The use of PSA as biomarker in nutritional intervention studies of prostate cancer

Epidemiological evidence suggests that environmental factors, such as diet, play a role in the development and progression of prostate cancer (PC). The number of potential protective dietary compounds or whole dietary products that are indicated to have preventive effects is piling up and demands further evaluation. The number of options urges for a reliable high-throughput screening system. To face this growing field, we suggest a strategy that combines prostate-specific antigen (PSA)-based clinical trials with experimental human xenograft studies to evaluate potential chemopreventive agents for PC. This review describes the first results that have come available using this method. In Rotterdam, two nutrition-based tertiary chemoprevention trials were conducted in patients aiming to delay progression of minimal PC. In these studies two different supplements were used both consisting of a (different) mixture of components reported to be related to cancer prevention. PC patients that were locally treated but had rising levels of circulating PSA of unknown origin were randomised into a double-blind, placebo-controlled study with a crossover design. PSA kinetics was followed during the two intervention periods. The time frame of the study design was 6 months. Results of these intervention studies showed increased PSA doubling times after dietary supplementation as compared to placebo. The lack of information on tumor burden in these patients requires the need for additional xenograft studies that can provide supplement-induced PSA and tumor responses. Such parallel experimental studies will enable to validate PSA as a biomarker for tumor volume response and may link clinical PSA kinetics to actual tumor response. For one of the clinical study, such an experimental confirmation study was performed. The dietary supplement similar to what was used in the clinical study was administered to animals that were injected intraprostatically with human PC-346C cells. Responses on tumor growth and PSA were recorded over time and allowed to monitor a potential differential effect on PSA or tumor growth. This animal study revealed no difference in response as determined by tumor volume or PSA release between supplemented and placebo mice, and confirmed that PSA levels reflected tumor response under this specific dietary intervention. We propose that the strategy of PSA-based early phase II clinical trials accompanied by experimental human xenograft studies, to assess the reliability of PSA response to reflect tumor response, allows for a concise, relatively fast test system that is able to screen the various treatment options for chemoprevention in a relatively short period of time.