Distribution and metabolism of [14C]-resveratrol in human prostate tissue after oral administration of a "dietary-achievable" or "pharmacological" dose: what are the implications for anticancer activity?

Background: The dietary polyphenol resveratrol prevents various malignancies in preclinical models, including prostate cancer. Despite attempts to translate findings to humans, gaps remain in understanding pharmacokinetic-pharmacodynamic relations and how tissue concentrations affect efficacy. Such information is necessary for dose selection and is particularly important given the low bioavailability of resveratrol.

Curcumin Combined with FOLFOX Chemotherapy Is Safe and Tolerable in Patients with Metastatic Colorectal Cancer in a Randomized Phase IIa Trial.

Background: Curcumin is the main active ingredient of the spice turmeric, investigated extensively for putative anticancer properties.

Objectives: This phase IIa open-labelled randomized controlled trial aimed to assess safety, efficacy, quality of life, neurotoxicity, curcuminoids, and C-X-C-motif chemokine ligand 1 (CXCL1) in patients receiving folinic acid/5-fluorouracil/oxaliplatin chemotherapy (FOLFOX) compared with FOLFOX + 2 g oral curcumin/d (CUFOX).

Methods: Twenty-eight patients aged >18 y with a histological diagnosis of metastatic colorectal cancer were randomly assigned (1:2) to receive either FOLFOX or CUFOX.

Circulating biomarkers during treatment in patients with advanced biliary tract cancer receiving cediranib in the UK ABC-03 trial.

Background: Advanced biliary tract cancer (ABC) has a poor prognosis. Cediranib, in addition to cisplatin/gemcitabine [CisGem], improved the response rate, but did not improve the progression-free survival (PFS) in the ABC-03 study. Minimally invasive biomarkers predictive of cediranib benefit may improve patient outcomes.

Cancer chemoprevention: Evidence of a nonlinear dose response for the protective effects of resveratrol in humans and mice.

Resveratrol is widely promoted as a potential cancer chemopreventive agent, but a lack of information on the optimal dose prohibits rationally designed trials to assess efficacy. To challenge the assumption that "more is better," we compared the pharmacokinetics and activity of a dietary dose with an intake 200 times higher. The dose-response relationship for concentrations generated and the metabolite profile of [(14)C]-resveratrol in colorectal tissue of cancer patients helped us to define clinically achievable levels.

Curcumin inhibits cancer stem cell phenotypes in ex vivo models of colorectal liver metastases, and is clinically safe and tolerable in combination with FOLFOX chemotherapy.

In vitro and pre-clinical studies have suggested that addition of the diet-derived agent curcumin may provide a suitable adjunct to enhance efficacy of chemotherapy in models of colorectal cancer. However, the majority of evidence for this currently derives from established cell lines. Here, we utilised patient-derived colorectal liver metastases (CRLM) to assess whether curcumin may provide added benefit over 5-fluorouracil (5-FU) and oxaliplatin (FOLFOX) in cancer stem cell (CSC) models.

Combining curcumin (C3-complex, Sabinsa) with standard care FOLFOX chemotherapy in patients with inoperable colorectal cancer (CUFOX): study protocol for a randomised control trial.

Background: The need for low toxicity adjuncts to standard care chemotherapy in inoperable colorectal cancer, with potential to improve outcomes and decrease the side-effect burden, is well recognised. Addition of the low toxicity diet-derived agent, curcumin (the active ingredient of turmeric), to standard oxaliplatin-based therapy has shown promise in numerous pre-clinical studies.

Methods/design: This study is the first to combine daily oral curcumin with standard care FOLFOX-based (5-fluorouracil, folinic acid and oxaliplatin) chemotherapy in colorectal cancer patients with inoperable liver metastases: the CUFOX trial.

Characterization and propagation of tumor initiating cells derived from colorectal liver metastases: trials, tribulations and a cautionary note.

Tumor initiating cells (TIC) are increasingly being put forward as a potential target for intervention within colorectal cancer. Whilst characterisation and outgrowth of these cells has been extensively undertaken in primary colorectal cancers, few data are available describing characteristics within the metastatic setting. Tissue was obtained from patients undergoing surgical resection for colorectal liver metastases, and processed into single cell suspension for assessment.

Comet assay measures of DNA damage are predictive of bladder cancer cell treatment sensitivity in vitro and outcome in vivo.

Bladder cancer patients suffer significant treatment failure, including high rates of recurrence and poor outcomes for advanced disease. If mechanisms to improve tumour cell treatment sensitivity could be identified and/or if tumour response could be predicted, it should be possible to improve local-control and survival. Previously, we have shown that radiation-induced DNA damage, measured by alkaline Comet assay (ACA), correlates bladder cancer cell radiosensitivity in vitro.

The role of cancer stem cells in the anti-carcinogenicity of curcumin.

Many cancers contain cell subpopulations that display characteristics of stem cells. These cells are characterised by their ability to self-renew, form differentiated progeny and develop resistance to chemotherapeutic strategies. Cancer stem cells may utilise many of the same signalling pathways as normal stem cells including Wnt, Notch and Hedgehog.

Resveratrol in the management of human cancer: how strong is the clinical evidence?

Among the plethora of biochemical mechanisms engaged by resveratrol in preclinical systems, its anticarcinogenic effects represent some of the most convincing and intriguing. As outlined in this review, there is considerable interest in developing resveratrol for cancer prevention and treatment. The plasma pharmacokinetics of resveratrol in humans are now reasonably well defined, and studies have shown that repeated daily doses up to 1 g are safe and well tolerated, although gastrointestinal toxicity is observed at higher intakes.

Prolonged biologically active colonic tissue levels of curcumin achieved after oral administration--a clinical pilot study including assessment of patient acceptability.

Curcumin, the main constituent of turmeric, is suspected to possess cancer chemopreventive properties. Pharmacokinetic and pharmacodynamic parameters have been reported, but few data exist describing whether methodologies are suitably robust for curcuminoid detection in colonic biopsy specimens. Information on the acceptability of prolonged administration of daily curcumin is not available.

Synthesis and biological evaluation of novel flavonols as potential anti-prostate cancer agents.

A library of flavonol analogues was synthesised and evaluated as potential anticancer agents against a human prostate cancer cell line, 22rν1. Compounds 3, 8 and 11 (IC(50) 2.6, 3.

Dietary intake of rosmarinic acid by Apc(Min) mice, a model of colorectal carcinogenesis: levels of parent agent in the target tissue and effect on adenoma development.

Scope: Rosmarinic acid (RA), a constituent of culinary herbs is considered to possess cancer chemopreventive properties. It has been shown to inhibit the development of cancer in preclinical models but data are conflicting and whether it can protect against gastrointestinal malignancies in vivo has not been examined. This study aimed to investigate the effect of RA on the development of intestinal adenomas in the Apc(Min) mouse model of colorectal carcinogenesis, and to correlate efficacy with levels of RA achieved in the plasma and gastrointestinal tract.

Tissue distribution and metabolism of the putative cancer chemopreventive agent 3',4',5'-trimethoxyflavonol (TMFol) in mice.

3',4',5'-Trimethoxyflavonol (TMFol) is a synthetic flavonol with preclinical cancer chemopreventive properties. The hypothesis was tested that, in mice, p.o.

Resveratrol in human cancer chemoprevention--choosing the 'right' dose.

There is now robust preclinical evidence to suggest that resveratrol possesses cancer chemopreventive properties. A series of clinical pilot studies has provided insights into its pharmacokinetics, and data on its human antineoplastic pharmacodynamics start to emerge. It is likely that resveratrol will be developed further in the clinic as a putative cancer chemopreventive agent.

Curcumin: the potential for efficacy in gastrointestinal diseases.

Curcumin is a naturally occurring phytochemical and an extract of turmeric. Extensive in vitro and in vivo data have paved the way for curcumin to become the subject of clinical trials. Curcumin modulates key signalling pathways important in cellular processes.

Evaluation of urinary ribonucleoside profiling for clinical biomarker discovery using constant neutral loss scanning liquid chromatography/tandem mass spectrometry.

The patterns and levels of urinary excreted ribonucleosides which reflect RNA turnover and metabolism in humans offer the potential for early detection of disease and monitoring of therapeutic intervention. A liquid chromatography/tandem mass spectrometry (LC/MS/MS) method employing constant neutral loss (CNL) scanning for the loss of the ribose moiety (132 u) was used to detect ribonucleosides in human urine and to evaluate this analytical platform for biomarker research in clinical trials. Ribonucleosides were stable and not influenced by the time spent at room temperature prior to freezing or long-term storage at -80 °C.

Pooled survival and response data from phase III randomized controlled trials for gemcitabine-based regimes in the treatment of advanced pancreatic cancer.

Although gemcitabine remains current first-line chemotherapy for patients with advanced pancreatic cancer, median survival times have not improved significantly since its introduction 15 years ago. Of the phase III trials which have investigated alternative regimens to single-agent gemcitabine, most have used combination regimens as the investigational arm. Accurate data on median overall, progression-free survival and objective response rates is important, for two principle reasons: advising patients about their prognosis and when powering phase II trials and evaluating the results of single-armed trials.

Clinical trials of resveratrol.

An expanding body of preclinical evidence suggests resveratrol has the potential to impact a variety of human diseases. To translate encouraging experimental findings into human benefits, information is first needed on the safety, pharmacokinetics, pharmacodynamics, and, ultimately, clinical efficacy of resveratrol. Published clinical trials have largely focused on characterizing the pharmacokinetics and metabolism of resveratrol.

Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: safety, pharmacokinetics, and effect on the insulin-like growth factor axis.

Resveratrol, a naturally occurring polyphenol, has cancer chemopreventive properties in preclinical models. It has been shown to downregulate the levels of insulin-like growth factor-1 (IGF-I) in rodents. The purpose of the study was to assess its safety, pharmacokinetics, and effects on circulating levels of IGF-I and IGF-binding protein-3 (IGFBP-3) after repeated dosing.

Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients.

Resveratrol is a phytochemical with chemopreventive activity in preclinical rodent models of colorectal carcinogenesis. Antiproliferation is one of the many chemopreventive modes of action it has been shown to engage in. Concentrations of resveratrol, which can be achieved in human tissues after p.

Curcumin ameliorates oxaliplatin-induced chemoresistance in HCT116 colorectal cancer cells in vitro and in vivo.

The aims of this study were to determine potency of oxaliplatin in combination with curcumin in oxaliplatin-resistant cell lines in vitro and to evaluate the efficacy of a novel curcumin formulation (Meriva®) alone and in combination with oxaliplatin in colorectal tumor-bearing mice, exploring relevant pharmacodynamic markers in vivo. Oxaliplatin-resistant HCT116 p53wt and p53(-/-) cell lines were generated, and the effects of oxaliplatin in combination with curcumin on resistance- and proliferation-associated proteins investigated. Eighty nude mice were implanted with HCT116 p53wt colorectal cancer cells before randomization into the following treatment groups: control; Meriva only; oxaliplatin only; Meriva + oxaliplatin.