Plasma metabolic profiling reveals age-dependency of systemic effects of green tea polyphenols in mice with and without prostate cancer.

Green tea polyphenols (GTP) have been widely investigated for their potential to prevent prostate cancer. However, results from epidemiological and clinical studies are equivocal. Studies in the TRAMP (TRansgenic Adenocarcinoma of the Mouse Prostate) mouse suggest that the chemopreventive efficacy of GTP is higher in young animals with early stages of carcinogenesis than in old ones.

Determination of 8-oxo-2'-deoxyguanosine and creatinine in murine and human urine by liquid chromatography/tandem mass spectrometry: application to chemoprevention studies.

Urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) represents a non-invasive biomarker for oxidative stress and may be useful for monitoring chemotherapeutic and chemopreventive interventions associated with cancer-related alterations in oxidative stress. We describe the development and validation of two separate liquid chromatography/tandem mass spectrometry (LC/MS/MS) selected reaction monitoring (SRM) methods for the determination of 8-oxodG and creatinine in both murine and human urine using stable isotope labelled internal standards. Levels of 8-oxodG were normalised to creatinine.

Simultaneous determination of 8-oxo-2'-deoxyguanosine and 8-oxo-2'-deoxyadenosine in DNA using online column-switching liquid chromatography/tandem mass spectrometry.

Sensitive and reliable methods are required for the assessment of oxidative DNA damage, which can result from reactive oxygen species that are generated endogenously from cellular metabolism and inflammatory responses, or by exposure to exogenous agents. The development of a liquid chromatography/tandem mass spectrometry (LC/MS/MS) selected reaction monitoring (SRM) method is described, that utilises online column-switching valve technology for the simultaneous determination of two DNA adduct biomarkers of oxidative stress, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydro-2'-deoxyadenosine (8-oxodA). To allow for the accurate quantitation of both adducts the corresponding [(15)N(5)]-labelled stable isotope internal standards were synthesised and added prior to enzymatic hydrolysis of the DNA samples to 2'-deoxynucleosides.

Metabolic profiling of transgenic adenocarcinoma of mouse prostate (TRAMP) tissue by 1H-NMR analysis: evidence for unusual phospholipid metabolism.

Background: The TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mouse model has frequently been used in preclinical studies with chemotherapeutic/chemopreventive rationales. Here the hypothesis was tested using (1)H-NMR-based metabolic profiling that the TRAMP tumor metabolic phenotype resembles that reported for human prostate cancer.

Methods: Aqueous extracts or intact tissues of normal prostate from 8- ("young") or 28-("old") week-old C57BL/6J wild-type mice or of prostate tumor from age-matched TRAMP mice were analyzed by (1)H-NMR.

Evaluation of the cancer chemopreventive efficacy of silibinin in genetic mouse models of prostate and intestinal carcinogenesis: relationship with silibinin levels.

Silibinin, a flavonolignan from milk thistle seeds, possesses cancer chemopreventive properties in rodent models of carcinogenesis. We tested the hypotheses that silibinin or silipide, silibinin formulated with phospholipids, delays tumour development in TRAMP or Apc(Min) mice, genetic models of prostate or intestinal malignancies, respectively. Mice received silibinin or silipide with their diet (0.

Androgen manipulation alters oxidative DNA adduct levels in androgen-sensitive prostate cancer cells grown in vitro and in vivo.

Intracellular reactive oxygen species (ROS) may cause oxidative DNA damage, resulting in the formation of adducts such as 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) and the cyclic pyrimidopurinone N-1, N(2) malondialdehyde-2'-deoxyguanosine (M(1)dG). These adducts have been associated with carcinogenesis, genomic instability and clonal evolution. We tested two hypotheses in human prostate cancer cells grown in vitro and in a xenograft model: (1) treatment of androgen-sensitive cells with DHT increases levels of oxidative DNA adduct levels; (2) flutamide, a competitive androgen receptor antagonist, prevents DHT-induced changes.

Putative cancer chemopreventive agents of dietary origin-how safe are they?

As cancer chemopreventive agents are intended for use by healthy individuals as prophylactics to prevent or retard the development of cancer, they must be amenable to ingestion over prolonged periods without toxicity. Therefore, putative chemopreventive agents need to undergo stringent testing to ensure their safety with regard to chronic exposure in humans. The diet is thought to be a source of chemopreventive agents, and dietary compounds are generally considered to be of low hazard, albeit this notion has not often been put to the test.

Consumption of silibinin, a flavonolignan from milk thistle, and mammary cancer development in the C3(1) SV40 T,t antigen transgenic multiple mammary adenocarcinoma (TAg) mouse.

Silibinin is a flavonolignan extracted from milk thistle with cancer chemopreventive activity in preclinical models of prostate and colorectal cancer. A milk thistle extract, of which silibin is a major component, has recently been shown to exacerbate mammary carcinogenesis in two rodent models. We tested the hypothesis that consumption of silibinin or silipide, a silibinin formulation with pharmaceutical properties superior to the unformulated agent, affect breast cancer development in the C3(1) SV40 T,t antigen transgenic multiple mammary adenocarcinoma mouse model.

Cytotoxic action of phorbol esters on human pancreatic cancer cells.

We previously showed that phorbol esters are cytotoxic to human thyroid epithelial cells expressing a mutant RAS oncogene. Here we explore the generality of this finding using cells derived from pancreatic cancer, which, like thyroid, shows a high frequency of RAS mutation, but is a much greater cause of cancer mortality. The response to phorbol myristate acetate (PMA) and related agents was assessed on a panel of 9 pancreatic cancer cell lines, using a range of assays for cell growth and death in vitro and in vivo.

Comparison of systemic availability of curcumin with that of curcumin formulated with phosphatidylcholine.

Purpose: Curcumin, a major constituent of the spice turmeric, suppresses expression of the enzyme cyclooxygenase 2 (Cox-2) and has cancer chemopreventive properties in rodents. It possesses poor systemic availability. We explored whether formulation with phosphatidylcholine increases the oral bioavailability or affects the metabolite profile of curcumin.

A synthetic approach to the generation of quercetin sulfates and the detection of quercetin 3'-O-sulfate as a urinary metabolite in the rat.

To study the biological effects of quercetin, authentic products of quercetin metabolism are required as standards. The synthesis of quercetin sulfate standards is thus described. Quercetin was reacted with a 10-fold molar excess of sulfur trioxide-N-triethylamine, and the products were analyzed by HPLC and mass spectrometry.

Preliminary safety evaluation of the putative cancer chemopreventive agent tricin, a naturally occurring flavone.

Purpose: Naturally occurring flavonoids such as quercetin and genistein possess cancer chemopreventive properties in experimental models. However, adverse effects such as their mutagenicity confound their potential clinical usefulness. Furthermore in leukaemia cells some flavonoids cleave the breakpoint cluster region of the mixed lineage leukaemia (MLL) gene as a consequence of inhibition of topoisomerase II.

Dietary agent indole-3-carbinol protects female rats against the hepatotoxicity of the antitumor drug ET-743 (trabectidin) without compromising efficacy in a rat mammary carcinoma.

ET-743, an experimental antitumor drug with promising activity in sarcoma, breast and ovarian carcinoma, is currently under phase 2 clinical evaluation. It is hepatotoxic in animals and patients. We tested the hypothesis that indole-3-carbinol (I3C), the hydrolysis product of glucosinolates occurring in cruciferous vegetables, may protect against ET-743-induced hepatotoxicity in the female Wistar rat, the animal species with the highest sensitivity toward the adverse hepatic effect of this drug.

Pharmacokinetics and tissue disposition of indole-3-carbinol and its acid condensation products after oral administration to mice.

Indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM) are promising cancer chemopreventive agents in rodent models, but there is a paucity of data on their pharmacokinetics and tissue disposition. The disposition of I3C and its acid condensation products, DIM, [2-(indol-3-ylmethyl)-indol-3-yl]indol-3-ylmethane (LTr(1)), indolo[3,2b]carbazole (ICZ) and 1-(3-hydroxymethyl)-indolyl-3-indolylmethane (HI-IM) was studied, after oral administration of I3C (250 mg/kg) to female CD-1 mice. Blood, liver, kidney, lung, heart, and brain were collected between 0.

Articular chondromatosis and chrondroid metaplasia in transgenic TAg mice.

The C3(1)/SV40 T antigen transgenic mouse model for which rapid mammary and prostate tumor development has been documented uses the FVB/N mouse as a background strain. In this study, where the background strain used was the C57BL/6J mouse, neither mammary nor prostate tumors developed over periods of up to 40 weeks. However, a disturbance of hyaline cartilage in joints was observed similar to that found in synovial chondromatosis in humans.

Comparison of four modulators of drug metabolism as protectants against the hepatotoxicity of the novel antitumor drug yondelis (ET-743) in the female rat and in hepatocytes in vitro.

Purpose: Yondelis (ET-743), a tetrahydroisoquinoline alkaloid isolated from a marine tunicate, is a novel drug with demonstrated anticancer activity in early clinical trials against sarcoma, breast and ovarian carcinoma. Yondelis has myelotoxic and hepatotoxic side effects, the latter reflected by reversible transaminitis and cholangitis. In the female rat pretreatment with high-dose dexamethasone has been shown to abrogate yondelis-mediated hepatotoxicity, an effect tentatively linked to its ability to induce cytochrome P450 CYP3A isoenzymes, which metabolize yondelis.

Determination of the flavone tricin in human plasma by high-performance liquid chromatography.

Tricin is a flavone constituent of brown rice and rice bran, which interferes potently with the survival of human-derived breast and colon cancer cells in vitro. A specific and simple high-performance liquid chromatographic (HPLC) method was developed for the determination of tricin in human plasma with UV-visible detection. HPLC separation on Hypersil-BDS C(18) (4.

Complete protection by high-dose dexamethasone against the hepatotoxicity of the novel antitumor drug yondelis (ET-743) in the rat.

Yondelis (ET-743) is a promising antitumor drug with hepatotoxic properties in animals and humans. Here the hypothesis was tested that dexamethasone can ameliorate manifestations of yondelis-induced hepatotoxicity in the female Wistar rat, which is the animal species with the highest sensitivity toward the adverse hepatic effect of yondelis. Hepatotoxicity was adjudged by measurement of plasma levels of alkaline phosphatase, aspartate aminotransferase, and bilirubin, and by liver histopathology.

Hepatobiliary damage and changes in hepatic gene expression caused by the antitumor drug ecteinascidin-743 (ET-743) in the female rat.

Ecteinascidin-743 (ET-743) is a novel marine-derived anticancer drug with clinical activity in soft tissue sarcoma and ovarian cancer. Reversible transaminitis and subclinical cholangitis have frequently been described in patients who receive ET-743. To facilitate understanding of this adverse effect and help design suitable therapeutic rescue strategies, we characterized the hepatic effects of ET-743 in rats.

Chemopreventive efficacy and pharmacokinetics of curcumin in the min/+ mouse, a model of familial adenomatous polyposis.

Curcumin, the major yellow pigment in turmeric, prevents the development of adenomas in the intestinal tract of the C57Bl/6J Min/+ mouse, a model of human familial APC. To aid the rational development of curcumin as a colorectal cancer-preventive agent, we explored the link between its chemopreventive potency in the Min/+ mouse and levels of drug and metabolites in target tissue and plasma. Mice received dietary curcumin for 15 weeks, after which adenomas were enumerated.