Drug resistance as a dynamic process in a model for multistep gene amplification under various levels of selection stringency.

Resistance to antineoplastic drugs has been a major impediment to the successful treatment of cancer. Recent studies suggest that several mechanisms are responsible for the emergence of drug resistance but that high levels of resistance and poor prognosis are strongly associated with gene or oncogene amplification. In this report we describe a probabilistic model for gene amplification in a tumor that grows under various drug protocols. The model is new in that it treats drug resistance as a dynamic process and examines specific assumptions about the underlying molecular events. Using this model, we specify the conditions for the emergence of drug-resistant mutants prior to selection as well as the relationship between the stringency of the selecting environment and the characteristics of the resultant cellular phenotype.