Resistance of schistosomes to hycanthone and oxamniquine

Abstract

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 which, 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.

(Epi)genetic Inheritance in Schistosoma mansoni: A Systems Approach

“…A relative recent threat that the parasite faces is exposure to anthelminthic drugs. Despite this, drug resistance can emerge rapidly in natural populations [53] and can be generated within few generations in the laboratory [54]. Genetic mutations that confer the resistance to hycanthone and oxamniquine have been identified 55, 56, but hycanthone-resistant worms that do not carry the corresponding mutations were also found.…”

Exposure to hycanthone alters chromatin structure around specific gene functions and specific repeats in Schistosoma mansoni

“…These observations lead us to think that the resistant phenotype in Type II and III could indeed be induced and transmitted to the progeny to a certain extent. Cioli and Pica-Mattoccia (1984), Cioli et al (1989) and Dias and Olivier (1986) stated that they were unable to reproduce Jansma's results in inducing Type II or III resistance. Three other antihelminthics, oxamniquine, praziquantel, and oltipraz were also unsuccessfully tested with the hope of inducing Type II resistance and selecting a new line of resistant schistosomes (Dias and Olivier, 1986).…”

“…Two laboratories obtained stable resistant lines of schistosomes by injecting infected mice with a single curative dose (i.e., killing >90% of the worms in susceptible lines, 80 mg/kg) repeated over 3–5 successive generations of the parasite (Cioli and Pica-Mattoccia, 1984; Dias and Olivier, 1985). In these lines, resistance was heritable and stable even in the absence of drug pressure over 9–30 generations (Dias and Olivier, 1985; Cioli et al, 1989; Drescher et al, 1993). Classic genetic crosses between sensitive and resistant strains, as well as genetic complementation demonstrated that a single recessive autosomal locus codes for the hycanthone/oxamniquine resistance in two strains, MAP (named from the initials of the patient from which it was isolated) and Baltimore Rome Resistant (BRR) (Cioli and Pica-Mattoccia, 1984; Cioli et al, 1989, 1992; Pica-Mattoccia et al, 1992b, 1993).…”

“…In these lines, resistance was heritable and stable even in the absence of drug pressure over 9–30 generations (Dias and Olivier, 1985; Cioli et al, 1989; Drescher et al, 1993). Classic genetic crosses between sensitive and resistant strains, as well as genetic complementation demonstrated that a single recessive autosomal locus codes for the hycanthone/oxamniquine resistance in two strains, MAP (named from the initials of the patient from which it was isolated) and Baltimore Rome Resistant (BRR) (Cioli and Pica-Mattoccia, 1984; Cioli et al, 1989, 1992; Pica-Mattoccia et al, 1992b, 1993). Similar results were also obtained in vitro by Coles and Bruce (1987).…”

Study of Schistosoma mansoni isolates from patients with failure of treatment with oxamniquine

“…Dias et al (1982) refered to the use of praziquantel in patients with oxamniquine and hycanthone resistant S. mansoni. According to Cioli et al (1989) genetic crosses between phenotypically resistant and sensitive schistosomes demonstrated that resistance to hycanthone and oxamniquine behaves like a resistant trait, thus suggesting that resistance is due to the lack of a bioactivation process, maybe owing to a specific enzyma that promotes the schistosomicide effect of the drug (Coelho et al 1997). Doenhoff and Bain (1978) showed the involvement of immune mechanisms in drug induced killing of adult worms (antimonial).…”