ON THE MECHANISM OF CHEMOTHERAPEUTIC ACTION. XII COMPARISON OF THE BINDING OF CHEMOTHERAPEUTIC AGENTS BY NORMAL AND RESISTANT TRYPANOSOMES

¹ From the Burroughs Wellcome & Company, U. S. A., Experimental Research Laboratories, Tuckahoe, New York

1. Normal and neoarsphenamine resistant strains of trypanosoma equiperdum bind arsenic from neoarsphenamine and Mapharsen solutions. With increasing concentration the binding increases in both cases. From solutions of equal concentrations, the neoarsphenamine resistant trypanosomes bind less arsenic than the normal trypanosomes if glucose is present. The latter are, however, more damaged (or more of them are killed). The binding is equal for both strains in the absence of glucose and other nutrient media. If concentrations are compared, which would kill both strains in the same average time, the binding is the same for both strains.

2. Factors which considerably influence the killing time do not appreciably affect the binding.

3. The binding of arsenic from neoarsphenamine solutions is greater in an oxygen atmosphere than in vacuum. Practically no such difference was found in the binding from Mapharsen solutions. The inference is drawn that the binding takes place in the form of 3-amino-4-hydroxyphenylarsenious oxide.

4. The binding of arsenic by normal trypanosomes in vivo is greater than by arsenic resistant strains if identical doses are injected. The dose used affects the course of a normal infection but does not affect noticeably the course of the infection with resistant trypanosomes.

5. Strains resistant to arsenicals bind less acriflavin from equally concentrated solutions than do normal trypanosomes. The difference in binding is much greater in vivo than in vitro.

6. The binding of acriflavin is slightly greater in the presence of glucose than in plain phosphate buffer. There was no indication that the damaged trypanosomes bind more acriflavin than the normal trypanosomes.

7. Previous treatment with acriflavin does not change the binding of arsenicals by trypanosomes, nor does treatment with neoarsphenamine alter the acriflavin binding. Sodium thioglycolate does not detoxify acriflavin.

8. The results are interpreted as contradictory to the theory that acquired resistance is due to loss of binding groups. The possibilities that acquired resistance is due to decreased affinity, or to increase tolerance are discussed.