Résumé
Genetic crosses between phenotypically resistant and sensitive schistosomes demonstrated that resistance to hycanthone and oxamniquine behaves like a recessive trait, thus suggesting that resistance is due to the lack of some factor. We hypothesized that, in order to kill schistosomes, hycanthone and oxamniquine need to be converted into an active metabolite by some parasite enzyme wich, if inactive, results in drug resistance. Esterification of the drugs seemed to be the most likely event as it would lead to the production of an alkylating agent upon dissociation of the ester. An artificial ester of hycanthone was indeed active even in resistant worms, thus indirectly supporting our hypothesis. In addition, several lines of evidence demonstrated that exposure to hycanthone and oxamniquine results in alkylation of worm macromolecules. Thus, radioactive drugs formed covalent bonds with the DNA of sensitive (but not of resistant) schistosomes; an antiserum raised against hycanthone detected the presence of the drug in the purified DNA fraction of sensitive (but not of resistant) schistosomes; a drug-DNA adduct was isolated from hycanthone-treated worms and fully characterized as hycanthone-deoxyguanosine.
Sujets)
Animaux , Cochons d'Inde , Souris , Schistosoma mansoni/effets des médicaments et des substances chimiques , Résistance aux substances/génétique , Hycanthone/pharmacologie , Gènes d'helminthe , Croisements génétiquesRésumé
A administraçäo de praziquantel a camundongos infectados pelo Schistosoma mansoni(50 cercarias/8 semanas) causou necrose de coagulaçäo e/ou lítica, e por vezes calcificaçäo dos miracídios nos tecidos a partir do 4§ dia do início do tratamento. A administraçäo conjugada de oxamniquine/hycanthone, embora muito efetiva para eliminar os vermes adultos, näo teve açäo sobre os miracídios no interior dos granulomas, tendo os testes de eclosäo sido positivos até o 15§ dia após o tratamento curativo. A açäo do praziquantel sobre os ovos do S. mansoni pode ter repercussäo sorológica ou patogênica, facilitando uma mais rápida reabsorçäo dos granulomas pelos tecidos do hospedeiro