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. Furthermore, whereas biomarkers are frequently used as surrogate efficacy end points to expedite the process, biomarker assessment and validation has proven difficult because dietary agents exert multiple actions with an unknown hierarchy of biological importance. These factors have made determining the dose for clinical investigation extremely challenging, and at present, there are no defined strategies for rationally identifying the most appropriate doses. In this commentary, the complexities involved in the development of dietary chemoprevention agents are discussed, and a tentative route towards selection of the optimal clinical dose is proposed. The approach highlights the need to conduct long-term preclinical studies with realistic concentrations that are achievable in human tissues and the importance of efficacy biomarkers that are intrinsically linked to the key mechanisms of action. A more logical design of studies should increase the likelihood that the encouraging preclinical results observed for many phytochemicals translate into tangible clinical benefit.
Scott
Edwina N
EN
Chemoprevention Group, Department of Cancer Studies and Molecular Medicine, Level 5, Leicester Royal Infirmary, Leicester, United Kingdom.
Gescher
Andreas J
AJ
Steward
William P
WP
Brown
Karen
K
D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D015415:Biomarkers; D045744:Cell Line, Tumor / Q000187:drug effects; D002986:Clinical Trials as Topic; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000517:prevention & control; D018736:DNA Adducts / Q000032:analysis; D004032:Diet; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005492:Folic Acid / Q000627:therapeutic use / Q000633:toxicity; D019833:Genistein / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D010945:Plants, Edible / Q000737:chemistry*; D051381:Rats; D019207:beta Carotene / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity
D016588:Anticarcinogenic Agents; D015415:Biomarkers; D018736:DNA Adducts; D010936:Plant Extracts; D019207:beta Carotene; D005492:Folic Acid; D019833:Genistein