Kelloff G J, Sigman C C, Hawk E T, Johnson K M, Crowell J A, Guyton K Z
National Cancer Institute, Division of Cancer Prevention, Bethesda, MD 20892-7322, USA.
IARC Sci Publ. 2001;154:13-26.
Relevant and feasible surrogate end-points are needed for the evaluation of intervention strategies against cancer and other chronic, life-threatening diseases. Carcinogenesis can be viewed as a process of progressive disorganization. This process is characterized by the accumulation of genotypic lesions and corresponding tissue and cellular abnormalities, including loss of proliferation and apoptosis controls. Potential surrogate end-points for cancer incidence include both phenotypic and genotypic biomarkers of this progression. In the US National Cancer Institute chemoprevention programme, histological modulation of a precancer (intraepithelial neoplasia) has so far been the primary phenotypic surrogate end-point in chemoprevention trials. Additionally, high priority has been given to biomarkers measuring specific and general genotypic changes correlated with the carcinogenesis progression model for the targeted cancer (e.g., progressive genomic instability as measured by loss of heterozygosity or amplification at specific microsatellite loci). Other potential surrogate end-points include proliferation and differentiation indices, specific gene and general chromosome damage, cell growth regulatory molecules, and biochemical activities (e.g., enzyme inhibition). Serum biomarkers thought to be associated with cancer progression (e.g., prostate-specific antigen) are particularly appealing surrogate end-points because of accessibility. Potentially chemopreventive effects of the test agent may also be measured (e.g., tissue and serum estrogen levels in studies of steroid aromatase inhibitors). To establish chemopreventive efficacy, prevention of virtually all biomarker lesions, or of those lesions with particular propensity for progression, may be required. Ideally, the phenotype and genotype of any new or remaining precancers in the target tissue of chemopreventive agent-treated subjects would show less, and certainly no greater, potential for progression than those of placebo-treated subjects.
评估针对癌症及其他慢性、危及生命疾病的干预策略需要相关且可行的替代终点。致癌作用可视为一个逐渐紊乱的过程。这一过程的特征是基因型损伤以及相应的组织和细胞异常的积累，包括增殖和凋亡控制的丧失。癌症发病率的潜在替代终点包括这一进展过程中的表型和基因型生物标志物。在美国国立癌症研究所的化学预防计划中，癌前病变（上皮内瘤变）的组织学改变一直是化学预防试验的主要表型替代终点。此外，对于测量与目标癌症致癌进展模型相关的特定和一般基因型变化的生物标志物给予了高度优先考虑（例如，通过杂合性缺失或特定微卫星位点的扩增来测量的渐进性基因组不稳定性）。其他潜在的替代终点包括增殖和分化指数、特定基因和一般染色体损伤、细胞生长调节分子以及生化活性（例如，酶抑制）。被认为与癌症进展相关的血清生物标志物（例如，前列腺特异性抗原）因其易于获取而特别有吸引力作为替代终点。测试药物的潜在化学预防作用也可以进行测量（例如，在类固醇芳香化酶抑制剂研究中的组织和血清雌激素水平）。为了确定化学预防效果，可能需要预防几乎所有的生物标志物损伤，或者预防那些具有特定进展倾向的损伤。理想情况下，化学预防剂治疗的受试者靶组织中任何新出现或残留的癌前病变的表型和基因型显示出的进展潜力应小于安慰剂治疗的受试者，当然肯定不会更大。
