CHAPTER X 



MODE OF ACTION OF 

 CHEMOTHERAPEUTIC AGENTS 



In recent years, the dramatic success of the sulphonamides 

 and antibiotics in the treatment of bacterial and viral infec- 

 tions of man has focused much attention on the mode of 

 action of these substances and the factors contributing to 

 their activity. Substances interfering with the continued 

 normal existence of an organism may owe their properties 

 to (i) denaturation of proteins, (ii) disruption of cellular 

 membranes and in consequence the leakage of essential 

 metabolites, or (iii) more specifically, inhibition of particular 

 enzymes. Substances bringing about the first two of these 

 effects are of little chemotherapeutic importance, because 

 of their adverse effect on the host as well as the pathogen. 

 The key to successful chemotherapy is contained in the 

 phrase selective toxicity, i.e. the drug is more toxic to the 

 pathogen than to the host. If a chemotherapeutic agent acts 

 by inhibiting an enzymic system of fundamental importance 

 to the pathogen, then this system must be absent from the 

 host, or, if present, it is for some reason less susceptible to 

 the drug, or not essential. (For a detailed exposition of the 

 principles of chemotherapy and selective toxicity, references 

 31 and I are recommended.) One of the aims of contem- 

 porary research is to establish a rational basis for chemo- 

 therapy, and with this in mind, the purpose of the following 

 paragraphs is to survey very briefly the observed effects 

 of the sulphonamides and antibiotics on the metabolism of 

 nitrogenous compounds. 



It must be emphasized that great care is required in 

 deciding whether the observed effect produced by a drug is 

 due to direct inhibition of the reaction leading to that end 

 result, or whether it is a secondary effect arising out of the 

 inhibition of some other, perhaps unknown, reaction. Even 

 if the drug inhibits cell-free preparations of an enzyme this 



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