166 Bernard D. Davis 



Possible physiological mechanisms of drug resistance 



For purposes of orientation it might be well to start by list- 

 ing the theoretically possible changes in the function of a cell 

 that could be expected to increase its resistance to an inhibitor. 

 These would include the following (Davis and Maas, 1952); 

 and there might well be others that we are missing. 



(1) Alternative metabolic pathway bypassing the inhibited 



reaction. 



(2) Increased concentration of a metabolite that antagon- 



izes the inhibitor. 



(3) Increased concentration of the enzyme that the drug 



inhibits. 



(4) Decreased requirement for a product of the inhibited 



metabolic system. 



(5) Increased destruction of the inhibitor (or decreased 



conversion of an administered compound into a more 

 active inhibitor). 



(6) Formation of an altered enzyme, with decreased affinity 



for the inhibitor or with increased relative affinity 

 for the substrate compared with a competitive inhibitor. 



(7) Decreased permeability of the cell (or of subcellular 



units) to the inhibitor. (As a special case pointed out by 

 Mr. Anton Kris, a medical student at Harvard, this could 

 include increased affinity of a permeation system for 

 other compounds which interfered with transport of the 

 inhibitor.) 



I should like to comment briefly on these mechanisms, first 

 pointing out that there is no reason to anticipate that any 

 one mechanism will ultimately be found to tell the whole 

 story. If mutations can give rise to an increment of resistance 

 through various mechanisms, the inhibitor would select them 

 aU; and there is little doubt that nature would avail itself of 

 all the means at its disposal to fill such an ecological niche. 



The first mechanism, involving an alternative metabolic 

 path, seems to have long been a speculative favourite, especi- 

 ally since drug resistance has been shown in many cases to 



