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At least 19 recordsLinked to original sources
PubMed1988

Binding of tritiated hycanthone and hycanthone N-methylcarbamate to macromolecules of drug-sensitive and drug-resistant schistosomes.

Adult Schistosoma mansoni of the hycanthone-sensitive and of the hycanthone-resistant strain were exposed in vitro to tritium-labeled hycanthone. The drug was taken up in similar amounts by the two strains, a result which is not compatible with hypothetical mechanisms of resistance based on reduced drug entry into the schistosomes. Labeled hycanthone was found to bind irreversibly to macromolecules of sensitive schistosomes, whereas the binding was minimal in resistant worms. In particular, the DNA of sensitive schistosomes showed high levels of tightly bound hycanthone, while the corresponding fraction of resistant schistosomes failed to do so. Female schistosomes and immature worms, which are less sensitive to hycanthone, showed a diminished drug-DNA binding with respect to adult males. Tritiated hycanthone N-methylcarbamate, which is effective against sensitive and resistant schistosomes, bound in similar amounts to the DNA of both strains. These results strongly support a previously proposed mechanism of action of hycanthone, which is based essentially on the alkylation of worm macromolecules by a drug derivative produced in sensitive schistosomes.

Animals↗
PubMed1992

Hycanthone resistance in schistosomes correlates with the lack of an enzymatic activity which produces the covalent binding of hycanthone to parasite macromolecules.

Crude extracts of hycanthone sensitive Schistosoma mansoni incubated at 37 degrees C in the presence of ATP and Mg2+ induced the covalent binding of tritiated hycanthone (HC) to macromolecules. The same behavior was shown by the HC sensitive species, Schistosoma rodhaini, whereas two independently isolated HC resistant S. mansoni strains had no detectable activity. Sensitive male schistosomes had more activity than females or immature worms. Virtually no activity was present in mouse liver, in human liver, in HeLa cells or in the naturally resistant species Schistosoma japonicum. The activity was destroyed by boiling or by Proteinase K treatment. Covalent binding of tritiated HC to macromolecules could be inhibited by cold HC, oxamniquine or IA-4, while none of the in vitro ineffective analogs, like lucanthone, UK-3883 or 4-desmethyl lucanthone, were inhibitory. These results strongly support the previously advanced suggestion that HC is activated by enzymatic mechanisms which are present only in drug sensitive schistosomes.

Adenosine Triphosphate↗
PubMed1988

Preparation and antischistosomal and antitumor activity of hycanthone and some of its congeners. Evidence for the mode of action of hycanthone.

The synthesis of a series of esters of hycanthone (HC) and 7-hydroxyhycanthone, their antitumor activity, and their antischistosomal effects on HC-sensitive and HC-resistant schistosomes are reported. Binding studies using tritium-labeled HC and hycanthone N-methylcarbamate (HNMC) with calf thymus DNA provided evidence that HNMC but not HC alkylated the DNA. Tritiated HNMC also bound to the DNA of intact HeLa cells exposed to the drug while very little tritiated HC bound to DNA under the same conditions. The mechanism proposed previously to account for the antischistosomal action of HC, namely, drug esterification followed by alkylation of DNA, applies also to the antitumor action of the drug as shown in Scheme I.

Animals↗
PubMed1978

Early steps in mutagenesis by hycanthone.

Hycanthone, the most potent mutagen in a series of nine thiaxanthenones, is a potent inducer of nuclear immunoreactivity to antinucleoside antibodies in HeLa cells. This response indicates exposure of single-stranded DNA regions. All classes of mutagens thus far tested share this property with hycanthone. Immunoreactivity to antinucleoside antibodies was also induced by brief exposure to hycanthone, 3 microgram/ml, in human fibroblasts from three normal subjects and in fibroblasts from seven patients with DNA repair deficiencies. Unlike those of many other mutagens, the metabolic effects and immunoreactivity induction of hycanthone were readily reversible. No evidence for covalent attachment of [3H]hycanthone to HeLa macromolecules could be found. Induction of DNA repair synthesis could not be detected by autoradiography after exposure of cells to hycanthone. Exposure of single-stranded DNA regions appears to be an important feature of the mechanism of action of hycanthone as a mutagen. Both hycanthone and lucanthone intercalate with DNA, but hycanthone was much less active than was lucanthone in reducing the rapid sedimentation of cell lysate DNA in alkaline sucrose gradients. Similarities and differences, therefore, have been found in the way the potent and the weak mutagen affect DNA of HeLa cells. This may provide clues to understanding the mechanism of mutagenesis by thiaxanthenones and other mutagens.

Antibodies↗
PubMed1981

Mutagenicity of hycanthone in Drosophila: additional results and a comparison with some analogs.

The data reported in this paper extend earlier results on the effects of hycanthone in Drosophila. The main findings are the following. (1) A refined brood-pattern analysis of hycanthone-induced sex-linked recessive lethals confirmed the specific sensitivity of mid- and late spermatids. Injection of young males 0--20 h old) did not cause a shift in the brood pattern, but tended to produce higher rates of recessive lethals than injection of 4-day-old males, although the difference was not significant. (2) An autosomal recessive lethal test (chromosome 2) similarly showed a low sensitivity of premeiotic stages. (3) Feeding of hycanthone was much less effective than injection. This difference was not observed for the methyl analog lucanthone. From the observation that hycanthone- and lucanthone-induced mutations exhibited different germ-cell-stage sensitivity patterns, it was concluded that lucanthone does not (at least not exclusively) act via metabolic activation to hycanthone. (4) After injection, the hycanthone analogs IA-3-N-oxide and IA-4-N-oxide were marginally mutagenic. (5) It was shown previously that hycanthone was ineffective in producing breakage events, in Drosophila. In this report, hycanthone is shown to be weakly active in inducing ring-X chromosome loss. This emphasizes the relative sensitivity of the ring-X-loss test, in comparison with the tests that detect translocations or dominant lethals.

Animals↗
PubMed1987

Enzymatic differences between hycanthone-resistant and sensitive strains of Schistosoma mansoni.

1. Hycanthone-sensitive and resistant adult worms of Schistosoma mansoni were found to have generally similar specific activities in ten enzymes of carbohydrate metabolism. 2. Kinetic analyses revealed that pyruvate kinase, glucose-6-phosphate (G6P) dehydrogenase and malate dehydrogenase from both strains possessed similar Michaelis-Menten constants and were not inhibited by hycanthone. 3. Hexokinase and lactate dehydrogenase from the drug-resistant strain were not inhibited by hycanthone and showed three to five times greater Km values than those from the drug-sensitive worms which were also inhibitable by hycanthone. 4. Hycanthone more drastically affected the Vmax of phosphofructokinase from the hycanthone-sensitive parasite. 5. These data showed that the hycanthone inhibitable enzymes were generally from the drug-sensitive strain whereas the enzymes from drug-resistant worms are mostly hycanthone insensitive.

Animals↗
PubMed1984

Genetic analysis of hycanthone resistance in Schistosoma mansoni.

Interbreeding between hycanthone-resistant and hycanthone-sensitive schistosomes was achieved using a worm transfer technique which considerably reduced the length and the complexity of the operations generally involved in performing schistosome genetic crosses. A mouse was considered to harbor resistant schistosomes if, three weeks or more after a single intrasmuscular injection of 80 mg/kg hycanthone schistosome eggs were still excreted in the feces, at least one normal worm pair was obtained by perfusion, or miracidia could be seen hatching from the liver. The F1 hybrid progeny from crosses between sensitive and resistant schistosomes proved to be sensitive to hycanthone, irrespective of whether the resistant parent was the male or the female. The resistant phenotype reappeared in back-crosses and in the F2 progeny. These results could be confirmed using the traditional technique of single sex infections. It can thus be concluded that hycanthone resistance behaves like an autosomal recessive trait. These results suggest that hycanthone-resistant schistosomes are deficient in some factor, possibly an enzymatic activity which transforms hycanthone into a biologically active molecule, as suggested in a recent hypothesis on the mode of action of hycanthone.

Animals↗
PubMed1985

Effects of hycanthone on the neuromuscular transmission.

The effects of the antischistosomal drug, hycanthone, on the synaptic transmission at the frog neuromuscular junction were studied. The mean quantal content increased in the presence of 20 microM hycanthone. The amplitude of the miniature end-plate current was unaffected by 20 microM hycanthone, while 2 microM hycanthone decreased the ionophoretic ACh response (ACh induced current). The decay time constants of the evoked end-plate current and the miniature end-plate current were increased with 1-5 microM hycanthone, but were decreased at concentrations over 20 microM. Analysis of the ACh induced noise revealed that 1 microM hycanthone slightly increased the channel lifetime whereas the single channel conductance was not affected. It was concluded that the primary site of action of hycanthone is the 'transient state' or ACh bound but closed conformation of the ACh receptor ion channel, but this drug also has other sites of action (presynaptic nerve terminal and open conformation of ACh receptor-ion channel complex).

Animals↗
PubMed1981

Effect of hycanthone on Schistosoma mansoni macromolecular synthesis in vitro.

Adult, immature and hycanthone-resistant schistosomes were allowed to incorporate tritiated precursors of macromolecule synthesis in vitro, either in the presence of various concentrations of hycanthone, or at various times after removal of the drug. The effect on worms was compared to that on HeLa cells. The results show that hycanthone markedly inhibited the incorporation of uridine in all the systems studied, while the incorporation of thymidine and leucine was only secondarily affected. The inhibition of uridine incorporation reflected in part a decreased uptake of the radioactive precursor. The hycanthone-induced inhibition of uridine incorporation was essentially irreversible upon removal of the drug in adult schistosomes, while it was completely reversible in hycanthone-resistant worms, in immature worms and in HeLa cells. The effects of a hycanthone analog, IA-4, were largely comparable to the effects of the parent compound. These results suggest that the inhibition of RNA synthesis can be a possible explanation for the mechanism of the schistosomicidal action of hycanthone.

Dactinomycin↗
PubMed1989

Resistance of schistosomes to hycanthone and oxamniquine.

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.

Alkylation↗
PubMed1975

Anticholinergic properties of the antischistosomal drug hycanthone.

The effect of the antischistosomal drug hycanthone on the motor activity of Schistosoma mansoni was studied in vitro. Hycanthone stimulates motor activity at concentrations of 10(-6) to 10(-5) M, and partially blocks the paralytic effects of carbachol and physostigmine. Lucanthone, a closely related although less active congener of hycanthone, does not produce these same effects in vitro. Some blocking of acetylcholine can also be produced by atropine, although this drug is less active in this regard than is hycanthone. These findings suggest that the therapeutic efficacy of hycanthone may be related to interference with acetylcholine receptors in schistosomes. Hycanthone is an inhibitor of acetylcholinesterase (ACHE) from S. mansoni, but is less effective against ACHE of mammalian origin. In contrast, physostigmine inhibits the mammalian enzyme more effectively than it does the helminth enzyme. These observations suggest that schistosome ACHE differs from the mammalian enzyme with respect to the configuration of the active center, and that hycanthone may have a selective affinity for schistosomal cholinergic systems.

Animals↗
PubMed1977

Comparative effects of hycanthone in Schistosoma mansoni and Schistosoma japonicum.

After in vitro hycanthone treatment followed by a 20-hour incubation in drug-free medium, Schistosoma mansoni were still resistant to labeling by a fluorescent analog of acetylcholine. S. japonicum, in contrast with the hycanthone sensitive species, showed prompt reversal of the blocking effects of hycanthone on fluorescent labeling. This finding suggests that differences in the reversibility of hycanthone may correlate with the usefulness of the drug in the therapy of schistosome infections by different species of parasites. Scanning electron microscopy has been used to demonstrate that hycanthone treatment causes degeneration of the integument of S. mansoni, but not S. japonicum, over a period of few days after in vivo exposure to hycanthone. The mechanism by which hycanthone causes this effect is not known.

Acetylcholine↗
PubMed1977

Experimentally produced resistance of Schistosoma mansoni to hycanthone.

Genetically transferred resistance to the antischistosomal drug hycanthone has been observed in several strains of Schistosoma mansoni: 1) in the progeny of worms to whose hosts hycanthone had been administered 54 to 70 days after exposure to cercariae (Type I); 2) in the progeny of worms to whose hosts hycanthone had been administered when the worms were still in an immature stage (27 to 29 days after percutaneous cercarial exposure) (Type II); and 3) in the progeny of worms from hosts that had been infected with cercariae of one sex followed by infection with the opposite sex 2 to 58 weeks later (Type III). In types I and II, drug resistance was transferred maternally. Hycanthone-resistant schistosomes were cross-resistant to antischistosomal drugs structurally related to hycanthone, such as oxamniquine and two chloro-indazole analogs of hycanthone, but not to niridazole and to another nitroheterocyclic compound.

Animals↗
PubMed1979

Carcinogenic potential of hycanthone in mice and hamsters.

Hycanthone was administered to Schistosoma mansoni-infected and non-infected Syrian golden hamsters and Swiss mice by intraperitoneal and intramuscular injection of amounts up to the maximum tolerated dose. No tumors attributable to treatment were observed in hamsters. In infected mice, the overall incidence of hepatomas and hepatocellular carcinomas increased from 3.4% in untreated mice to 10.6% in those treated with hycanthone. Non-infected control mice developed 0.8% of these tumors compared to 10.2% in mice treated with hycanthone. Despite the use of high dose levels of hycanthone, statistical significance was attained only with non-infected female mice injected intraperitoneally and intramuscularly with hycanthone and then only at confidence levels of 92 and 95% respectively.

Animals↗
PubMed1975

Evaluation of the teratogenic activity of hycanthone in mice and rabbits.

Hycanthone has been tested for embryotoxic activity in mice and rabbits. Treatment of mice on days 6-11 of gestation produced little embryotoxicity at a dose of 12.5 mg/kg, but produced teratogenic effects at 25 mg/kg and induced almost complete intrauterine death at 50 mg/kg. Single injections on various days of gestation demonstrated that the mouse conceptus is most sensitive to hycanthone-induced teratogenesis on gestation days 6 and 7, at which time a high incidence of exencephaly and skeletal malformations was found. Hycanthone (50 mg/kg) given to pregnant mice on day 7 of gestation depressed DNA synthesis in embryonic tissue, an effect which was evident 30 minutes after drug treatment and which lasted at least 3 hours. Following a single injection of [3H-U]hycanthone into 7-day pregnant mice, radioactivity was rapidly cleared from the maternal plasma, having a half-life of 1-2 hours; higher levels of radioactivity were attained in the embryonic vesicles than in maternal plasma at all time intervals tested. Hycanthone also had embryotoxic activity in rabbits. A dose of 25 mg/kg increased the incidence of intrauterine death, and at 50 mg/kg both embryolethal and teratogenic effects were noted.

Abnormalities, Drug-Induced↗