Development of Drug-Resistant Models

The observation that tumors are capable of developing resistance to anticancer agents is a well-established fact in the clinic. In order to explain this phenomenon in the laboratory, fluctuation analysis has been used in a number of studies involving tumor cell lines (1 –3 ), although it was first used by Luria and Delbruck (4 ) in the study of bacterial cultures. Subsequently, work by Goldie and Coldman (5 ) using fluctuation analysis focused on the genetic instability of tumor cells as pivotal to the emergence of drug-resistant cells. The hypothesis suggested that a drug-resistant cell emerged from the clonal expansion of spontaneously mutated cells and not from changes in cellular function induced by drugs. The methodology used in fluctuation analysis is described elsewhere (3 ) and can be used to assess the mutation rate of drug treated tumor cells.