorigenic response in the prostate gland of castrated F344 rats by 3,2'-dimethyl-4-aminobiphenyl given with methyltestosterone

In an attempt to induce a high incidence of prostate carcinoma, 3,2'-dimethyl-4-aminobiphenyl (DMAB), a prostatic carcinogen, was given during the period of cell proliferation of the prostate gland induced by the administration of methyltestosterone (MT) to castrated F344 rats. Three weeks after the surgical castration, rats were given diet containing 300 ppm of MT for 2 weeks and basal for 2 weeks alternately 12 times. During each treatment with MT, one (group 1) or two (group 2) subcutaneous injections of 50 mg/kg body wt. of DMAB was given. After the last treatment of MT, a pellet of testosterone propionate (TP) was implanted in the subcutis of all animals until the end of the experiment (week 60). No carcinomas developed in the prostate gland of any of the rats. Atypical hyperplasia of the ventral lobe of prostate was found in 4 of 22 rats in group 1 and 2 of 20 rats in group 2. The incidences of atypical hyperplasia of the seminal vesicles in groups 1 and 2 were 64% and 75%, respectively. No pathological lesions in the prostate were observed in 32 rats given DMAB without MT treatment.     

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 5α-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 hy TP/EE of DMAB-initiated prostate carcinogenesis and that it may not contribute to the actions of DHT.     

Development of Androgen-independent Carcinomas from Androgen-dependent Preneoplastic Lesions in the Male Accessory Sex Organs of Rats Treated with 3,2'-Dimethyl-4-aminobiphenyl and Testosterone Propionate

Two kinds of cancer can be induced in rat male accessory sex organs, one a non-invasive carcinoma arising in the ventral lobe and the other an invasive lesion which develops in the dorsolateral and anterior lobe as well as the seminal vesicles. In the present study, one group of male rats were given biweekly s.c. injections of 3,2'-dimethyl-4-aminobiphenyl (DMAB) for 20 weeks for induction of non-invasive carcinomas and the other group received DMAB with 40-week testosterone propionate for induction of invasive carcinomas. Half of the animals in each group were then subjected to bilateral orchiectomy at week 41 to remove testicular androgen, in order to examine the androgen dependence of both types of carcinomas as well as precancerous lesions. Animals were killed at weeks 41, 46 and 60. All parts of the prostate complex showed involution and significant weight reduction after castration, with a complete disappearance of atypical hyperplasias and carcinomas of the ventral prostate. However, in spite of suppression of development of atypical hyperplasias in the anterior prostate and seminal vesicles, the incidence of invasive carcinomas was not changed. Normal epithelial cells and atypical hyperplasias of all parts of the prostate and seminal vesicles and carcinomas of the ventral prostate were immunohistochemically positive for nuclear androgen receptor, while invasive carcinomas that developed in either castrated or non-castrated animals were negative. These findings suggest that in the ventral prostate, both precancerous and cancerous lesions are androgen-dependent, but in the anterior and seminal vesicles, cancerous lesions (invasive carcinomas) are androgen-independent while precancerous lesions are hormone-dependent.     

Development of androgen-independent carcinomas from androgen-dependent preneoplastic lesions in the male accessory sex organs of rats treated with 3,2'-dimethyl-4-aminobiphenyl and testosterone propionate.

Two kinds of cancer can be induced in rat male accessory sex organs, one a non-invasive carcinoma arising in the ventral lobe and the other an invasive lesion which develops in the dorsolateral and anterior lobe as well as the seminal vesicles. In the present study, one group of male rats were given biweekly s.c. injections of 3,2'-dimethyl-4-aminobiphenyl (DMAB) for 20 weeks for induction of non-invasive carcinomas and the other group received DMAB with 40-week testosterone propionate for induction of invasive carcinomas. Half of the animals in each group were then subjected to bilateral orchiectomy at week 41 to remove testicular androgen, in order to examine the androgen dependence of both types of carcinomas as well as precancerous lesions. Animals were killed at weeks 41, 46 and 60. All parts of the prostate complex showed involution and significant weight reduction after castration, with a complete disappearance of atypical hyperplasias and carcinomas of the ventral prostate. However, in spite of suppression of development of atypical hyperplasias in the anterior prostate and seminal vesicles, the incidence of invasive carcinomas was not changed. Normal epithelial cells and atypical hyperplasias of all parts of the prostate and seminal vesicles and carcinomas of the ventral prostate were immunohistochemically positive for nuclear androgen receptor, while invasive carcinomas that developed in either castrated or non-castrated animals were negative. These findings suggest that in the ventral prostate, both precancerous and cancerous lesions are androgen-dependent, but in the anterior and seminal vesicles, cancerous lesions (invasive carcinomas) are androgen-independent while precancerous lesions are hormone-dependent.     

Induction of invasive carcinomas of the seminal vesicles and coagulating glands of F344 rats by administration of N-methylnitrosourea or N-nitrosobis(2-oxopropyl)amine and followed by testosterone propionate with or without high-fat diet

The potential modifying effects of testosterone propionate (TP) and high-caloric high-fat diet (20% corn oil, HF) on rat accessory sex gland carcinogenesis were investigated. Male F344 rats were treated five times at 4-week intervals with N-methylnitrosourea (MNU) i.v. or N-nitrosobis(2-oxopropyl)amine (BOP) s.c., each injection following 2 weeks pretreatment with dietary ethinyl estradiol. After completion of this carcinogen administration stage, animal groups received subcutaneous implantation of Silastic tubes filled with 40 mg TP with or without HF for 40 weeks. Carcinomas of the seminal vesicles and/or coagulating glands were induced in 5, 39 and 56% of rats given MNU alone, MNU and TP, and MNU and HF plus TP respectively. No equivalent tumors were found in rats given MNU and HF. In the BOP-treated groups, 11% of animals receiving TP but no HF diet demonstrated seminal vesicle carcinomas and 6% of rats receiving TP plus HF diet had coagulating gland carcinoma. Thus while TP exerted a strong enhancing effect on tumor growth in the seminal vesicles and coagulating glands, high caloric HF did not manifest any significant influence.     

Decrease of Prostaglandin E2 and 5–Bromo–2'–deoxyuridine Labeling but Not Prostate Tumor Development by Indomethacin Treatment of Rats Given 3,2'–Dimethyl-4-aminobiphenyl and Testosterone Propionate

The modifying effects of indomethacin (IM) on rat prostate carcinogenesis induced by 3,2'–dimethyl–4–aminobiphenyl (DMAB) were investigated. F344 rats were given 50 mg/kg body weight of DMAB at 2–week intervals for 20 weeks and then received IM at a dose of 20 ppm in the drinking water for 37 weeks. Separate groups additionally received testosterone propionate (TP) in Silastic tubes throughout the experiment. DMAB alone induced carcinomas in situ in the ventral lobe and in combination with TP caused invasive carcinomas of the dorso–lateral and anterior lobes and seminal vesicles. No clear suppression by IM of development of in situ carcinomas or in vasive carcinomas was observed. In a short–term satellite experiment, it was revealed that prostaglandin E₂ (PGE₂) levels in the dorso–lateral prostate and seminal vesicles, but not the ventral prostate, were significantly reduced by IM and that TP itself also suppressed PGE₂ levels. The 5–bromo–2'–deoxyuridine labeling index in the ventral prostate was significantly decreased by IM administration. These results indicate that while IM can efficiently suppress tissue PGE₂ levels, it does not inhibit tumor development in the prostate or seminal vesicles of rats in the present model.     

Lobe specific effects of testosterone and estrogen on 3,2'-dimethyl-4-aminobiphenyl-induced rat prostate carcinogenesis

We have previously shown that chronic administration of a pharmacological dose of testosterone propionate (TP) after treatment with the carcinogen, 3,2'-dimethyl-4-aminobiphenyl (DMAB), results in development of invasive and metastatic adenocarcinomas arising from the dorso-lateral and anterior prostate, as well as the seminal vesicles. Co-administration of ethinyl estradiol (EE) with TP increased the yield of carcinomas in the lateral and anterior lobes. In the present experiment, male F344 rats were treated with DMAB for 20 weeks and then co-administered a pharmacological dose of TP together with various doses of EE for 40 weeks. Without hormone(s) administration, carcinomas were confined to the ventral prostate and all were of intra-acinar type. TP administration suppressed development of the ventral prostate carcinomas but caused invasive carcinomas of the lateral and anterior lobes and of seminal vesicles and intra-acinar carcinomas in the dorsal prostate. The appearance of carcinomas in the lateral and anterior prostate was increased by co-administration of EE in a dose-related fashion but carcinomas of the seminal vesicles were inversely reduced. The suppressive influence of TP on ventral carcinoma development was overcome by only the highest dose of EE. It is concluded that estrogen can modify the enhancing effects of TP on induction of rat prostate and seminal vesicle carcinomas in a dose-related fashion with lobe specificity.     

Suppressive effects of dietary genistin and daidzin on rat prostate carcinogenesis.

High intake of phytoestrogens through soybeans and their products is thought to be associated with low incidences of prostate and / or breast cancer in Asian countries. Possible chemopreventive effects of genistin or daidzin on rat prostate carcinogenesis were therefore investigated. Male F344 rats were given 10 biweekly subcutaneous injections of 3,2'-dimethyl-4-aminobiphenyl (DMAB) and then either genistin or daidzin in the diet at a concentration of 0.1% for 40 weeks. Other groups of rats given DMAB were treated with genistin or daidzin together with a high dose of testosterone propionate (TP). Both genistin and daidzin reduced the numbers of ventral prostate carcinomas (P < 0.05), with a tendency for decrease in incidence. Invasive carcinomas which developed in the anterior prostate and seminal vesicles with TP were, however, not influenced by the two isoflavones. Thus, the present data suggest that genistin and daidzin possess anti-cancer effects at relatively early stages of prostate cancer development, providing experimental support for epidemiological findings.     

Suppressive Effects of Dietary Genistin and Daidzin on Rat Prostate Carcinogenesis

High intake of phytoestrogens through soybeans and their products is thought to be associated with low incidences of prostate and/or breast cancer in Asian countries. Possible chemopreventive effects of genistin or daidzin on rat prostate carcinogenesis were therefore investigated. Male F344 rats were given 10 biweekly subcutaneous injections of 3,2'-dimethyl-4-aminobiphenyl (DMAB) and then either genistin or daidzin in the diet at a concentration of 0.1% for 40 weeks. Other groups of rats given DMAB were treated with genistin or daidzin together with a high dose of testosterone propionate (TP). Both genistin and daidzin reduced the numbers of ventral prostate carcinomas (P<0.05), with a tendency for decrease in incidence. Invasive carcinomas which developed in the anterior prostate and seminal vesicles with TP were, however, not influenced by the two isoflavones. Thus, the present data suggest that genistin and daidzin possess anti-cancer effects at relatively early stages of prostate cancer development, providing experimental support for epide-miological findings.     

Rat prostate as one of the target organs for 3,2'-dimethyl-4-aminobiphenyl-induced carcinogenesis: effects of dietary ethinyl estradiol and methyltestosterone

Twenty consecutive weekly sc injections of 50 mg/kg body weight of 3,2'-dimethyl-4-aminobiphenyl (DMAB), a multipotential carcinogen, were given to male F344 rats and subsequently groups of animals were treated with dietary ethinyl estradiol (EE, 2.5 ppm) or methyltestosterone (MT, 300 ppm) for up to 40 weeks. Prostate carcinomas were found in 4 out of 32 rats given DMAB followed by MT and in 2 out of 29 rats given DMAB alone. Atypical hyperplasia of the prostate epithelium in these two groups was found in 22% and 14%, respectively. Neither carcinoma nor atypical hyperplasia was seen in the prostate of animals given DMAB followed by EE. In other organs, tumors were frequently found in the ear duct, skin, and large intestine and less frequently in the lung, preputial glands, small intestine and liver. EE significantly suppressed tumor incidence of the ear duct and sebaceous glands while increasing the incidence of liver tumor and mesothelioma. The present data indicates DMAB to be a useful carcinogen for the induction of prostate carcinomas in rats.     

Sequential Observation of Rat Prostate Lesion Development Induced by 3,2'-Dimethyl-4-aminobiphenyl and Testosterone

3,2'-Dimethyl-4-aminobiphenyl (DMAB), when combined with high doses of testosterone propionate (TP) induces invasive adenocarcinomas with metastatic potential in the rat prostate. The processes underlying this tumor development, including the involvement of atypical hyperplasias, were sequentially investigated in F344 rats. DMAB was given subcutaneously at a dose of 50 mg/kg body weight 10 times at 2-week intervals. TP was administered chronically (in Silastic tubes) from the beginning of the experiment or after the DMAB administration until termination (week 60). Invasive adenocarcinomas were induced in the lateral and anterior prostate as well as the seminal vesicles. Atypical hyperplasias appeared from an early stage, with the later appearance of cancers being closely associated with such foci of morphological alteration. The findings confirm that combined administration of DMAB and pharmacological doses of TP yields invasive adenocarcinomas in the rat prostate and provide further support for the conclusion that atypical hyperplasias are premalignant lesions.     

Induction of dorsolateral prostate adenocarcinomas and other accessory sex gland lesions in male Wistar rats by a single administration of N-methyl-N-nitrosourea, 7,12-dimethylbenz(a)anthracene, and 3,2'-dimethyl-4-aminobiphenyl after sequential treatment with cyproterone acetate and testosterone propionate

Groups of 20-25 male Wistar rats (Cpb:WU), nine groups of 4-week-old rats, and nine groups of 8-week-old rats, were given cyproterone acetate (CA) s.c. or by gavage daily for 18 days at a dose of 50 mg/kg/day. Directly following CA treatment, the rats received 3 daily s.c. injections with testosterone propionate (TP) at a dose of 100 mg/kg/day. On the day after the last TP administration, a single dose of one of the following carcinogens was given to 3 groups: N-methyl-N-nitrosourea (MNU), 50 mg/kg i.v.; 7,12-dimethylbenz(a)anthracene, 30 mg/kg i.v.; 3,2'-dimethyl-4-aminobiphenyl, 250 mg/kg s.c. Three other groups received the same carcinogen treatments after 7 days of recovery from the CA administration. The last 3 groups received carcinogen without TP treatment, but immediately after CA pretreatment was stopped. A 25% incidence of invasively growing, metastasizing adenocarcinomas was found in the dorsolateral prostate region of 8-week-old rats that had received MNU after treatment with CA plus TP. In addition, this group had a 5% incidence of carcinoma in situ and a 5% incidence of atypical hyperplasia in the dorsolateral prostate. Lower incidences of adenocarcinoma of the dorsolateral prostate region and of carcinoma in situ and atypical hyperplasia of the dorsolateral prostate were found in other groups that were treated with MNU or 7,12-dimethylbenz(a)anthracene after pretreatment with CA, followed by TP or recovery, but never in rats that had been treated with CA only. In the groups treated with 3,2'-dimethyl-4-aminobiphenyl, which is slowly metabolized, these lesions were also found in groups that were pretreated with only CA. The carcinomas seemed to originate from the dorsolateral prostate and their average latency time was approximately 61 weeks. The 8-week-old rat given a MNU injection after sequential treatment with CA and TP may provide a relevant animal model for human prostatic cancer.     

Enhancing Effect of Cadmium on Rat Ventral Prostate Carcinogenesis Induced by 3,2'-Dimethyl-4-aminobiphenyl

The effects of cadmium given at different stages during 3,2'-dimethyl-4-aminobiphenyl (DMAB)-induced rat prostate carcinogenesis were investigated using male F344 rats. Animals were given 10 subcutaneous injections of 50 mg/kg body weight of DMAB or the corn oil vehicle at two-week intervals. In addition, cadmium was administered at doses of 0, 10, or 30 /μmol/kg body weight as single intramuscular injection on the 1st day of the experiment or one day after the last injection of DMAB at week 20. Two further groups were subjected to administration of cadmium at 10 μmol/kg at week 20 and then 5 μmol/kg at week 40, or 10 μmol/kg at week 20 and then 5 μmol/kg at weeks 30, 40 and 50. At the termination, 60 weeks after the beginning of the experiment, the incidences and multiplicity of ventral prostate carcinomas in the groups given cadmium plus DMAB demonstrated a consistent tendency for increase over control values (groups receiving DMAB or cadmium alone). The numbers of carcinomas per rat and per unit area of prostate section were significantly elevated in the two groups given low doses of cadmium after cessation of DMAB administration. Cadmium alone also induced a few prostate carcinomas. The influence on development of prostate tumors did not appear to be a result of the induced severe testicular atrophy because serum testosterone levels were not affected. The results indicate that cadmium and DMAB can act synergistically to cause rat prostate carcinogenesis.     

Promoting action of prolactin released from a grafted transplantable pituitary tumor (MtT/F84) on rat prostate carcinogenesis

The potential modifying effects of high prolactinemia on rat prostate carcinogenesis was investigated. Male F344 rats were treated at 5 times of 5-week intervals with s.c. injections of 3,2'-dimethyl-4-aminobiphenyl (DMAB), each injection following 3 weeks pretreatment with dietary ethinyl estradiol. After completion of the carcinogen administration stage, rats received multiple s.c. transplantations of a prolactin producing transplantable pituitary tumor, MtT/F84 until sacrifice at week 51. The effects of additional or single treatment with bromocriptine, a prolactin suppressing agent, were also investigated. The body, liver and kidney but prostate weights were significantly increased in the groups given MtT/F84. Although the development of prostate carcinomas was not affected by the observed hyperprolactinemia, the incidences of atypical hyperplasia of both ventral and lateral prostate were significantly enhanced. The findings thus indicate that prolactin may have promoting potential for prostate carcinogenesis.     

Effects of a Soybean Isoflavone Mixture on Carcinogenesis in Prostate and Seminal Vesicles of F344 Rats

Several epidemiological studies have suggested an inverse association between the risk of prostate cancer and intake of soybeans and their products. In vitro data pointing to possible anti-carcinogenic properties of the soybean isoflavone, genistein, led us to investigate the chemopreventive potential of soybean isoflavones in a rat carcinogenesis model induced by 3,2'-dimethyl-4-aminobi-phenyl (DMAB) and testosterone propionate (TP). Animals received DMAB s.c. injections at 2-week intervals for the first 20 weeks and implanted silicon tubes containing 40 mg of TP, replaced at 6-week intervals throughout the experiment. The soybean isoflavone mixture consisting of 74% genistein and 21% daidzein was mixed in basal diet (AIN-76A) at concentrations of 100 and 400 ppm and fed to F344 male rats throughout the experiment. Rats treated with carcinogens and administered isoflavone mixture at 100 and 400 ppm developed adenocarcinomas at incidences of 35% and 29%, respectively, in the prostate and seminal vesicles, whereas the figure was 60% for those maintained on control diet. Feeding of the isoflavone mixture at 100 and 400 ppm significantly inhibited the number of argyrophilic nucleolar organizer regions (AgNORs) in adenocarcinomas of the accessory sex glands as compared to those of rats fed control diet. No influence on the development of neoplastic lesions originating in other organs was noted. The results of this study provide evidence that soybean isoflavones may have potential as chemopreventive agents against carcinogenesis in the prostate.     

Effects of a soybean isoflavone mixture on carcinogenesis in prostate and seminal vesicles of F344 rats.

Several epidemiological studies have suggested an inverse association between the risk of prostate cancer and intake of soybeans and their products. In vitro data pointing to possible anti-carcinogenic properties of the soybean isoflavone, genistein, led us to investigate the chemopreventive potential of soybean isoflavones in a rat carcinogenesis model induced by 3,2'-dimethyl-4-aminobiphenyl (DMAB) and testosterone propionate (TP). Animals received DMAB s.c. injections at 2-week intervals for the first 20 weeks and implanted silicon tubes containing 40 mg of TP, replaced at 6-week intervals throughout the experiment. The soybean isoflavone mixture consisting of 74% genistein and 21% daidzein was mixed in basal diet (AIN-76A) at concentrations of 100 and 400 ppm and fed to F344 male rats throughout the experiment. Rats treated with carcinogens and administered isoflavone mixture at 100 and 400 ppm developed adenocarcinomas at incidences of 35% and 29%, respectively, in the prostate and seminal vesicles, whereas the figure was 60% for those maintained on control diet. Feeding of the isoflavone mixture at 100 and 400 ppm significantly inhibited the number of argyrophilic nucleolar organizer regions (AgNORs) in adenocarcinomas of the accessory sex glands as compared to those of rats fed control diet. No influence on the development of neoplastic lesions originating in other organs was noted. The results of this study provide evidence that soybean isoflavones may have potential as chemopreventive agents against carcinogenesis in the prostate.     

Variation in tumor yield in the prostate and other target organs of the rat in response to varied dosage and duration of administration of 3,2'-dimethyl-4-aminobiphenyl

The effects of varying dosages of 3,2'-dimethyl-4-aminobiphenyl (DMAB) in combination with cyclic dietary administration of ethinyl estradiol (EE) on induction of prostate carcinoma were investigated in male F344 rats. Animals received repeated treatment with 0.75 ppm of EE for 3 wk with intervals of 2 wk on basal diet. The cycle was repeated 10, 5, and 3 times in Groups 1, 2, and 3, respectively, a single s.c. injection of DMAB being given 2 days after each change to basal diet at a dose of 50 mg/kg of body weight in Group 1, 100 mg/kg of body weight in Group 2, and 167 mg/kg of body weight in Group 3. With this dosing schedule, the total dose of DMAB (500 mg/kg of body weight) per rat was the same in each group. Subsequent to the last treatment with EE, all rats were given basal diet until the end of the experiment (Wk 60) when all surviving animals were sacrificed for histological examination. Carcinoma of the prostate was found in 58.6, 45.0, and 25.9% of rats surviving for 60 wk in Groups 1 to 3, respectively, the incidences of atypical hyperplasia being 86.2, 85.0, and 74.1%. However, tumors of the small and large intestines, preputial gland, and pancreas developed in a dosage-dependent manner, the largest incidences being found in the group given 167 mg of carcinogen 3 times. Thus the present experiment confirmed that administration of DMAB combined with cyclic treatment with EE induces a high incidence of prostate carcinoma in rats and demonstrated that a low dosage of DMAB given over a long period is superior to a high dosage over a short period for specific induction of prostate lesions.     

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. © 1995 Wiley-Liss, Inc.