van Weerden Wytske M, Schröder Fritz H
Department of Urology, Erasmus MC, Rotterdam, The Netherlands.
Chem Biol Interact. 2008 Jan 30;171(2):204-11. doi: 10.1016/j.cbi.2007.11.006. Epub 2007 Nov 22.
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.
流行病学证据表明，环境因素，如饮食，在前列腺癌（PC）的发生和发展中起作用。有预防作用的潜在保护性膳食化合物或全膳食产品的数量不断增加，需要进一步评估。众多的选择迫切需要一个可靠的高通量筛选系统。为了应对这个不断发展的领域，我们提出了一种将基于前列腺特异性抗原（PSA）的临床试验与人体异种移植实验研究相结合的策略，以评估PC的潜在化学预防剂。本综述描述了使用该方法获得的首批结果。在鹿特丹，针对患者进行了两项基于营养的三级化学预防试验，旨在延缓微小PC的进展。在这些研究中，使用了两种不同的补充剂，均由据报道与癌症预防相关的成分（不同）混合物组成。局部治疗但循环PSA水平不明原因升高的PC患者被随机分为一项采用交叉设计的双盲、安慰剂对照研究。在两个干预期内跟踪PSA动力学。研究设计的时间框架为6个月。这些干预研究的结果显示，与安慰剂相比，膳食补充后PSA倍增时间增加。这些患者缺乏肿瘤负荷信息，因此需要进行额外的异种移植研究，以提供补充剂诱导的PSA和肿瘤反应。这种平行的实验研究将能够验证PSA作为肿瘤体积反应生物标志物的有效性，并可能将临床PSA动力学与实际肿瘤反应联系起来。对于其中一项临床研究，进行了这样一项实验性验证研究。将与临床研究中使用的类似的膳食补充剂给予经前列腺内注射人PC-346C细胞的动物。随时间记录对肿瘤生长和PSA的反应，并监测对PSA或肿瘤生长的潜在差异效应。这项动物研究显示，补充剂组和安慰剂组小鼠在肿瘤体积或PSA释放方面的反应没有差异，并证实了在这种特定的膳食干预下，PSA水平反映了肿瘤反应。我们建议，基于PSA的II期早期临床试验策略，辅以人体异种移植实验研究，以评估PSA反应反映肿瘤反应的可靠性，可提供一个简洁、相对快速的测试系统，能够在相对较短的时间内筛选出各种化学预防治疗方案。
