STUDIES ON CHEMOTHERAPEUTIC ACTION I. THE ABSORPTION OF ARSENICAL COMPOUNDS AND TARTAR EMETIC BY NORMAL AND RESISTANT TRYPANOSOMES AND ITS RELATION TO DRUGRESISTANCE

1. The absorption of arsenical compounds by normal and atoxyl-resistant trypanosomes was investigated by exposing them in vitro at 37°C. to suitable concentrations of these compounds, after which they were centrifuged and the distribution of the arsenical was determined ( a ) by measuring the trypanocidal activity of the supernatant fluid for fresh trypanosomes, ( b ) by chemical estimations of the arsenic-content of the supernatant fluid and of the deposited trypanosomes. 2. Normal trypanosomes absorb all the available drug from suitable concentrations of typical trivalent compounds (reduced tryparsamide, halarsol, and novarsenobillon), and with low concentrations of the drug, the trypanosomes suffer no appreciable damage during the process. Absorption occurs very rapidly, being complete at 37°C. in a few minutes; at 5°C. it takes a few minutes longer. 3. Living resistant trypanosomes absorb little or none of the drug from similar concentrations of the above compounds, although absorption will occur if stronger concentrations are used, or if the trypanosomes are dead. A similar difference between the behaviour of normal and resistant trypanosomes, respectively, is observed when the parasites are exposed to reduced tryparsamide in vivo . 4. Compounds to which the atoxyl-fast trypanosomes show no resistance, e.g. phenyl-arsenoxide, sodium arsenite, and tartar emetic, are absorbed to the same extent by both types of parasite. Arseno-phenyl-glycine, which is rather less active on the resistant trypanosomes than it is on the normal ones, is absorbed in somewhat smaller amounts by the former. 5. The pentavalent compound, tryparsamide, which is inactive in vitro is not absorbed by either. 6. A certain proportion of the trivalent arsenical compound enters into combination with some component of the serum so that it is no longer trypanocidal, although it is not distinguished by the chemical method from the part which remains active—novarsenobillon is especially liable to be diverted in this manner. 7. It is considered that the comparative failure of atoxyl-fast trypanosomes to absorb typical trivalent arsenical compounds constitutes the explanation of the drug-resistance of these parasites. 8. Attention is drawn to the importance of the side-chains attached to the phenyl-arsenoxide nucleus in determining the presence and degree of resistance to these compounds. The hypothesis is developed that the phenyl-arsenoxide nucleus combines with "receptors" of the normal trypanosome, but that such combination with the "receptors" of the resistant trypanosome is prevented by the presence and nature of the side-chain. A similar influence of the side-chain can be traced upon the chemotherapeutic index of the various compounds; the side-chain tends to diminish the toxicity, while leaving the trypanocidal activity for normal trypanosomes relatively unchanged. It seems probable that when the receptors of the trypanosome are modified in the development of drug-resistance, they tend to approximate to those of the host.