Hormone-refractory prostate cancer in the Lobund-Wistar rat

Research on cancer prevention and therapy must focus on the refractory disease, the fatal end-stage of cancer that develops in patients with organ-related solid tumors. Refractory cancers develop spontaneously in advanced-stage tumors or in relapsed cases after failed therapy. Because neither prevention nor therapy is currently feasible, refractory cancer is a major impediment to survival. There is a great need for an animal model of prostate cancer (PC), one that develops cancer from initial premalignant to the terminal refractory stages. We describe here a model of hormone-refractory prostate cancer (HRPC) that develops spontaneously through two stages by endogenous mechanisms in the Lobund-Wistar (LW) rat. The early premalignant, testosterone (T)-dependent stage is promoted by high levels of endogenous T, and up to age 12 months is reversible by T deprivation; without this intervention, the tumorigenic process progresses to the refractory stage, which is highly aggressive and does not respond to T deprivation or to a wide range of therapies. Initial refractory tumors are palpable at approximately 18 months of age. As they continue to grow, the tumors express characteristics seen in refractory cancers in humans (i.e., hypoxia, expression of hypoxia-inducible factors, and metastasis). Chemically induced HRPCs in LW rats manifest the same two developmental stages, but with shorter latency periods. A transplantable, metastasizing cell line (PAIII) was derived from a germfree LW rat with advanced-stage cancer. Both spontaneous and chemically induced autochthonous HRPC model systems serve as outstanding models for studies on the prevention and therapy of refractory cancer.     

Soy of dietary source plays a preventive role against the pathogenesis of prostatitis in rats.

This study examined the effects of diet on the development of prostatitis in male rats. Adult male rats were placed on either of two specially formulated diets which differed from one another by the presence or absence of soy as the protein source. A third group of rats (control) was fed standard laboratory rat chow which also includes soy as a source of protein. After 11 weeks, it was found that rats maintained on soy-free diet developed prostatitis mainly in the lateral lobe of the prostate. Increased severity and incidence of prostatitis in rats maintained on the soy-free diet coincided with a significant decrease in urinary excretion of various phytoestrogens. There was no evidence of prostatitis in rats maintained on soy-containing diets. Urinary excretion of phytoestrogens in rats maintained on soy-containing diet was also not different from controls. These results suggest that soy as a dietary source plays a protective role against the development of prostatitis in rats, and indicate that the ventral, lateral and dorsal lobes of the rat prostate have different sensitivities to alterations in dietary factors.     

The soy effect in the disease models of nonbacterial prostatitis and obstructive voiding

The goal of this study was to improve the understanding of the potential significance of dietary soy for human health by investigating its effects in the animal models of nonbacterial prostatitis and urethral obstruction. Nonbacterial prostatitis was induced in adult Noble rats with the combined treatment of testosterone and 17beta-estradiol. The inflammatory foci categorized into three forms were counted and correlated with expression of an estrogen-responsive gene, progesterone receptor (PR), in the dorsolateral lobes of the rats on soy (+) and soy (-) diets. Development of obstructive voiding after neonatal estrogenization of Noble rats (NeoDES rats) was followed with urodynamic measurements in rats on soy (+) and soy (-) diets. The amounts of genistein and daidzein, two major soy-derived isoflavones, were measured in the urine of Noble rats by the high-performance liquid chromatography-photodiodearray method. Dietary soy decreased the total number of inflammatory foci while no demonstrable effects were seen on the cellular composition of the infiltrates. Soy did not increase the weights of the pituitary gland, testes, or sex accessory glands, but it did increase the number of PR-positive epithelial cells in the dorsolateral prostate. It also decreased the bladder pressures in NeoDES rats but did not increase the flow rates. The soy effects may be mediated by the strong estrogen influence involved in the animal models. Dietary soy had anti-inflammatory effects in the prostate but only marginal effects on the development of obstructive voiding in Noble rats. The anti-inflammatory effects of soy may contribute to the lower prevalence of prostatitis-like symptoms and the historically lower risk of benign prostatic hyperplasia in Japan; however, no evidence was found that regular consumption of soy influences the age-related development of lower urinary tract symptoms or decline of flow rate.     

Androgen receptor expression in primary prostate cancers of lobund-wistar rats and in tumor-derived cell lines

Summary Prostate tumors were induced in Lobund-Wistar rats by treatment with N-methyl-N-nitrosourea (MNU) and testosterone propionate (TP). Androgen receptor (AR) expression was confirmed in 16 (100%) of the primary prostate cancers, with strong uniform staining in well-differentiated tumors and more variable AR immunoreactivity in poorly differentiated tumors. Epithelial cell lines were established from nine of the tumors. At early passages, four of the tumor cell lines tested were strongly immunoreactive for AR; however, only two of the cell lines, E2(A) and F2, have remained AR-positive. These cell lines specifically bind ³H-DHT at 40 and 19 fmol/mg protein, respectively, and express a 110 kDa AR immunoreactive protein. Proliferation in in vitro culture of both E2(A) and F2 cells was increased in the presence of 5α-dihydrotestosterone (DHT). The antiandrogen, hydroxyflutamide was able to prevent the DHT-induced growth of E2(A) but not F2 cells. Furthermore, hydroxyflutamide alone increased proliferation of F2 cells, suggesting that the androgen signalling pathway in this cell line may be abnormal. Tumorigenicity of the AR-expressing and nonexpressing cell lines was confirmed by xenograft formation following subcutaneous inoculation into intact male nude mice. In summary, carcinogen-induced prostate tumors of Lobund-Wistar rats express AR and two of nine cell lines derived from the tumors express AR. Further evaluation of AR structure in primary prostate tumors forming spontaneously or following MNU and TP induction will determine whether, as in human prostate cancers, disease progression in Lobund-Wistar rats is associated with mutations in the AR gene.     

Dietary soy and tea mitigate chronic inflammation and prostate cancer via NFκB pathway in the Noble rat model

Chronic inflammation and nuclear factor-kappa B (NFκB) have been implicated in prostate cancer development; thus, dietary factors that inhibit NFκB may serve as effective chemo-preventative agents. Prostate cancer risk is significantly lower in Asian countries compared to the United States, which has prompted interest in the potential chemopreventative action of Asian dietary components such as soy and green tea. This study examined the effects of dietary soy and tea on NFκB activation and inflammation in vivo using a hormone-induced rat model for prostate cancer. Male Noble rats implanted with estradiol and testosterone were divided into 4 dietary groups: control, soy, tea, or soy+tea. NFκB activation and inflammatory cytokines were measured post implantation. The combination of soy and tea suppressed NFκB p50 binding activity and protein levels via induction of IκBα. Soy and tea also decreased prostate inflammatory infiltration, increased Bax/BcL2 ratio and decreased protein expression of tumor necrosis factor-alpha, interleukin (IL)-6 and IL-1β compared to control. Soy and tea attenuated prostate malignancy by decreasing prostate hyperplasia. These effects were not apparent in groups treated with soy or tea alone. The ongoing in vivo studies thus far suggest that combination of foods, such as soy and tea, may inhibit hormone-induced proinflammatory NFκB signals that contribute to prostate cancer development.     

Coexistence of different tissue tumourigenesis in an N-methyl-N-nitrosourea-induced mammary carcinoma model: a histopathological report in Sprague-Dawley rats

N-methyl-N-nitrosourea (MNU), a highly potent carginogen, is widely used to generate mammary tumours in murine species. In a model of MNU-induced mammary carcinogenesis using immature female Sprague-Dawley rats, large mammary tumours (largest dimension > or =0.5 cm) were obtained within a very short period of time. In addition, in the rats bearing MNU-induced mammary carcinomas, there were a number of tumours whose origins were not from mammary tissue but from several different tissues and from mammary non-epithelial tissue. The tumours were of mesenchymal or epithelial origin and they were located in the inguinal region. These tumours were diagnosed as fibroadenoma, combined tubular adenoma and fibroadenoma, hyperkeratotic papilloma, keratinous cyst and malignant peripheral nerve sheath tumour (MPNST) with smooth muscle differentiation. The occurrence of these other tumours in addition to the development of the mammary carcinomas may be attributed to a direct local effect of the intraperitoneal administration of MNU during the sexual development of the immature rats. In the MNU-induced mammary tumour model, coexistence of tumourigenesis in various non-mammary tissues should be considered an important factor that may interfere with experimental procedures and results and also the quality of life of the tumour-bearing animals.     

Soy based diet attenuates the development of hypertension when compared to casein based diet in spontaneously hypertensive rat

The purpose of this study was to compare the effects of soy and casein based diets on blood pressure and cardiovascular functions in male and female spontaneously hypertensive rats (SHR). The systolic blood pressure was measured at the beginning and at the end of study. After a five week supplementation period with three different diets, the rats were decapitated and arterial responses and the weight-to-body weight-ratios of the organs were studied. The development of hypertension was attenuated in both female and male rats on soy protein diet when compared to the casein diet. Soy based diet lowered serum total cholesterol level when compared to the control diet. Both casein and soy protein supplementation in diet induced a significant renal hypertrophy in both female and male SHR rats when compared to SHR rats on the control diet. Soy protein supplementation reduced significantly serum estradiol-17beta concentration when compared to the control diet. There were no differences in the serum testosterone concentrations between the diet groups. When compared to the casein based diet the soy based diet attenuated the development of hypertension and decreased serum total cholesterol level in SHRs. These effects were independent of gender. The mechanisms and clinical importance of these findings remain to be clarified.     

Zinc accumulation in N-methyl-N-nitrosourea-induced rat mammary tumors is accompanied by an altered expression of ZnT-1 and metallothionein

Zinc is essential for cell proliferation. Several human studies have shown that in breast cancer tissues, zinc concentration expressed on a per tissue weight basis is higher than that in normal breast tissues. However, the mechanisms involved are unknown. N-methyl-N-nitrosourea (MNU)-induced rat mammary tumorigenesis is one of the most widely used rodent mammary tumorigenesis models for studying human breast cancer due to their similarities in hormone dependency, pathogenesis, histological classification, and immunocytochemical markers. This study was to establish if there was an accumulation of zinc in MNU-induced rat mammary tumors and, if there was, to explore the possible mechanisms involved. Sprague-Dawley rats were sham-treated or MNU-treated (50 mg/kg; n = 12) for 100 days. In MNU-induced mammary tumors (mammary tumors), zinc concentration expressed on a per dry weight basis was 12 times of that in normal mammary glands. Moreover, the mRNA level of ZnT-1 (a transporter involved in zinc efflux) in mammary tumors was reduced by 55% as compared with that in normal mammary glands. The mRNA level of Nramp2 (a divalent cation importer) and ZnT-4 (another transporter involved in zinc efflux) was unaffected by MNU-induced mammary tumorigenesis. The mRNA and protein levels of metallothionein (a putative zinc storage protein) in mammary tumors were 1.3 and 3.5 times of that in normal mammary glands, respectively. Collectively, our observations showed that zinc is accumulated in MNU-induced rat mammary tumors and this accumulation is accompanied by an altered expression of ZnT-1 and metallothionein, suggesting that zinc homeostasis might be altered in MNU-induced rat mammary tumorigenesis. Because zinc is essential to cell proliferation and cell proliferation is increased in mammary tumors, zinc accumulation is likely a part of an integrated effort to ensure sufficient zinc supply to sustain tumor growth.     

Prevention of de novo prostate cancer by immunization with tumor-derived vaccines

Since advanced prostate cancer is difficult to treat, we have chosen a very different approach: the development of vaccines to prevent initial de novo tumor formation. To test the hypothesis that prostate cancer can be prevented by vaccination, Lobund–Wistar (LW) rats were vaccinated subcutaneously with complete Freunds adjuvant (CFA) plus glutaraldehyde-fixed (GFT) whole cell or potassium thiocyanate extract (PTE) preparations derived from in vivo tumors, or with media and CFA (media-vaccinated). Rats were vaccinated each month substituting incomplete Freunds adjuvant for CFA, from age 3 to 12 months, and methylnitrosourea (30 mg/kg) was administered intravenously at 4 months of age. Groups of 30 GFT cell–vaccinated rats showed a 90% reduction, and PTE-vaccinated rats, a 50% reduction in the occurrence of de novo prostate tumors compared with media-vaccinated controls. When splenocytes from vaccinated rats were incubated with tumor cells prior to subcutaneous implantation, PTE-vaccinated rats showed a 80% reduction, and GFT cell–vaccinated rats showed a 40% reduction in the occurrence of tumors, demonstrating a role for the spleen in the protective response. The inflammatory responses in tumors from GFT cell–vaccinated rats and PTE-vaccinated rats were distinguished by an influx of eosinophils compared with the responses in tumors from media-vaccinated rats. These results demonstrate the possibility that prostate cancer can be prevented by immunization with vaccines based on whole tumor–derived vaccines.     

Effect of dietary zinc intake on N-methyl-N-nitrosourea-induced mammary tumorigenesis in rats

Numerous studies have shown that zinc nutrition influences the growth of several types of tumor. However, the influence of zinc nutrition on mammary tumorigenesis is not known. To study the effects of dietary zinc intake on N-methyl-N-nitrosourea (MNU)-induced mammary tumorigenesis, female Sprague-Dawley rats were fed an egg-white-based diet providing 3 (Z3), 12 (Z12), or 31 (Z31) mg zinc/kg diet ad libitum. In addition, two pair-fed controls, PFZ12 and PFZ31, were also included. Fourteen weeks after MNU injection, cumulative tumor incidence and total number of tumors were lower in Z3 rats than in Z12 and Z31 rats. Cumulative tumor incidence and total number of tumors were lower in Z3 rats than in PFZ12 rats, but were the same as in PFZ31 rats. Cumulative tumor incidence and total number of tumors were also lower in pair-fed controls than in their corresponding ad libitum controls, but were the same between the ad libitum controls. Overall, the results showed that the effect of marginal zinc deficiency on MNU-induced mammary tumorigenesis in rats was primarily the result of a reduced feed intake associated with marginal zinc deficiency rather than zinc per se.     

Reduction of paraquat-induced oxidative stress in rats by dietary soy peptide

The effect of a dietary soy protein isolate (SPI), soy peptide (PEP) and the amino acids in soy protein on paraquat (PQ)-induced oxidative stress was investigated in rats. In the first experiment, male Wistar rats were fed on experimental diets containing casein (CAS), SPI and PEP as nitrogen sources with or without 0.025% PQ. The reduced food intake and body weight gain of the rats fed with PQ was mitigated by either the SPI or PEP intake. Both SPI and PEP prevented the elevation of the serum TBARS concentration and tended to prevent the elevation of lung weight induced by PQ. In the second experiment, the rats were fed on diets containing an amino acid mixture resembling casein (CASAA) or soy protein (SPIAA) with or without PQ. The SPIAA intake did not affect the reduction of food intake and body weight gain, nor the elevation of lung weight and TBARS in the serum and liver induced by PQ. These results demonstrate that the intake of either dietary SPI or PEP, but not an amino acid mixture resembling soy protein, had the effect of reducing PQ-induced oxidative stress in rats.     

Effects of astaxanthin supplementation on chemically induced tumorigenesis in Wistar rats

ABSTRACT: BACKGROUND: Astaxanthin (ASTA) is a fat-soluble xanthophyll with powerful antioxidant functions. It is extracted from e.g. salmon, an important food source for certain human populations known to have a reduced risk of tumor development. It is possible that ASTA plays a role in cancer chemoprevention in such populations. The purpose of this study was to investigate the effects of dietary ASTA on chemically induced mammary tumorigenesis using N-methyl-N-nitroso-urea (MNU) in immature Wistar rats. METHODS: Thirty-six 37 days old juvenile female Wistar rats were at random allocated to 4 groups of which Groups 1 and 2 received a single dose of 55 mg MNU/kg body weight. The effects of ASTA was evaluated by giving rats of Groups 2 and 4 a dose of 50 mg ASTA/kg/day for the entire duration of the study. Group 3 rats received feed added alimentary oil.Necropsy and histopathological examinations were carried out on each rat 14 months after the administration of MNU. Haematological values and antioxidative status were determined. Oxidative stress was evaluated by monitoring superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities in hepatic tissue. Lipid peroxidation and carbonylation of proteins was determined in protein extracts from the liver. RESULTS: Tumor development occurred only in rats of Groups 1 and 2, i.e. MNU exposed animals. Frequency of tumor development in general and average number of tumors per animal were insignificant between these two groups. Mammary gland tumors developed in equal frequencies in Group 1 and 2 rats, respectively. Although only rather few tumors were found in the mammary glands, a substantial number of other tumors were found in Group 1 and 2 rats, but at equal rates.Biochemical analyses showed significant higher levels of GPx, malondialdehyde and dinitrophenylhydrazine in Group 1 rats that for rats in all other groups thus indicating protective effects of ASTA on MNU induced hepatic oxidative stress. CONCLUSIONS: Supplementation with ASTA did not reduce tumorigenesis induced by MNU in Wistar rats. However, supplementation with ASTA seemed to have anti-inflammatory effects.     

Innovative therapies for prostate cancer treatment

Androgen ablation is effective therapy for metastatic prostate cancer, but the majority of men eventually become refractory to this intervention. Cytotoxic chemotherapy offers palliation to symptomatic patients with hormone-refractory prostate cancer (HRPC); however, no chemotherapy regimen has yet been shown to prolong survival. There is a clear need for new agents and drug targets for the treatment of HRPC. A number of innovative therapeutic approaches that are rationally based and target driven are under investigation. This article reviews the development of antisense oligonucleotides that inhibit the anti-apoptotic bcL-2 protein. Approaches that target the epidermal growth factor receptor, the platelet derived growth factor receptor, and nuclear factor kappa-B are also discussed. There is much expectation that these therapies alone or in combination with cytotoxic chemotherapy will impact the clinical outcome of patients with HRPC.     

Phytosterol feeding induces alteration in testosterone metabolism in rat tissues

The objective of the present study was to examine the metabolism of testosterone in rat tissues as influenced by dietary phytosterols. Testosterone metabolism includes reductions to more active metabolites or aromatization to estrogen. Both higher levels of androgens and estrogens are implicated as risk factors in the development of prostate cancer. Tissues studied included liver, testis, and prostate. Feeding 2% phytosterols with 0.2% cholic acid to rats for 22 days resulted in a 33% reduction in serum testosterone compared with controls, which received only 0.2% cholic acid in the diet. 5-α-Reductase was reduced by 41 to 44% and 33% in the liver and prostate, respectively. No effect of phytosterols was observed in the testis. Only aromatase activity of the prostate was reduced by 55% upon feeding phytosterols. It was concluded that dietary phytosterols may reduce the risk of prostate cancer by lowering the activities of the enzymes of testosterone metabolism.     

Increased aggressive behavior and decreased affiliative behavior in adult male monkeys after long-term consumption of diets rich in soy protein and isoflavones

Estrogen produced by aromatization of gonadal androgen has an important facilitative role in male-typical aggressive behavior that is mediated through its interaction with estrogen receptors (ER) in the brain. Isoflavones found in soybeans and soy-based dietary supplements bind ER and have dose- and tissue-dependent effects on estrogen-mediated responses. Yet, effects of isoflavone-rich diets on social and aggressive behavior have not been studied. We studied the effects of long-term (15 months) consumption of diets rich in soy isoflavones on spontaneous social behavior among adult male cynomolgus macaques (Macaca fascicularis) (n = 44) living in nine stable social groups. There were three experimental conditions which differed only by the source of dietary protein: casein and lactalbumin (no isoflavones), soy protein isolate containing 0.94 mg isoflavones/g protein, and soy protein isolate containing 1.88 mg isoflavones/g protein. In the monkeys fed the higher amount of isoflavones, frequencies of intense aggressive (67% higher) and submissive (203% higher) behavior were elevated relative to monkeys fed the control diet (P's < 0.05). In addition, the proportion of time spent by these monkeys in physical contact with other monkeys was reduced by 68%, time spent in proximity to other monkeys was reduced 50%, and time spent alone was increased 30% (P's < 0.02). There were no effects of treatment on serum testosterone or estradiol concentrations or the response of plasma testosterone to exogenous gonadotropin-releasing hormone (GnRH). The results indicate that long-term consumption of a diet rich in soy isoflavones can have marked influences on patterns of aggressive and social behavior.     

Etiology of MNU-induced melanomas in Xiphophorus hybrids

Genetic hybrids of the genus Xiphophorus have historically been useful models for study of the genetic aspects of tumor formation. In the most studied Xiphophorus tumor model, two-gene loci, XMRK and DIFF, are implicated as critical both to UV-induced and spontaneous melanoma formation in BC(1) hybrids of crosses between X. maculatus and X. helleri, with X. helleri as the recurrent backcross parent. In addition to UV, the direct-acting carcinogen N-methyl-N-nitrosourea (MNU) has been used to induce tumors in Xiphophorus BC(1) hybrids from several cross types. In the present study, we address the hypothesis that excess melanomas in MNU-treated BC(1) hybrids may have been generated by direct mutation of CDKN2AB, a candidate gene for DIFF. MNU treatment of F(1) and BC(1) hybrid fish significantly increased tumor incidence at 6 months; however, no association was found between MNU-induced tumor formation and zygosity of the candidate tumor tumor-suppressor CDKN2AB in BC(1) hybrids, consistent with previously reported results. Sequence analysis of the X. maculatus CDKN2AB locus of heterozygous individuals (both BC(1) and F(1) hybrids) did not reveal any mutations caused by MNU, suggesting that the mechanism of MNU-induced melanoma formation in this Xiphophorus model does not involve direct mutation of CDKN2AB but may result from mutation of other critical genes.     

Influence of murine leukemia proviral integrations on development of N-methyl-N-nitrosourea-induced thymic lymphomas in AKR mice.

The AKR mouse strain is characterized by a high incidence of spontaneous thymic lymphoma that appears in older animals (greater than 6 months of age) and is associated with novel provirus integrations of ecotropic and recombinant murine leukemia viruses (MuLVs). Treatment of 4- to 6-week-old AKR/J mice with the carcinogen N-methyl-N-nitrosourea (MNU) results in thymic lymphomas that arise as early as 3 to 4 months of age and contain novel somatically acquired MuLV provirus integrations. The AKR/J strain develops MNU-induced lymphoma with a higher incidence and shorter latency than has been observed for other inbred mouse strains. To determine whether provirus integrations of endogenous MuLV account for the enhanced susceptibility of the AKR strain, the incidence and latency of MNU-induced lymphoma development was compared in AKR/J and AKR.Fv-1b mice. The restrictive b allele of the Fv-1 locus restricts integration and replication of endogenous N-tropic MuLV; therefore, AKR-Fv-1b mice have a very low incidence of spontaneous lymphoma. In contrast, AKR.Fv-1b mice develop MNU-induced lymphomas with an incidence and latency similar to those of the AKR/J strain. Furthermore, thymic lymphomas from both strains express an immature CD4-8+ phenotype, indicating neoplastic transformation of the same thymocyte subset. Southern blot analysis confirmed that lymphoma DNA from AKR.Fv-1b mice did not contain somatically acquired provirus integrations. These results demonstrate that provirus integration does not contribute to the predisposition of AKR mice to develop a high incidence of early MNU-induced lymphomas. Nevertheless, MNU treatment stimulated high-level expression of infectious ecotropic MuLV in AKR.Fv-1b as well as in AKR/J mice, suggesting that viral gene products might enhance lymphoma progression.     

Anticancer effects of a plant lignan 7-hydroxymatairesinol on a prostate cancer model in vivo

Clinical intervention studies and experimental studies with lignan-rich diets suggest that lignans may have inhibitory effects on prostate cancer, but no clinical or experimental studies with purified lignans have been published. The purpose of this study was to investigate the effect of a plant lignan 7-hydroxymatairesinol (HMR) on LNCaP human prostate cancer xenografts in athymic mice. Athymic nude male mice were injected subcutaneously with LNCaP cells. Starting 3 days after tumor cell injections, a control diet or a control diet supplemented with 0.15% or 0.30% of HMR was administered to mice and the tumor take rate and growth was observed for 9 weeks. HMR diet inhibited the growth of LNCaP tumors. Mice treated with HMR had smaller tumor volume, lower tumor take rate, increased proportion of nongrowing tumors, and higher tumor cell apoptotic index compared with controls. Furthermore, the cell proliferation index was reduced in mice receiving the 0.30% HMR diet compared with mice receiving the control diet. Our results suggest that dietary HMR started at the early phase of the tumor development inhibits the growth of the LNCaP human prostate cancer xenografts in athymic male mice.     

Dietary gamma-linolenate attenuates tumor growth in a rodent model of prostatic adenocarcinoma via suppression of elevated generation of PGE(2) and 5S-HETE

Prostate cancer poses considerable threat to the aging male population as it has become a leading cause of cancer death to this group. Due to the complexity of this age-related disease, the mechanism(s) and factors resulting in prostate cancer remain unclear. Reports showing an increase risk in prostatic cancer with increasing dietary fat are contrasted by other studies suggesting the beneficial effects of certain polyunsaturated fatty acid (PUFA) in the modulation of tumor development. The n-6 PUFA, gamma-linolenic acid (GLA), has been shown to suppress tumor growth in vitro. Therefore, using the Lobund-Wistar (L-W) rat model of prostate cancer, we tested the hypothesis whether dietary supplementation of GLA could suppress tumor growth and development in vivo. Prostatic adenocarcinomas were induced in two groups of L-W rats, the experimental group (N-nitroso-N-methylurea, NMU/testosterone propionate, TP) and the GLA group (NMU/TP/GLA fed) undergoing similar treatment but fed a purified diet supplemented with GLA. Our findings revealed a decrease in prostate growth in the NMU/TP/GLA-fed group as determined by weight, tissue size, DNA content and prostate-specific antigen (tumor marker of prostate cancer). Comparison between the two groups showed a significant increase in 5S-hydroxyeicosatetraenoic acid and prostaglandin E(2) in the NMU/TP group. These increases paralleled the increased protein expression and activity of cyclooxygenase-2 as well as increased activity of 5-lipoxygenase. Taken together, the findings showed that intake of GLA-enriched diet does reduce prostatic cancer development in L-W rats and could serve as a non-toxic adjunct in management of human prostatic cancer.     

Proinflammatory gene expression and renal lipogenesis are modulated by dietary protein content in obese Zucker fa/fa rats

Obesity is a risk factor for the development of chronic kidney disease (CKD) and end-stage renal disease. It is not clear whether the adoption of a high-protein diet in obese patients affects renal lipid metabolism or kidney function. Thus the aims of this study were to assess in obese Zuckerfa/fa rats the effects of different types and amounts of dietary protein on the expression of lipogenic and inflammatory genes, as well as renal lipid concentration and biochemical parameters of kidney function. Rats were fed different concentrations of soy protein or casein (20, 30, 45%) for 2 mo. Independent of the type of protein ingested, higher dietary protein intake led to higher serum triglycerides (TG) than rats fed adequate concentrations of protein. Additionally, the soy protein diet significantly increased serum TG compared with the casein diet. However, rats fed soy protein had significantly decreased serum cholesterol concentrations compared with those fed a casein diet. No significant differences in renal TG and cholesterol concentrations were observed between rats fed with either protein diets. Renal expression of sterol-regulatory element binding protein 2 (SREBP-2) and its target gene HMG-CoA reductase was significantly increased as the concentration of dietary protein increased. The highest protein diets were associated with greater expression of proinflammatory cytokines in the kidney, independent of the type of dietary protein. These results indicate that high soy or casein protein diets upregulate the expression of lipogenic and proinflammatory genes in the kidney.