760 6. ARSENICALS 



Ability of Different Arsenicals to Induce Resistance 



It has been known from the time of Ehrlich that resistance is much 

 easier to produce with some arsenicals than with others. In general it 

 appears that pentavalent arsenicals, such as atoxyl and tryparsamide, 

 induce resistance most readily, certain trivalent arsenicals, such as oxo- 

 phenarsine, dichlorophenarsine, and butarsen, are intermediate, while 

 arsenophenylglycine and arsenite induce resistance only with difficulty. 

 No rapid or marked resistance has ever been produced with arsenite in any 

 organism, and in many cases even prolonged exposure has resulted in 

 failure to demonstrate tolerance, as in the exposure of Trypanosoma gam- 

 biense to arsenite over 13 months and during 40 passages (Tobie and von 

 Brand, 1954). Organisms resistant to various arsenicals are usually suscep- 

 tible to arsenophenylglycine, and it has been very difficult to induce resis- 

 tance to this compound; the only instance is that in which a resistance 

 factor of 4 was reached after 10 months of exposure by the relapse method 

 (Yorke et al., 1932). Such behavior might imply basic differences in the 

 mechanism of action of the various arsenicals, but we shall see that it 

 may also be explained on the basis of different modes of penetration. 



Cross-Resistance 



If all the arsenicals penetrated and acted in the same manner, and if 

 there is some common basic change in the resistant forms, one would expect 

 cross-resistance to be complete. In fact, the earliest observations in Ehr- 

 lich's laboratory showed that this is not the case and all recent work has 

 confirmed this. An organism made resistant to one arsenical may or may 

 not be resistant to another arsenical, or will generally show a degree of 

 resistance either greater or less than to the inducing compound. It is 

 interesting that strains made resistant to certain nonarsenical substances 

 may show resistance to the arsenicals or, conversely, that arsenical-resistant 

 strains may be resistant to nonarsenicals. Occasionally, for example, arsen- 

 ical-resistant strains may be resistant to p-rosaniline; however, p-rosani- 

 line-resistant strains have never been found to be resistant to the arsenicals. 

 Typical arsenical-resistant organisms are usually not resistant to other 

 trypanocidal agents, such as the diamidines, quinolines, or suramin, but 

 may be resistant to the acridine dyes of the acriflavine type. Yet organisms 

 made resistant to Melarsen exhibit resistance to the diamidines and other 

 compounds, indicating that the resistance here may be unrelated to the 

 arsenic group, or reaction with SH groups (Williamson and Rollo, 1959). 

 A stilbamidine-resistant strain of Trypanosoma rhodesiense showed a resis- 

 tance factor of 64 with Melarsen oxide, although the trypanocidal concen- 

 trations of numerous inhibitors were not altered (Williamson, 1959 b). 

 It may also be noted that organisms resistant to some arsenicals are gener- 

 ally resistant to the antimonials. 



