Stability of Schistosoma mansoni progeny to antischistosomal drugs

Abstract

The susceptibility of the MAP Brazilian strain (F1 to F5 progenies) of S. mansoni to four antischistosomal drugs has been reported in a previous study. In the present investigation, progeny F14 of the same strain, was tested for stability to the same 4 drugs. A new medication, Oltipraz (35,972 RP), was added to the study. Five groups of 12 mice infected with cercariae by tail immersion were treated with hycanthone, oxamniquine, niridazole, praziquantel and Oltipraz. An untreated group was used as control. Schistosomal activity was assessed by the localization of worms in the portal vein system, by oogram changes, and percentage of parasite reduction. The stability of the susceptibility of progeny F14 did not change in relation to generations F1 to F5; the progeny was resistant to hycanthone and oxamniquine; but sensitive to niridazole, praziquantel and Oltipraz. We emphasize the importance of the phenomenon of resistance of the worm in view of the fact that oxamniquine has been widely used in Brazilian areas where mansonic schistosomiasis is endemic.

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

“…The low fidelity of the epigenetic system means the adaptative phenotype could theoretically be loss as quickly as it appears, unless a strong selective pressure is applied. This is consistent with the observations of the metastability of hycanthone resistance in absence of drug pressure (Jansma et al, 1977; Brindley et al, 1989), and the stability of the phenotype after 3–5 successive generations of schistosomes where under drug pressure (Cioli and Pica-Mattoccia, 1984; Dias and Olivier, 1985). Basically, epigenetic variation allows to “buy time” for a few generation (in this case, 3–5) until a stable, genetically transmitted phenotype occurs.…”

“…Three generations of selection were necessary to obtain a phenotype that was stably inherited by the progeny (Cioli and Pica-Mattoccia, 1984). The same observation was made by Dias and Olivier (1985), as in their experiments, resistance was stable only after the 5th generation (experiments were continued until 14th generation). Unfortunately, the data for the first 3–5 generations are not available but one can assume that incomplete penetrance of the phenotype was observed.…”

“…First evidences of resistant worms to this molecule were published in the early 1970's (Rogers and Bueding, 1971). It was later demonstrated several times that schistosomes were in general cross-resistant or cross-susceptible to both hycanthone and another schistosomicide, oxamniquine (Jansma et al, 1977; Cioli and Pica-Mattoccia, 1984; Dias and Olivier, 1985; Bruce et al, 1987). Oxamniquine was often used as a proxy for hycanthone, as the later is not commercially produced anymore and was toxic to the host to a certain degree.…”

“…Oxamniquine was often used as a proxy for hycanthone, as the later is not commercially produced anymore and was toxic to the host to a certain degree. 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).…”

“…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).…”