PHYSIOLOGICAL (PHENOTYPIG) MEGHANISMS 

 RESPONSIBLE FOR DRUG RESISTANCE 



Bernard D. Davis 



Department of Pharmacology , New York University College oj Medicine 



For the most part this symposium has been concerned with 

 the genetic aspect of the development of drug resistance: i.e. 

 the mechanism or mechanisms by which a hereditary change 

 in resistance to an inhibitor arises in a cell and becomes trans- 

 mitted to succeeding generations. But the problem of drug 

 resistance has another side that also merits attention: the 

 nature of the physiological changes, regardless of origin, that 

 are directly responsible for the decreased susceptibility of the 

 cell to inhibition by the drug. In other words, for present 

 purposes I am interested in changes in those units in the cell 

 that do its everyday work, such as its enzymes and membranes, 

 rather than in changes in the more intellectual units which 

 govern, in interaction with the environment, the pattern of 

 formation of these working units. Furthermore, I should 

 like to emphasize the distinctness of the two problems. For 

 regardless of the origin of drug resistance, an analysis of its 

 phenotypic mechanism, at a biochemical level, would in- 

 evitably lead us to measure such parameters as the level of 

 various metabolites and enzymes, the ability of the cell to 

 concentrate or bind various compounds, and the affinity of 

 enzymes and transport systems for the drug. 



As the physiological problem has so far been much less 

 extensively explored than the genetic one, it may offer a 

 greater challenge at the present time. The literature on the 

 subject has recently been comprehensively reviewed (Abraham 

 1953; Schnitzer and Grunberg, 1957), and so the present paper 

 will be restricted to selected aspects of the problem. 



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