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.

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.

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.

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.

Safety and tolerability of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib (AZD2281) in combination with topotecan for the treatment of patients with advanced solid tumors: a phase I study.

Background: The aim of this phase I study was to determine the safety and tolerability and to establish the maximum tolerated dose (MTD) of orally administered olaparib (AZD2281) in combination with topotecan in patients with advanced solid tumors.

Patients And Methods: Patients aged ≥ 18 years with histologically or cytologically diagnosed advanced solid tumors for whom no suitable effective therapy exists were included. Patients in four cohorts received topotecan (0.

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.

Novel VEGF signalling inhibitors: how helpful are biomarkers in their early development?

Background: The development of vascular endothelial growth factor (VEGF) inhibitors of tumour angiogenesis can only be described as prolific. It is therefore interesting to speculate which will reach the clinic. Of course, the most effective agents will succeed, but how is effectiveness measured? When presented with a summary of competitive compounds, it can be difficult to discriminate between their potency on target, toxicity and response rates.

Surgical bypass vs. endoscopic stenting for pancreatic ductal adenocarcinoma.

Background: The majority of patients with pancreatic cancer are non-resectable and jaundiced at presentation. Methods of palliation in such patients with locally advanced disease comprise endoscopic placement of a biliary endoprosthesis or surgical bypass.

Methods: This retrospective study compared morbidity, mortality, hospital stay, readmission rate and survival in consecutive patients with incurable locally advanced pancreatic ductal adenocarcinoma.

Development of dietary phytochemical chemopreventive agents: biomarkers and choice of dose for early clinical trials.

In view of safety concerns surrounding the use of pharmaceuticals such as nonsteroidal anti-inflammatory drugs and tamoxifen as cancer chemopreventive agents, potentially innocuous phytochemicals derived from the diet are considered attractive alternatives. However, results from cancer chemoprevention trials of dietary agents have been disappointing to date, as promising activities observed in rodent models and cells in vitro have not translated into clinical success. This may be partly due to the development process for these agents, which is complex for a number of reasons; the definitive end point, inhibition of carcinogenesis, requires large numbers of individuals followed-up over many years.

A phase I dose escalation study of the pharmacokinetics and tolerability of ZK 304709, an oral multi-targeted growth inhibitor (MTGI), in patients with advanced solid tumours.

Purpose: The toxicities, pharmacokinetics and recommended dose of oral once daily ZK 304709, a novel multi-targeted growth inhibitor (MTGI) with activity against cell-cycle progression and angiogenesis, was investigated in patients by administration for 14 consecutive days followed by 14 days recovery.

Methods: Patients with solid tumours resistant to standard treatments were enrolled in an accelerated titration design.

Results: Thirty-seven patients received ZK 304709 from 15 to 285 mg daily.

Vatalanib: the clinical development of a tyrosine kinase inhibitor of angiogenesis in solid tumours.

The licensing of bevacizumab in patients with metastatic colorectal cancer has fueled research in angiogenesis. Vatalanib (PTK787/ZK 222584), a potent oral tyrosine kinase inhibitor with a selective range of molecular targets, has been extensively investigated and has shown promising results in patients with colorectal cancer in early trials. Dynamic contrast-enhanced MRI has been useful as a pharmacodynamic tool to define the dose that has a biological effect.