Kuo M T, Sen S, Hittelman W N, Hsu T C
Department of Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Biochem Pharmacol. 1998 Jul 1;56(1):7-13. doi: 10.1016/s0006-2952(98)00040-9.
It has been well established that DNA amplification is one of the important mechanisms by which cultured cells acquire resistance to many cytotoxic compounds. Amplification of important genes including those encoding oncoproteins, growth factors, their receptors and cell-cycle regulators has been reported in human neoplasms. Yet, despite intensive research since the first description of DNA amplification in cultured cells about 20 years ago, the mechanisms of DNA amplification remain largely unknown. Many models have been proposed to account for the diverse manifestations of amplified DNA in many different cell sources. It is not the intention of this commentary to review these many different models. Rather, we wil focus on the recent advances in this area of research, made mainly via the fluorescence in situ hybridization technique, that have revealed a fairly common chromosomal manifestation of amplified DNA in the drug-resistant hamster cell lines and have demonstrated the association of chromosomal fragile site breakage with early events in DNA amplification. These new developments underscore the importance of future research toward understanding the molecular bases of chromosomal fragile sites, including mechanisms involved in DNA strand breakage and repair, chromosomal translocations, and deletions, which may, in turn, provide important new insights into genomic plasticity and neoplastic transformation.
DNA扩增是培养细胞获得对许多细胞毒性化合物耐药性的重要机制之一，这一点已经得到充分证实。在人类肿瘤中，已经报道了包括编码癌蛋白、生长因子、其受体和细胞周期调节因子的基因在内的重要基因的扩增。然而，尽管自大约20年前首次描述培养细胞中的DNA扩增以来进行了深入研究，但DNA扩增的机制在很大程度上仍然未知。已经提出了许多模型来解释在许多不同细胞来源中扩增DNA的多种表现形式。本评论无意回顾这些众多不同的模型。相反，我们将关注该研究领域的最新进展，这些进展主要通过荧光原位杂交技术取得，揭示了耐药仓鼠细胞系中扩增DNA相当常见的染色体表现，并证明了染色体脆性位点断裂与DNA扩增早期事件的关联。这些新进展强调了未来研究理解染色体脆性位点分子基础的重要性，包括DNA链断裂和修复、染色体易位和缺失所涉及的机制，这反过来可能为基因组可塑性和肿瘤转化提供重要的新见解。
