Cytochrome P450 induction in feral Cricetid rodents: a review of field and laboratory investigations.

The constitutive and inducible hepatic cytochromes P450 of various feral Cricetid rodents (family Cricetidae, comprising various New World rats and mice, hamsters, gerbils and voles), have been examined in a relatively limited number of field and laboratory investigations. These studies, reviewed herein, have employed substrates and immunochemical reagents that are diagnostic for individual P450 subfamilies of Rattus norvegicus (the common laboratory species derived from the Norway rat, a member of the family Muridae). The results have demonstrated that the feral rodents display hepatic responses to prototypic CYP1A inducers (3-methylcholanthrene, beta-naphthoflavone) similar to those displayed by R.

Effect of reduced body weight gain on the evaluation of chemopreventive agents in the methylnitrosourea-induced mammary cancer model.

These studies examined whether the small to moderate reductions in body weight gain (< or = 15%) affect mammary carcinogenesis. Beginning 1 week prior to methylnitrosourea (MNU) administration (experiment 1), rats received diets supplemented with 4-hydroxyphenylretinamide (4-HPR) (782 mg/kg of diet) and retinyl acetate (328 mg/kg of diet) or underwent food restrictions. Rats were administered an i.

Preclinical drug development paradigms for chemopreventives.

Preclinical screening studies and animal efficacy testing models currently are used by the National Cancer Institute's chemoprevention drug discovery program to assess and identify chemical agents and natural products that may have the potential to prevent human cancer. Identification of potential cancer preventing agents begins by subjecting each compound to a sequential series of short-term, in vitro prescreens of mechanistic, biochemical assays to provide quantitative data to help establish an early indication of chemopreventive efficacy and to assist in prioritizing agents for further evaluation in longer-term, in vitro transformation bioassays and whole animal models. Promising chemical agents or combinations of agents that work through different inhibitory mechanisms subsequently are tested in well-established, chemically induced, animal tumor models, which include models of the lung, bladder, mammaries, prostate, and skin.

The effect of vitamin E acetate on ultraviolet-induced mouse skin carcinogenesis.

Despite the benefits of sunscreens, ultraviolet (UV) exposure can still lead to skin cancer. In this study we investigated the effect of topical application of the antioxidant vitamin E acetate (VEA) on the inhibition of UV-induced carcinogenesis. Hairless SKH-1 mice received 5.

Inhibition of cigarette smoke-related lipophilic DNA adducts in rat tissues by dietary oltipraz.

The present study investigated the effects of dietary oltipraz on cigarette smoke-related lipophilic DNA adduct formation. Female Sprague-Dawley rats were exposed daily to sidestream cigarette smoke in a whole-body exposure chamber 6 h/day for 4 consecutive weeks. One group of rats was maintained on control diet while another group received the same diet supplemented with either a low (167 p.

Chemopreventive effects of the aromatase inhibitor vorozole (R 83842) in the methylnitrosourea-induced mammary cancer model.

The chemopreventive activity of the highly specific nonsteroidal aromatase inhibitor, vorozole, was examined in the methylnitrosourea (MNU)-induced rat model of mammary carcinogenesis. Various doses of vorozole (0.08-1.

Influence of N-methyl-N-nitrosourea, testosterone, and N-(4-hydroxyphenyl)-all-trans-retinamide on prostate cancer induction in Wistar-Unilever rats.

The influence of chemical carcinogen, hormonal stimulation, and chronic dietary administration of the synthetic retinoid, N-(4-hydroxyphenyl)-all-trans-retinamide (4-HPR), on the induction of prostate cancer in male Wistar-Unilever rats was determined. Three different tumor induction regimens were used: (a) a single i.v.

Expression of cell cycle proteins in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced mouse lung tumors.

Cyclin D1 dysregulation and differential inactivation of p16INK4a and Rb have been observed in human lung cancer. In chemically induced mouse lung tumors, the p16INK4a gene is a target of inactivation, and Rb is reduced at the mRNA level (Northern blot) although similar at the protein level (Western blot) when compared to normal lung tissues. The expression of cyclin D1, cdk4, p16INK4a, and Rb protein was examined by immunohistochemistry in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced mouse lung tumors.

Comparative pharmacodynamics of CYP2B induction by DDT, DDE, and DDD in male rat liver and cultured rat hepatocytes.

In this study the pharmacodynamics were characterized of rat hepatic cytochrome P-450 2B (CYP2B) induction by the pesticide DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane] and its metabolites DDE [1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene], which is bioretained, and DDD [1,1-dichloro-2,2-bis(p-chlorophenyl)ethane], which is metabolized further and therefore less prone to bioaccumulate. DDT, DDE, and DDD were each found to be pure phenobarbital-type cytochrome P-450 inducers in the male F344/NCr rat, causing induction of hepatic CYP2B and CYP3A, but not CYP1A. The ED50 values for CYP2B induction (benzyloxyresorufin O-dealkylation) by DDT, DDE, and DDD were, respectively, 103, 88, and > or = 620 ppm in diet (14 d of exposure).

Modulation of methylnitrosourea-induced breast cancer in Sprague Dawley rats by dehydroepiandrosterone: dose-dependent inhibition, effects of limited exposure, effects on peroxisomal enzymes, and lack of effects on levels of Ha-Ras mutations.

Dehydroepiandrosterone (DHEA), the major steroid precursor of androgens and estrogens produced in peripheral tissues in primates, is an effective chemopreventive agent in the N-methyl-N-nitrosourea (MNU)-induced rat mammary tumor model. Dietary DHEA (5-600 ppm; 600 mg/kg diet) was administered beginning 1 week before MNU and administered continually throughout the duration of the experiment. The highest dose of DHEA (600 ppm) significantly decreased tumor incidence from 95 to 45% and increased tumor latency and decreased tumor multiplicity from 4.

Effect of calcium on azoxymethane-induced aberrant crypt foci and cell proliferation in the colon of rats.

Calcium has been proposed for prevention of colon cancer. The effects of calcium on azoxymethane (AOM)-induced aberrant crypt foci (ACP), a putative precancerous lesion, and cell proliferation were determined in rat colon. Male F344 rats were given AIN-76A diet that contained calcium at concentrations of 0.

Aromatase inhibitors as potential cancer chemopreventives.

Epidemiological and experimental evidence strongly supports a role for estrogens in the development and growth of breast tumors. A role for estrogen in prostate neoplasia has also been postulated. Therefore, one chemopreventive strategy for breast and prostate cancers is to decrease estrogen production.

Prevention by retinoids of azoxymethane-induced tumors and aberrant crypt foci and their modulation of cell proliferation in the colon of rats.

Retinoids are proposed chemopreventive agents that inhibit cell proliferation and induce differentiation. Their ability to prevent azoxymethane (AOM)-induced aberrant crypt foci (ACF) and tumors and to modulate cell proliferation was investigated in the colon of male F344 rats. Thirteen retinoids were evaluated for prevention of ACF and two of them, 9-cis-retinoic acid (RA) and 4-(hydroxyphenyl)retinamide (4-HPR), were also evaluated for prevention of colon cancer.

Effects of dietary supplementation of N-acetylcysteine on cigarette smoke-related DNA adducts in rat tissues.

Cigarette smoking plays a major role in the etiology of several human cancers. It is believed that formation of DNA adducts is an initial step in the carcinogenic process. In this study, we have examined the ability of dietary N-acetylcysteine (NAG) to inhibit the formation of cigarette smoke-related DNA adducts in various tissues of rats.

Enhancement of experimental colon cancer by genistein.

Several phytochemicals and micronutrients that are present in fruits and vegetables are known to exert cancer chemopreventive effects in several organs, including the colon. Among them, the soybean isoflavonoid genistein received much attention due to its potential anticarcinogenic, antiproliferative effects and its potential role in several signal transduction pathways. The present study was designed to investigate the effect of genistein on azoxymethane (AOM)-induced colon carcinogenesis and to study its modulatory role on the levels of activity of 8-isoprostane, cyclooxygenase (COX), and 15-hydroxyprostaglandin F2alpha dehydrogenase (15-PGDH) in the colonic mucosa and colon tumors of male F344 rats.

Chemopreventive efficacy of anethole trithione, N-acetyl-L-cysteine, miconazole and phenethylisothiocyanate in the DMBA-induced rat mammary cancer model.

The chemopreventive efficacy of N-acetyl-L-cysteine (NAC), anethole trithione, miconazole and phenethylisothiocyanate (PEITC), each of which would be expected to alter carcinogen metabolism, was examined in the dimethylbenzanthracene (DMBA) mammary carcinogenesis model. In this protocol, animals were exposed to non-toxic doses of the chemopreventives in the diet beginning 7 days prior to DMBA administration and then continuously throughout the duration of the assay (100 days post carcinogen). Miconazole, an antifungal agent with relatively broad inhibitory activity toward a variety of cytochromes P450, increased mammary tumor latency, decreased tumor incidence at the highest dose and decreased tumor multiplicity up to 60%.

In vivo induction and in vitro inhibition of hepatic cytochrome P450 activity by the benzodiazepine anticonvulsants clonazepam and diazepam.

The ability of the benzodiazepines, as a chemical class, to cause the induction and/or inhibition of cytochromes P450 has not been well characterized. In the present study, the induction of the cytochrome P450 2B subfamily (CYP2B) in vivo and the inhibition of CYP2B activity in vitro by selected benzodiazepines was examined in hepatic tissues derived from male F344/NCr rats. Initial studies of the in vivo induction or in vitro inhibition of benzyloxyresorufin O-dealkylation activity revealed that both clonazepam and diazepam were relatively effective in vivo inducers of CYP2B when administered in the diet at 500 ppm for 5 days and also were fairly potent inhibitors of the activity of these hemoproteins in vitro.

Tissue-specific expression of the K-ras allele from the A/J parent in (A/J x TSG-p53) F1 mice.

Tissue-specific expression of parental K-ras allele(s) was investigated by single-strand conformation polymorphism analysis of the 3' untranslated region of the K-ras gene in normal lung, spleen, liver and kidney from (A/J x TSG-p53) F1 mice. The expression of A/J K-ras allele was equal to that of C57BL/6J allele in normal spleen, liver and kidney. However, transcripts from A/J K-ras allele were found to be 2-12-times greater than those from C57BL/6J allele in lung tissues harvested over a 20-week period.

Progress in clinical chemoprevention.

Chemoprevention has four goals: (1) inhibition of carcinogens, (2) logical intervention for persons at genetic risk for cancer, (3) treatment of precancerous lesions, and (4) confirmation and translation of leads from dietary epidemiology into intervention strategies. The National Cancer Institute has described a multidisciplinary, cancer science-based program for chemopreventive drug development that addresses these objectives, and has collaborated with the US Food and Drug Administration to provide consensus guidance for applying this approach. A critical component is the identification and characterization of intermediate biomarkers of cancer and their validation as surrogate end points for cancer incidence in clinical chemoprevention trials.

Farnesyl protein transferase inhibitors as potential cancer chemopreventives.

Among the most important targets for chemopreventive intervention and drug development are deregulated signal transduction pathways. Ras proteins serve as central connectors between signals generated at the plasma membrane and nuclear effectors; thus, disrupting the Ras signaling pathway could have significant potential as a cancer chemopreventive strategy. Target organs for Ras-based chemopreventive strategies include those associated with activating ras mutations (e.

Chemoprevention of colon carcinogenesis by dietary perillyl alcohol.

Epidemiological studies suggest that consumption of diets containing fruits and vegetables, major sources of phytochemicals and micronutrients, may reduce the risk of developing cancer of the colon. Several phytochemicals and micronutrients present in fruits and vegetables are known to exert cancer-chemopreventive effects in several organs, including the colon. Monoterpenes such as d-limonene and perillyl alcohol derived from orange peels and lavender, respectively, have been shown to possess chemopreventive properties against mammary, liver, and/or lung carcinogenesis.

Effect of early vs. late administration of 4-hydroxyphenylretinamide (4-HPR) on N-methyl-N-nitrosourea (MNU)-induced mammary tumorigenesis.

Mammary tumors were induced in 48-52-day-old female Sprague-Dawley rats in metestrus or diestrus with a single jugular injection of MNU (50 mg/kg). Control rats received the saline vehicle (Group 4 n = 9). Rats were fed 4% Teklad diet containing either 0 (Group 3, n = 20) or 782 mg 4-HPR/kg diet.

Chemopreventive effect of perillyl alcohol on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induced tumorigenesis in (C3H/HeJ X A/J)F1 mouse lung.

This study was designed to test the chemopreventive potential of perillyl alcohol, an inhibitor of farnesyltransferase, in a mouse lung tumor bioassay. Perillyl alcohol is a naturally occurring monoterpene found in lavender, cherries, and mint. We have shown previously that the majority of lung tumors in this bioassay have an activating mutation in the K-ras gene, which occurs early in the development of mouse lung carcinogenesis.

Detection of differentially expressed genes in methylnitrosourea-induced rat mammary adenocarcinomas.

In this study, altered gene expression in five methylnitrosourea (MNU)-induced rat mammary adenocarcinomas was investigated using a newly developed competitive cDNA library screening assay. In order to detect the differentially expressed cDNA transcripts, three cDNA libraries (rat mammary, rat liver, and rat kidney) with over 18,000 clones were differentially screened with competing normal and neoplastic mammary cDNA probes. Ninety-eight clones indicated by competitive hybridization to be differentially expressed in tumors were verified by dot-blot hybridization analysis.

Genetic alterations in mouse lung tumors: implications for cancer chemoprevention.

Specific genetic alterations affecting known tumor suppressor genes and proto-oncogenes occur during mouse lung tumorigenesis. These include mutational activation of the K-ras gene, commonly seen at a frequency of about 80% in both spontaneously occurring and chemically induced adenomas and adenocarcinomas of the lung, suggesting that it is an early event that persists into malignancy. Allelic loss of the p16 tumor suppressor gene also is a frequent event, occurring in about 50% of mouse lung adenocarcinomas, but rarely in lung adenomas, suggesting that it may play a role in malignant conversion or progression of lung tumors.