Enhancement of x-ray damage in HeLa cells by exposure to lucanthone (Miracil D) following radiation.
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Cell Division↗
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Schistosomicidal activity of lucanthone hydrochloride, hycanthone and their metabolites in mice and hamsters.
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Animals↗
Modification of the heat response and thermotolerance by cycloheximide, hydroxyurea, and lucanthone in CHO cells.
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Acclimatization↗
Hycanthone and lucanthone in the treatment of Bilharziasis. A clinical trial.
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Adolescent↗
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↗
Mutagenic evaluation of antischistosomal drugs and their derivatives in Neurospora crassa.
The mutagenic activities of lucanthone, hycanthone, niridazole, and the indazole analogs of lucanthone (IA-3 and IA-5) or hycanthone (IA-4 and IA-6) were studied by assaying for the induction of specific locus mutations in the ad-3 region of N. crassa. The results show that lucanthone, hycanthone, and their indazole analogs (IA-3 through IA-6) are all mutagenic in N. crassa when conidia are treated with any of these compounds. On a per mole basis, hycanthone is the least toxic and mutagenic, whereas IA-3 is the most toxic and mutagenic compound among the six closely related agents. In general, compounds with a methyl group at the C-4 position are more mutagenic than compounds with a methanol group; 6-chloroindazole analogs are more mutagenic and more toxic than nonchlorinated analogs. Niridazole is not mutagenic when conidial suspensions are treated. However, the mutation frequency increased more than 50-fold when niridazole was added to the medium used to grow vegetative cultures. Thus, it appears that the mutagenic activity of this latter compound requires metabolic activation.
Hycanthone↗
Studies on the mode of action of oxamniquine and related schistosomicidal drugs.
Adult Schistosoma mansoni were incubated for 1 hour in vitro with various drugs and then returned into the mesenteric veins of permissive animal hosts. Survival of schistosomes was assessed 3-4 weeks later by portal perfusion. Under these conditions, oxamniquine and hycanthone proved effective in killing S. mansoni, whereas UK-3883, lucanthone and lucanthone-4-desmethyl had no lethal activity. The same drugs which were schistosomicidal in vitro also persistently inhibited DNA, RNA, and protein synthesis in S. mansoni, whereas they were only transiently inhibitory against Schistosoma japonicum, against hycanthone-resistant S. mansoni and against immature worms. When drugs were administered in vivo to infected mice and the synthesis of macromolecules was assayed in vitro on worms obtained 1 or 3 days after treatment, not only oxamniquine and hycanthone, but also UK-3883 and lucanthone, proved effective in inhibiting the synthesis of macromolecules in sensitive--but not in resistant--S. mansoni. It is suggested that oxamniquine, like hycanthone, may exert its schistosomicidal activity by inhibiting nucleic acid synthesis in the parasite.
Animals↗
Detection of mammalian cell mutagens in urine from carcinogen-dosed mice.
Urine from drug-treated rodents was tested directly in the L5178Y TK+/-leads to TK-/- gene mutation assay for the induction of trifluorothymidine-resistant (TFTR) mutants. 18-h urine samples collected from male CD-1 mice which had been treated with either 2-aminofluorene, cyclophosphamide, or lucanthone were incubated with beta-glucuronidase, then added directly to cultures of L5178Y TK+/- mouse lymphoma cells for 3 h. All 3 urine sources produced significant, dose-dependent increases in the frequency of TFTR mutants compared to normal urine or saline controls. When these same chemicals were tested directly as mutagens in L5178Y TK+/- cells, lucanthone and, to a lesser extent, cyclophosphamide were positive both with or without metabolic activation; and aminofluorene was only positive with activation. These results indicate that the urinary metabolites of aminofluorene, cyclophosphamide, and either the parental molecule or urinary metabolites of lucanthone can readily be detected as mutagens in a mammalian cell assay.
Animals↗
Microsomal activation to mutagens of antischistosomal methyl thioxanthenones and initial tests on a possibly non-mutagenic analogue.
Five methylthioxanthenone and methylbenzothiopyranoindazole analogues, including lucanthone (Miracil D), are non-mutagenic for Salmonella typhimurium but are activated to mutagens by a rat liver microsome preparation. Hydroxymethyl analogues, including hycathone (Etrenol), are mutagenic in the absence of microsomes. It seems reasonable to assume that the hydroxymethyl derivatives are the more proximal mutagens and that Salmonella is unable to carry out the hydroxylation necessary for mutagen activation. During the pase 24 years, several million patients with schistosomiasis have been treated with lucanthone, and in recent years about 700 000 persons with hycanthone. The possible long-term deleterious effects of these agents for man even now remain to be determined. Our studies indicate that particular modifications in the structure of thioxanthenones drastically alter their mutagenicity. One apparently non-mutagenic thioxanthenone has been found. A number of the less mutagenic compounds also exhibit decreased acute toxicity in the mouse while retaining appreciable antischistosomal activity, suggesting that genetic and schistosomicidal activities may be dissociated from each other.
Animals↗
Schistosoma mansoni: an in vivo study of drug-induced autophagy in the gastrodermis.
The effects of Astiban, Lucanthone, Hycanthone and Niridazole on autophagic activities in the gastrodermis of Schistosoma mansoni were determined in vivo, using different dosage levels and dosage times. With Astiban, high levels of autophagy were observed in the gastrodermis 2 hours after an injection of the drug into the mouse, and this response had declined by 20 hours, marking a recovery by the parasite from the drug. Hycanthone and Lucanthone produced an autophagic response several days after the onset of treatment, and no recovery was observed in the morphology of the gastrodermis after the drug was discontinued. The effects of Niridazole on the gastrodermis were to produce the most dramatic ultrastructural changes after high doses and over several days of treatment. With all the drugs examined, gastrodermal autophagy was characterized by the formation of vacuoles containing cell components, lipid droplets and sometimes hydrolytic enzyme reaction product. The autophagic vacuoles appeared to be formed by the sequestration of cytoplasmic material by the basal membrane infoldings, and the transfer of enzymes into the vacuole from within the limiting membrane. The residues from intracellular digestion appeared to be emptied into the caecal lumen.
Animals↗
Radiation damage in mouse embryos exposed to 1 rad x-rays or negative pions.
Pregnant mice of two different strains (F/A and NMRI) were exposed to 1 rad of whole-body pion- or X-irradiation at day 8 of gestation. Lucanthone (Miracil D), a known radiosensitizer in various biological systems, was applicated 30 min before irradiation. Five days after treatment the fetuses were observed for developmental anomalies. In both strains of mice it was found that the radiation dose as low as 1 rad results in a significant increase in the rate of abnormal fetuses compared to nonirradiated, but restrained fetuses. Comparing the effectiveness of negative pions (peak irradiation) with X-rays for teratogenic effects, the RBE was between 1.7 and 1.9. The application of Lucanthone increased the number of damaged fetuses and led to various degrees of sensitization depending on the mouse strain and dosage used. Differences between the strains as regards the frequency of damages are explained by different development stages at the time of treatment.
Animals↗
The interaction of aminoalkylaminoanthraquinones with deoxyribonucleic acid.
A series of aminoalkylaminoanthraquinones have been prepared as potential intercalating agents. The binding to DNA of these compounds and the known intercalating drugs chloroquine, lucanthone, daunorubicin and doxorubicin has been characterized by spectrophotometric titration. The association constant for the interaction with DNA has been determined for each compound from a Scatchard plot. The compounds synthesized had association constants between 0-5 and 4-2 times 10(6) compared with 0-93, 0-90, 3-10 and 2-49 times 10(6) for chloroquine, lucanthone, daunorubicin and doxorubicin respectively.
Animals↗
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↗
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↗
Effect of nucleic-acid-binding compounds on the hydrolytic activity of various ribonucleases.
Studies were conducted on the stimulatory effect that various nucleic-acid-binding compounds have on the hydrolysis of RNA and polyribonucleotides by pancreatic ribonuclease A and by other ribonucleases. The stimulatory activity of chloroquine on tRNA hydrolysis by pancreatic ribonuclease was due to the formation of oligonucleotides of a wide range of sizes and was not due to the formation of very short ( n greater than 5) oligonucleotide fragments of tRNA. The dextrorotatory and levorotatory isomers of chloroquine did not differ in their ability to stimulate the hydrolysis of tRNA by pancreatic ribonuclease A. In addition to chloroquine and primaquine, other nucleic-acid-binding compounds (e.g., quinacrine, lucanthone, and proflavin) stimulated the hydrolysis of tRNA by pancreatic ribonuclease A. Chloroquine did not alter the rate of hydrolysis by pancreatic ribonuclease A of low-molecular-weight substrates (cytidine cyclic 2':o'-monophosphate, uridine cyclic 2':3'-monophosphate, cytidylyl-adenosine, or uridylyl-uridine). Furthermore, chloroquine and primaquine did not affect the hydrolysis of poly(A) by high concentrations of pancreatic ribonuclease A. In studies on the hydrolysis of tRNA by other endoribonucleases, several of the nucleic-acid-binding compounds (e.g., quinacrine and ethidium) exhibited appreciable inhibition of both ribonuclease N1 and ribonuclease T1. None of the compounds tested stimulated the activity of ribonuclease T1, and only chloroquine, and perhaps lucanthone, stimulated the hydrolysis of tRNA by ribonuclease N1.
Acridines↗
Clinically available antischistosomal drugs.
The indications, the contraindications, and the characteristics of the antimonial and nonantimonial drugs clinically available for the treatment of human schistosomiasis are outlined. Of the antimonial compounds, antimony potassium tartrate or antimony sodium tartrate, both given by the intravenous route, are effective against Schistosoma japonicum, S. mansoni, and S. hematobium, but the production of severe side effects limits their use outside the treatment of individuals. Sodium antimonyl gluconate is less effective against S. mansoni and S. hemotobium and is also given intravenously. Of those antimonial compounds given intramuscularly, antimony dimercaptosuccinate is the most effective against all three common human schistosomes. Four available nonmetallic schistosomicides are considered. Niridazole, orally administered, is effective against all three common species of schistosome infecting man, but activity is maximal against S. hematobium. Many minor side effects have been described, but the major and most important side effects, neuropsychiatric symptoms and signs, are fortunately rare. Lucanthone hydrochloride, of moderate efficiency when given orally for S. hematobium or S. mansoni infections, is probably best used as a suppressant in small doses. Troublesome gastrointestinal toxicity limits its therapeutic use. Metrifonate, a cholinesterase-inhibiting organophosphorus compound, is effective only against S. hematobium. Clinical tolerance is very good. Hycanthone mesylate is highly effective against S. mansoni and S. hematobium but ineffective against S. japonicum. It is given as a single intramuscular dose. Many contraindications to its use exist, and acute hepatotoxicity has occurred infrequently. Its association with mutagenicity in certain experimental test systems has stimulated numerous ongoing studies to clarify the implications of its use in humans.
Antimony↗
The schistosomicidal and toxic effects of some N-p-aminophenoxyalkylamides.
Several N-(omega-p-aminophenoxyalkyl)amides were active against Schistosoma mansoni in mice. One of the most effective, N-(5-p-aminophenoxypentyl)benzamide (M&B3002), acted more rapidly than lucanthone on adult worms but less rapidly than antimony potassium tartrate. It was inactive against immature worms. This compound and M&B2948A (N-(5-p-aminophenoxypentyl)phthalimide) were both active against S. mansoni in hamsters. In monkeys M&B2948A was inactive, whilst M&B3002 was not tested for therapeutic activity. Several of the compounds were examined for the production of visual impairment in cats. Although this property was not entirely absent, its incidence was very much lower in this amide series than among other omega-p-aminophenoxyalkyl derivatives not containing an amide group. M&B3002 and M&B2948A produced impairment of vision in only a small proportion of the large number of cats tested. The general toxicology of the two drugs was studied in several species, and also their absorption and excretion in mice and rats; this was to provide information for a clinical trial.
Amides↗
Hycanthone analogs: dissociation of mutagenic effects from antischistosomal effects.
N-Oxidation at the diethylamino group of hycanthone, of lucanthone, and of two chlorobenzothiopyranoindazoles resulted in a marked reduction in mutagenic activity, while antischistosomal activity was retained or even enhanced. Introduction of chlorine into the 8-position of benzothiopyranoindazoles reduced acute toxicity but had no effect on chemnotherapeutic potency. These dissociations of biological activities indicate that safer antischistosomal compounds of this class can be developed.
Animals↗