CHAPTER 10 



EFFECTS OF MORE THAN ONE INHIBITOR 



The use of two or more inhibitors simultaneously will often produce 

 results or achieve effects not possible with a single inhibitor, just as the 

 administration of more than one drug will occasionally provide a more 

 effective or selective response. As knowledge of the actions of inhibitors 

 increases, it becomes more and more feasible to apply combinations of 

 inhibitors rationally in the investigation of enzyme mechanisms or patterns 

 of metabolism. It may also be possible with multiple inhibitors to establish 

 effective metabolic blockades in abnormal cells, as has been envisioned by 

 Potter (1951) for the selective depression of neoplastic growth by sequential 

 inhibition. The different inhibitors may act on the same enzyme; on the 

 other hand, entirely different enzymes may be inhibited and these enzymes 

 can be either closely related functionally, as in a multienzyme sequence, 

 or quite separated in the cellular metabolic pattern. Inasmuch as no gen- 

 eral term has been used for situations in which two or more inhibitors act 

 simultaneously, it is suggested that this be called multiple inhihition, and 

 this term will be used to include all the various possible types. There are 

 only a few isolated examples of multiple inhibition in the literature and 

 these will be discussed in some detail, but it is likely that this is an approach 

 that will become increasingly more important and therefore a generalized 

 treatment, that may be useful in future investigations, will be given. The 

 kinetics of multiple inhibition have been previously worked out only for 

 some special cases so that it may be valuable to present expressions for sit- 

 uations that have not yet been experimentally demonstrated, in order 

 that both the advantages and disadvantages of multiple inhibition can be 

 visualized in particular instances. It should be obvious that the use of two 

 or more inhibitors introduces complications into an already complex subject, 

 especially when a living cellular system is under investigation, and that the 

 indiscriminate application of multiple inhibitors will be detrimental to 

 progress in both the theoretical and practical aspects. It might be suggested 

 that two or more inhibitors should be used simultaneously only when there 

 is a rational reason for their use, based vipon an accurate knowledge of the 

 actions of the individual inhibitors. 



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