RESISTANCE TO THE ARSENICALS 767 



arsenite, to which an atoxyl-resistant strain showed no resistance, is taken 

 up equally and poorly by both normals and resistants. Eagle and Magnuson 

 (1944) found the same relations in their spontaneously resistant strain, 

 and the correlation between trypanocidal activity and uptake is shown 

 in Fig. 6-8. This type of experiment has been criticized on the basis that 

 normal susceptible strains would be killed by the arsenical, whereas resis- 

 tants w^ould not, and that dead trypanosomes probably take up more of 

 the arsenical. Hawking (1937) showed that living and dead trypanosomes 

 take up roughly the same amounts of arsenical, and Eagle and Magnuson 

 (1944) pointed out that their uptake studies were in the period before even 

 motility was affected and hence there was no question of dead organisms. 

 It is thus certain that resistant organisms take up less arsenicals than 

 normal strains. The problem is whether this is a matter of altered membrane 

 permeability or altered binding sites on or in the cells. Some have favored 

 the former explanation (King and Strange ways, 1942; Eagle and Magnu- 

 son, 1944) and some the latter (Pedlow and Eeiner, 1935; Hawking, 1937; 

 Schueler, 1947), but in no case has clear evidence been produced on either 

 side. If we assume that the arsenicals are bound to cellular SH groups, a 

 change in binding would imply either a disappearance of SH groups or a 

 modification of their environment so as to make them unavailable for the 

 arsenicals; as we have noted, there is evidence that the former is not correct. 

 In connection with the latter explanation, the work of Schueler (1947) 

 is pertinent. Trypanosomes resistant to amino- or amide-substituted plienyl- 

 arsenoxides show resistance to other basic arsenicals but not to acidic or 

 neutral derivatives; thus the development of resistance might be more 

 related to these substituent groups than to the phenylarsenoxide nucleus. 

 This is confirmed by the fact that organisms highly resistant to the various 

 substituted phenylarsenoxides show little or no resistance to phenylarsen- 

 oxide itself. However, resistance to the acidic arsenicals (e. g. butarsen) 

 certainly implies no great specificity and we have seen that a butarsen- 

 resistant strain is identical to a tryparsamide-resistant strain, except that 

 the former is resistant to butarsen. Schueler postulated that the develop- 

 ment of resistance might be associated with a change in the isoelectric point 

 of the trypanosomal proteins; if, for example, an organism were resistant 

 to a basic arsenical (+ charge) it would be expected to have its isoelectric 

 point shifted upward, so that there would be more + charges to repel the 

 basic arsenicals and prevent them from combining with the SH groups. 

 If such did occur, differences in staining with acidic and basic dyes should 

 be demonstrable and Schueler showed some differences with methylene 

 blue and basic toluidine blue, these differences particularly involving gran- 

 ules within the cells. When these trypanosomes are first treated with 

 oxophenarsine, the stainability of the normals is decreased, whereas the 

 resistants are not affected; treatment with butarsen, against which the or- 



