Conti C J, Gimenez-Conti I B
University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville 78957, USA.
IARC Sci Publ. 1996(139):249-60.
It is generally accepted that carcinogenesis is related to the accumulation of genetic damage in somatic cells. In support of this concept, numerous studies have identified and characterized genes that are mutated or deleted in carcinogenesis. Some of these genetic alterations occur very frequently, and therefore it is theoretically possible to use them as diagnostic tools or as intermediate end points for chemoprevention studies. This is particularly relevant for some animal models, in which certain genetic alterations are found at a frequently close to 100%. In contrast, specific genetic alterations normally occur less frequently in human cancer, probably because humans are genetically more heterogeneous and are exposed to multiple carcinogens, tumour promoters, and other modifiers of carcinogenesis. Some genetic alterations occur early in tumour development, as in the case of ras mutations in some chemical carcinogenesis models. Similarly, p53 mutations also appear to be a frequent and early event in ultraviolet light (UV)-induced skin tumours in mice and possibly in humans. However, in other neoplasias such as prostate cancer, p53 alterations occur at late stages of tumour development. Alterations that occur early in neoplastic development may be valuable as early markers of tumour development, whereas those that occur late in development may be useful for determining the action of chemopreventive agents on tumour progression. Although the use of genetic markers as intermediate end points of cancer prevention studies has not been completely developed, it has great potential. The development of simple and sensitive molecular techniques such as the polymerase chain reaction and in situ hybridization has opened the possibility of using these markers in large-scale cancer prevention studies.
人们普遍认为，致癌作用与体细胞中遗传损伤的积累有关。为支持这一概念，众多研究已鉴定并表征了在致癌过程中发生突变或缺失的基因。其中一些基因改变非常频繁发生，因此理论上有可能将它们用作诊断工具或化学预防研究的中间终点。这对于某些动物模型尤为重要，在这些模型中某些基因改变的发生率常常接近100%。相比之下，特定的基因改变在人类癌症中通常发生频率较低，这可能是因为人类在基因上更加异质，并且接触多种致癌物、肿瘤促进剂和其他致癌作用的调节剂。一些基因改变在肿瘤发展早期出现，如在某些化学致癌模型中的ras突变情况。同样，p53突变在小鼠紫外线（UV）诱导的皮肤肿瘤以及可能在人类中似乎也是常见且早期出现的事件。然而，在其他肿瘤如前列腺癌中，p53改变发生在肿瘤发展的晚期。在肿瘤发展早期出现的改变作为肿瘤发展的早期标志物可能很有价值，而在发展后期出现的改变可能有助于确定化学预防剂对肿瘤进展的作用。尽管将遗传标志物用作癌症预防研究的中间终点尚未完全发展起来，但它具有很大的潜力。诸如聚合酶链反应和原位杂交等简单且灵敏的分子技术的发展为在大规模癌症预防研究中使用这些标志物开辟了可能性。
