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.     

Lesions of the prostate glands and seminal vesicles induced by N-methylnitrosourea in F344 rats pretreated with ethinyl estradiol

In an attempt to induce a high incidence of prostate carcinoma, N-methylnitrosourea (MNU), a multipotential carcinogen, was given during the period of cell proliferation of the prostate gland induced by administration of methyltestosterone (MT) to F344 rats pretreated with ethinyl estradiol (EE). Rats were given diet containing EE for 3 weeks and then diet containing 300 ppm of MT for 5 days. On the 3rd day of MT-treatment, they were given a single intravenous injection of 50 mg/kg body wt. of MNU. Control rats (group 4) were given vehicle only. After treatment with MT for 5 days, the rats were given basal diet (group 1), diet containing MT (group 2) or diet periodically containing EE (groups 3 and 4) until the end of the experiment (week 60). Carcinoma of the prostate was found only in 1 of 17 rats in group 3. Atypical hyperplasia of the prostate was found in 1 of 10 rats in group 1 and 3 of 17 rats in group 2. The incidences of atypical hyperplasia of the seminal vesicles in groups 1-3 were 0%, 41% and 29%, respectively. No tumor promoting effect of MT or EE was observed except promotion by MT on the development of atypical hyperplasia of the seminal vesicles.     

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.     

Induction of invasive carcinomas in the accessory sex organs other than the ventral prostate of rats given 3,2'-dimethyl-4-aminobiphenyl and testosterone propionate

The promotion effects of testosterone propionate (TP) on prostate carcinogenesis were investigated in F344 rats given the prostatic carcinogen, 3,2'-dimethyl-4-aminobiphenyl (DMAB). One group of animals received s.c. DMAB injections at a dose of 50 mg/kg body weight at 2-week intervals for a total of 10 injections along with s.c. implantations of TP-containing Silastic tubes. A second experimental group of rats was given DMAB at the same dose and intervals but each injection of DMAB was combined with 3 prior consecutive daily 100-mg/kg body weight s.c. injections of TP. After cessation of carcinogen administration, animals in these two groups received TP implants from week 21 to the end of the experiment. All surviving animals were killed at week 56 and accessory sex gland tumor incidences were compared to those in DMAB alone and other appropriate control groups. The groups given TP plus DMAB and subsequent long term administration of TP developed lesions of the dorsolateral prostate, seminal vesicles, and coagulating glands which were all invasive adenocarcinomas. Incidences were 84.2% (16 of 19 rats) and 66.7% (12 of 18 rats), respectively. Macroscopic large tumors were induced in 13 animals among which 8 demonstrated metastasis to the abdominal cavity, liver, or lung. None of the control groups except for the group given TP injections plus DMAB had equivalent tumors. Development of carcinomas of the ventral prostate, which were all of in situ type, were not increased by subsequent treatment with TP. These data thus clearly showed that TP can exert strong enhancing effects on tumor development in the dorsolateral prostate, seminal vesicles, and coagulating glands but not in the ventral prostate.     

Trial to Induce Prostatic Cancer in ACI/Seg Rats Treated with a Combination of 3,2'-Dimethyl-4-aminobiphenyl and Ethinyl Estradiol

In an attempt to induce prostatic adenocarcinoma at higher incidence in a shorter period, we administered diet containing 0.75 ppm of ethinyl estradiol (EE) for three weeks to ACI/Seg rats, which are predisposed to develop a high incidence of microscopic adenocarcinoma of the prostate at higher age. Then, feeding was changed to basal diet and a single subcutaneous injection of 50 mg/kg body weight of 3,2'-dimethyl-4-aminobiphenyl (DMAB) was given two days after the change. We repeated this schedule 10 times. The rats were killed in week 60 of the experiment and subjected to routine autopsy. The average body weight of rats in group 1 given EE and DMAB was lower than that of control rats in group 2. The incidence of adenocarcinoma was not significantly different in the two groups, i.e. 6/74 (8.1%) in group 1 and 2/54 (3.7%) in group 2. The lesions were all microscopic. The incidence of atypical hyperplasia was significantly higher in group 1 at 17 of 74 rats (23.0%) whereas in group 2, it was only 2 of 54 rats (3.7%). Simple hyperplasia was also observed in 25 of 74 rats (33.8%) in group 1, which was significantly higher than that in group 2, where six of 54 rats (11.1%) had this lesion. The reduced growth of animals due to treatments with EE and DMAB probably suppressed the development of prostate cancer in this experiment. Further studies are needed to develop an appropriate model to induce prostate carcinoma at higher incidence in a shorter period.     

Trial to induce prostatic cancer in ACI/Seg rats treated with a combination of 3,2'-dimethyl-4-aminobiphenyl and ethinyl estradiol.

In an attempt to induce prostatic adenocarcinoma at higher incidence in a shorter period, we administered diet containing 0.75 ppm of ethinyl estradiol (EE) for three weeks to ACI/Seg rats, which are predisposed to develop a high incidence of microscopic adenocarcinoma of the prostate at higher age. Then, feeding was changed to basal diet and a single subcutaneous injection of 50 mg/kg body weight of 3,2'-dimethyl-4-aminobiphenyl (DMAB) was given two days after the change. We repeated this schedule 10 times. The rats were killed in week 60 of the experiment and subjected to routine autopsy. The average body weight of rats in group 1 given EE and DMAB was lower than that of control rats in group 2. The incidence of adenocarcinoma was not significantly different in the two groups, i.e., 6/74 (8.1%) in group 1 and 2/54 (3.7%) in group 2. The lesions were all microscopic. The incidence of atypical hyperplasia was significantly higher in group 1 at 17 of 74 rats (23.0%) whereas in group 2, it was only 2 of 54 rats (3.7%). Simple hyperplasia was also observed in 25 of 74 rats (33.8%) in group 1, which was significantly higher than that in group 2, where six of 54 rats (11.1%) had this lesion. The reduced growth of animals due to treatments with EE and DMAB probably suppressed the development of prostate cancer in this experiment. Further studies are needed to develop an appropriate model to induce prostate carcinoma at higher incidence in a shorter period.     

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.     

Selective induction of rat urinary bladder tumors by simultaneous administration of 3,2'-dimethyl-4-aminobiphenyl (DMAB) and butylated hydroxyanisole or butylated hydroxytoluene is associated with increased DMAB-DNA adduct formation

Modification of 3,2'-dimethyl-4-aminobiphenyl (DMAB) multi-organ carcinogenesis by simultaneous treatment with butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT) was studied using young and old male F344 rats. Animals, 4 or 54 weeks old, were given DMAB (s.c. injection of 50 mg/kg body wt once a week for 10 weeks) along with BHA (2.0% in diet for 11 weeks) or BHT (1.0% in diet for 11 weeks). The experiments were terminated 55 weeks after the commencement. Combined administration of BHA or BHT with the carcinogen resulted in development of urinary bladder tumors in greater than 90% of both young and old rats thus treated, whereas no tumors were induced in animals given DMAB alone. In contrast, the appearance of preneoplastic lesions in the liver and pancreas was reduced by BHA or BHT treatment. Tumor development (less than 30% incidence) was also evident in the small and large intestines, prostate, preputial glands, skin/subcutis and ear duct, with no modification by BHA or BHT. No ageing effects were evident. The formations of DMAB-DNA adducts, evaluated by the enzyme-linked immunosorbent assay and immunohistochemical staining, correlated well with tumorigenesis in the urinary bladder, liver and pancreas. The selective enhancement of urinary bladder tumor induction by BHA and BHT appeared to be due to both increased DMAB-DNA adduct formation caused by metabolic alteration of DMAB in the liver and increased DNA synthesis in the urothelial cells.     

The effect of disulfiram on the carcinogenicity of 3,2' dimethyl-4-aminobiphenyl in Syrian golden hamsters and rats

3,2' -Dimethyl-4-aminobiphenyl (DMAB) was administered s.c.to Syrian golden hamsters and CDF rats with and without disulfiramin the diet. In a group of male hamsters given only weekly injectionsof DMAB over a period of 18–22 months, 10 of 25 hamstersdeveloped adenocarcinomas of the small or large intestine. Threehad carcinomas in both the large and small intestine, 3 hadonly colon carcinomas and 4 only small intestinal carcinomas.In the group fed disulfiram and carcinogen, 10 of 25 hamstersdeveloped adenocarcinomas of the colon, but only one carcinomaof the small intestine occurred. Furthermore, the appearanceof intestinal tumors was delayed. Urinary bladder carcinomasoccurred in both groups exposed to DMAB, with the appearancebeing slightly delayed in the group also receiving disulfiram.In male rats given DMAB s.c. once a week for 10 months, theaddition of disulfiram in the diet reduced the incidence ofcancers of the small intestine, similar to the effects in hamsters,but resulted in the occurrence of a small number of bladdercancers. An unusual occurrence was the development of prostaticcarcinoma in rats given DMAB.     

Different carcinogenic responses in a variety of organs, including the prostate, of five different rat strains given 3,2'-dimethyl-4-aminobiphenyl

Tumorigemc response in the prostate of F344, ACI, Lewis, CDand Wistar rat strains to 3,2'-dimethyl-4-amtnobiphenyl (DMAB)was examined in relation to development of other types of tumors.Rats of each strain aged 6 weeks were divided into two groupsreceiving DMAB S.C. at a dose of 50 mg/kg body wt once everyother week for 10 times, with or without 1 week dietary ethynylestradiol (EE) pretreatment. The experiment was terminated atweek 60, carcinomas of the ventral prostate, all of microscopicsize, being respectively found in 50, 17, 21, 15 and 0% of F344,ACI, Lewis, CD and Wistar strain animals treated with EE plusDMAB. The tumor yield correlated well with DMAB–DNA adductfor mation. One invasive adenocarcinoma also developed in theperlurethral part (occupying both of lateral and dorsal areas)of the prostate. The final survival rates were 46, 24, 65, 4and 0% in F344, ACI, Lewis, CD and Wistar rats respec tively.DMAB administration without EE pretreatment resulted in similarincidences of prostate tumors and mor talities. Tumors arosein >14 dIfferent sites with strain dependency, lesions predominatingin the skin/subcutis of ACI and F344, preputial gland of F344,urinary bladder of ACI, and mammary glands of CD rats respectively.Consideration of mortality and the relative incidence of prostatecancer and other types of tumors indicates the F344 rat strainto be the most appropriate for investigation of DMAB prostatecarcinogenesis.     

Effect of intestinal microflora on 2,2'-dimethyl-4-aminobiphenyl-induced carcinogenesis in F344 rats.

The effect of intestinal microflora on colon and breast carcinogenesis induced by 3,2'-dimethyl-4-aminobiphenyl (DMAB) was studied with the use of germfree and conventional F344 rats of both sexes. At 7 weeks of age, all animals except controls were given 20 weekly sc injections of DMAB in corn oil (100 mg/kg body wt/wk). Male animals were autopsied 15 weeks after the last injection, whereas female animals were autopsied 10 weeks after the last injection. Tumors were induced in the colons, duodena, breasts, ear ducts, salivary glands, and skin of conventional rats, and in the colons, breasts, ear ducts, salivary glands, and skin of germfree rats. No consistent difference was found in the incidence of tumors in the ear ducts, salivary glands, and skin between the germfree and conventional rats. None of the germfree rats showed duodenal tumors, whereas 13% of the female and 53% of the male conventional rats developed duodenal tumors. The incidence of intestinal tumors was lower in the germfree rats than in conventional animals. The mammary tumor incidence was lower in germfree female rats than in the conventional female rats than in the conventional females. DMAB induced fewer intestinal and breast tumors in germfree rats than in conventional rats.     

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.     

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.     

Rapid hepatoma induction in rats by dipentylnitrosamine and its modification by other carcinogens

Dipentylnitrosamine (DPN), administered in the diet at a concentration of 2,000 ppm to Fischer-344 rats, produced hepatomas in 27% of both males and females within 8 weeks. Bile-duct carcinomas were also produced. All animals also showed liver nodular hyperplasia and bile-duct cell proliferation. Feeding DPN at 1,500 ppm produced hepatomas or bile-duct carcinomas in 7% of the males and varying degrees of nodular hyperplasia and duct cell proliferation after 8 weeks of feeding. The total cumulative dose after feeding 2,000 ppm DPN was of the order of 7,700 mg/kg body weight in males and 8,200 mg/kg in females. There was a 28% weight decrement in animals fed 2,000 ppm DPN when compared to controls but no mortality. DPN carcinogenicity was enhanced when DPN was combined with a liver carcinogen, cycasin (fed as cycad nut flour, equivalent to 160 ppm cycasin). No effect on DPN carcinogenicity was found in rats fed DPN and lasiocarpine, another known liver carcinogen with antimitotic activity. Neither was there any effect on DPN carcinogenicity in rats fed DPN and N-butyl-N-(4-hydroxybutyl) nitrosamine or N-methyl-N′-nitro-N-nitrosoguanidine. In contrast, the trisodium salt of nitrilotriacetic acid reduced the hepatocarcinogenic action of DPN. The enhancement of DPN carcinogenicity with cycasin is compatible with the hypothesis that DPN-induced liver cell populations (hyperplastic nodules) can resist the cytotoxic effect of cycasin and differentiate rapidly toward hepatomas, while other areas of the liver are suppressed.     

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.     

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 age on multiple organ carcinogenesis induced by 3,2'-dimethyl-4-aminobiphenyl in rats, with particular reference to the prostate

The effects of age on multi-organ carcinogenesis induced by 3,2'-dimethyl-4-aminobiphenyl (DMAB) in male F344 rats were examined. Groups of 5-, 35-, and 65-week-old animals were given 4 weekly sc injections of DMAB at a dose of 200 or 150 mg/kg body weight. Prostate carcinomas were induced in 8 to 19% of rats treated, no significant differences in the incidence between different ages being observed. Tumors in the small intestine, skin, pancreas and peritoneum, however, developed more frequently in young than in old animals, whereas higher incidences of testis, preputial and mammary gland lesions were found in the 35- and/or 65-week-old groups. Colon and Zymbal gland carcinogenesis did not reveal any age dependence.     

Effects of Age on Multiple Organ Carcinogenesis Induced by 3,2'-Dimethyl-4-aminobiphenyl in Rats, with Particular Reference to the Prostate

The effects of age on multi-organ carcinogenesis induced by 3,2'-dimethyl-4-aminobiphenyl (DMAB) in male F344 rats were examined. Groups of 5-, 35-, and 65-week-old animals were given 4 weekly sc injections of DMAB at a dose of 200 or 150 mgAg body weight. Prostate carcinomas were induced in 8 to 19% of rats treated, no significant differences in the incidence between different ages being observed. Tumors in the small intestine, skin, pancreas and peritoneum, however, developed more frequently in young than in old animals, whereas higher incidences of testis, preputial and mammary gland lesions were found in the 35- and/or 65-week-old groups. Colon and Zymbal gland carcinogenesis did not reveal any age dependence.     

Lack of modifying effects of 4-ter t-octylphenol and benzyl butyl phthalate on 3,2-dimethyl-4-aminobiphenyl-induced prostate carcinogenesis in rats

The modifying effects of dietary feeding of two estrogenic compounds, 4-tert-octylphenol (tOP) and benzyl butyl phthalate (BBP), on 3,2-dimethyl-4-aminobiphenol (DMAB)-induced prostatic carcinogenesis were investigated in male F344 rats. We also assessed the effects of the test compounds on the proliferating cell nuclear antigen (PCNA) index in induced neoplasms, prostatic intra-epithelial neoplasm (PIN), and non-lesional glands in the prostate. To induce prostatic neoplasms, rats were given subcutaneous injections of DMAB (25 mg/kg body weight) every other week, 10 times in total. They also received the experimental diet containing 10 or 100 ppm tOP and BBP for 40 weeks, starting 1 week after the last dosing of DMAB. DMAB exposure produced prostatic adenocarcinoma with an incidence of 41.2% at the end of the study (week 60). Dietary administration of tOP and BBP did not affect the incidence of prostatic adenocarcinoma: 43.8% in the DMAB --> 10 ppm tOP group; 25.0% in the DMAB --> 100 ppm tOP group; 43.8% in the DMAB --> 10 ppm BBP group; and 43.8% in the DMAB --> 100 ppm BBP group. The PCNA indices in adenocarcinomas, PIN, and non-lesional glands in rats treated with DMAB and tOP or BBP were slightly lower than that of the DMAB alone group, but the differences were not statistically significant. These results might suggest that dietary feeding of the estrogenic compounds tOP and BBP did not modulate DMAB-induced prostatic carcinogenesis in rats.     

Lack of modification by naturally occurring antioxidants of 3,2'-dimethyl-4-aminobiphenyl-initiated rat prostate carcinogenesis

The modifying effects of 6 naturally occurring antioxidants on 3,2'-dimethyl-4-aminobiphenyl (DMAB)-initiated rat prostate carcinogenesis were investigated in male F344 rats. Animals were pretreated with DMAB in a 20-week initiation protocol and then administered basal diet containing 0.8% catechol, 0.8% resorcinol, 0.8% hydroquinone, 2 ppm selenium, 2% gamma-orysanol or 1% alpha-tocopherol for 40 weeks. The experiment was terminated at week 60 for histopathological assessment of lesion development. Atypical hyperplasias and carcinomas of the prostate were observed in the ventral lobe in all groups treated with DMAB. However, the incidences of these lesions were not significantly different between carcinogen control and antioxidant-treated groups. There were also no significant increases or decreases in the incidences of tumors in any other organs.