PRINCIPLES OF CHEMOTHERAPY 789 



the marked difference between the lethal and tolerated doses and the 

 curative dose. 



Drug "Fastness." In the foregoing chapters we have sought to 

 emphasize the importance of the microorganism in the processes of in- 

 fection and immunity from the standpoint of the possibilities of these 

 cells immunizing themselves against the deleterious agencies of the host, 

 and particularly the antibodies, as explained in the hypothesis of Welch. 

 (See p. 103.) It soon appeared that the problem of chemotherapy was 

 greatly complicated by these activities on the part of the parasite, so 

 that the hypothesis appears to be further supported as a result of chemo- 

 therapeutic studies. If the dose of a chemical is just small enough to 

 allow a few microorganisms to escape, these immediately fortify (" im- 

 munize") themselves against the drug and become invulnerable to its 

 effects. It was found that these microparasites were then able to multi- 

 ply, even in the presence of the drug, and, further, that this property of 

 "drug resistance" was transmitted from one generation to another. If, 

 for example, the trypanosomes in a mouse have become resistant to 

 trypan red, a quantity of these trypanosomes may be inoculated into 

 another mouse, and from this one to another, and so on, for many gen- 

 erations, and it would finally be found that the trypanosomes still re- 

 tained their immunity to the action of trypan red. 



This acquired resistance or "fastness" is in a large measure specific. 

 A strain of trypanosomes resistant to the benzidin dyes is non-resistant 

 to arsenic and the triphenylmethane dyes, whereas one resistant to ar- 

 senic is not resistant to the dyes, etc. As Levaditi and Fraser have 

 shown, the antibody-resistant trypanosomes do not anchor the antibody, 

 hence it is probable that the analogy holds for the drug-resistant micro- 

 parasites. 



As was previously stated, Ehrlich has explained this phenomenon 

 on the basis of chemoreceptors. He has ascertained that "fastness" 

 for a certain chemical agent does not depend on atrophy of the corres- 

 ponding receptors, but upon a modification in their structure, as is evi- 

 denced by the fact that, by changing the structure of the chemical, it 

 may still find suitable receptors and lead to the destruction of the para- 

 site. For example, mice that have been infected with arsenic-fast try- 

 panosomes may be cured by an injection of arsenophenylglycin, even 

 at a time when death is imminent. It would appear, therefore, that 

 the arsenic-fast receptors of the trypanosomes were but slightly altered, 

 and were still capable of uniting with an allied product. 



This factor greatly complicates chemotherapy. If, for instance, the 



