Kelloff G J, Malone W F, Boone C W, Steele V E, Doody L A
Chemoprevention Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892.
J Cell Biochem Suppl. 1992;16G:15-21. doi: 10.1002/jcb.240501103.
The Chemoprevention Branch of the National Cancer Institute has established a program for the development of safe and effective cancer chemopreventive agents. This program includes identification of new agents, testing for efficacy in vitro and in animals, studies in animals to model clinical use, and preclinical toxicity and metabolism evaluation. Ultimately, the most promising agents progress to clinical trials. The long period required for cancer onset presents a significant challenge to the design of clinical trials for chemoprevention. Phase III trials in which cancer reduction is the endpoint require large subject groups (tens of thousands) and follow-up duration of more than five years. Because of these requirements, the cost of such trials are high. The Chemoprevention Branch is addressing this challenge by expansion of the preclinical and Phase II clinical efficacy efforts to include intermediate biomarkers of carcinogenesis as study endpoints. The Chemoprevention Branch's studies focus on the development of biomarkers with high reliability and predictive value for cancer. Both single markers and batteries of complementary and parallel markers are evaluated. Among the criteria for biomarkers for chemoprevention studies are the following: (1) differential expression in normal and high risk tissue, (2) appearance early in carcinogenesis (the earlier a reliable biomarker appears, the greater is the chance for successful intervention with a chemopreventive agent), (3) high sensitivity, specificity, and accuracy relative to cancer, (4) ease of measurement (use of non-invasive techniques and small tissue samples is preferable), (5) demonstration of modulation by chemopreventive agents, and (6) correlation of modulation with decreased cancer incidence.
美国国立癌症研究所化学预防分部已制定了一项计划，旨在开发安全有效的癌症化学预防剂。该计划包括新药剂的鉴定、体外和动物体内疗效测试、动物模型临床应用研究以及临床前毒性和代谢评估。最终，最有前景的药剂将进入临床试验阶段。癌症发病所需的漫长时间对化学预防临床试验的设计提出了重大挑战。以降低癌症发病率为终点的III期试验需要大量的受试者群体（数万人），且随访时间超过五年。由于这些要求，此类试验的成本很高。化学预防分部正在通过扩大临床前和II期临床疗效研究来应对这一挑战，将致癌作用的中间生物标志物纳入研究终点。化学预防分部的研究重点是开发对癌症具有高可靠性和预测价值的生物标志物。单一标志物以及互补和并行标志物组合都在进行评估。化学预防研究生物标志物的标准如下：（1）在正常组织和高危组织中的差异表达；（2）在致癌过程早期出现（可靠的生物标志物出现得越早，使用化学预防剂成功干预的机会就越大）；（3）相对于癌症具有高敏感性、特异性和准确性；（4）易于测量（最好使用非侵入性技术和小组织样本）；（5）证明可被化学预防剂调节；（6）调节与癌症发病率降低相关。
