Lønning P E, Knappskog S, Staalesen V, Chrisanthar R, Lillehaug J R
Section of Oncology, Institute of Medicine, University of Bergen, Norway.
Ann Oncol. 2007 Aug;18(8):1293-306. doi: 10.1093/annonc/mdm013. Epub 2007 Feb 21.
Expanding knowledge, together with implementation of new techniques, has fuelled the area of translational medical research aiming at improving prognostication as well as prediction in cancer therapy. At the same time, new discoveries have revealed a biological complexity we were unaware of only a decade ago. Thus, we are faced with novel challenges with respect to how we may explore issues such as prognostication and predict drug resistance in vivo. While microarray analysis exploring expression of thousands of genes in concert represents a major methodological advancement, discoveries such as the finding of different mechanisms of epigenetic silencing, intronic mutations, that most gene transcripts in the human genome are subject to alternative splicing and that hypersplicing seems to be a tumour-related phenomenon, exemplifies a complex pathology that may not be explored with use of single analytical methods only. This paper discusses clinical settings for studying drug resistance in vivo together with a discussion of contemporary biology in this field. Notably, each individual parameter which has been found correlated to drug resistance in vivo so far represents either a direct drug target or a factor involved in DNA repair or apoptosis. On the basis of these findings, we suggest drug resistance may be explored on the basis of upfront biological hypotheses.
知识的不断拓展以及新技术的应用，推动了转化医学研究领域的发展，其旨在改善癌症治疗中的预后评估和预测。与此同时，新的发现揭示了一种仅在十年前我们还一无所知的生物学复杂性。因此，在如何探索诸如体内预后评估和预测耐药性等问题方面，我们面临着新的挑战。虽然微阵列分析能够同时探究数千个基因的表达情况，代表了一项重大的方法学进步，但诸如发现表观遗传沉默的不同机制、内含子突变、人类基因组中的大多数基因转录本会发生可变剪接以及超剪接似乎是一种肿瘤相关现象等发现，例证了一种复杂的病理学，仅使用单一分析方法可能无法对其进行探究。本文讨论了在体内研究耐药性的临床背景，并探讨了该领域的当代生物学。值得注意的是，迄今为止发现的与体内耐药性相关的每个单独参数，要么代表直接的药物靶点，要么代表参与DNA修复或细胞凋亡的一个因素。基于这些发现，我们建议可以根据预先提出的生物学假设来探索耐药性。
