Chromosomal fragile sites and DNA amplification in drug-resistant cells

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.