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PubMed2005

Clonogenicity of human leukemic cells protected from cell-lethal agents by heat shock protein 70.

Pretreatment of human leukemia THP-1 cells with heat shock protein Hsp70 (Hsp70) protected them from the cell-lethal effects of the topoisomerase II inhibitor, lucanthone and from ionizing radiation. Cell viability was scored in clonogenic assays of single cells grown in liquid medium containing 0.5% methyl cellulose. Colonies were observed and rapidly scored after staining with the tetrazolium salt, 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide. The frequency of abasic sites in the deoxyribonucleic acid (DNA) of THP-1 cells was reduced when these cells were treated with Hsp70. Hsp70 is presumed to have protected the cells by promoting repair of cell DNA, in agreement with previous studies that showed that Hsp70 enhanced base excision repair by purified enzymes. The shoulders of radiation dose-response curves were enhanced by pretreatment of cells with Hsp70 and, importantly, were reduced when cells were transfected with ribonucleic acid designed to silence Hsp70. Hsp70 influenced repair of sublethal damage after radiation.

Cell Line, Tumor↗
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↗
PubMed1975

[Inhibition by actinomycin D of ribosomal RNA synthesis in the presynthesis period of the mitotic cycle of Chinese hamster cell cultures].

Using radioautographic technique actinomycin D at a concentration of 0.08 mug/ml was shown to inhibit selectively ribosomal RNA (rRNA) synthesis in monolayer cultures of Chinese hamster cells. The treatment with actinomycin D of cells synchronized by mitotic selection in the beginning of the G1 period causes a delay in the onset of DNA synthesis. However, a similar treatment in the late G1 period does not prevent cells from entering the S-period. The same effect has been produced by 9 mug/ml lucanthone, another inhibitor of rRNA synthesis. The experiments demonstrate a pronounced difference in cell reaction to the depression of rRNA synthesis in early and late G1 period. The data imply that the formation of rRNA, essential for the initiation of DNA synthesis, is accomplished in the first half of the G1 period, while part of rRNA has been already formed in the previous cycle.

Animals↗
PubMed1986

Lack of correlation between schistosomicidal and anticholinergic properties of hycanthone and related drugs.

Visual observation of the motor activity of Schistosoma mansoni kept in vitro showed an increase of activity in the presence of hycanthone (HC). In addition, HC caused a delay in the paralytic effects of carbachol. Similar results were observed in the presence of oxamniquine (OXA). The same pattern of motor activity, however, was shown by HC-resistant worms, by Schistosoma japonicum, and by worms exposed to drug precursors (lucanthone and UK-3883), which are not schistosomicidal in vitro. Other analogs with in vitro killing activity (IA-4 and IA-4 N-oxide) showed minimal anticholinergic effects. The anticholinergic effects of HC and OXA were quickly reversible in vitro and in vivo, whereas their antischistosomal effects are irreversible and delayed. Incubation of schistosomes with high concentrations of carbachol or with anticholinergic drugs failed to compete with the schistosomicidal effects of HC. These results are viewed as contradictory to the hypothesis that HC kills schistosomes by blocking their acetylcholine receptors.

Animals↗
PubMed1975

Activity of known antischistosomal agents on early-developing forms of Schistosoma mansoni.

Sixteen compounds, including several series of antischistosomal agents, were tested in mice (subcutaneous, oral, and intramuscular routes), previously injected intraperitoneally with 175 plus or minus 25 Schistosoma mansoni cercariae. Most drugs were given in a 5-day regimen, first dose being administered 3 hr before cercarial inoculation. Ten days after infection the animals were killed, the schistosomules collected from peritoneal washings, and counted under a dissecting microscopy (free organisms and larvae surrounded by macrophages). A high degree of activity (abscess of free larvae) was observed with Hoechst S-616 and S668, Ciba 17,581, Oxamniquine (Pfizer), and RD 12,869 compounds. A significant reduction (P less than 0.05) in the number of larvae was observed with A-16,612, Sb-EDTA, Hycanthone, Schistomide, Trichlorphone, and Antiomaline. No activity on nearly developing forms of S. mansoni was observed after treatment with Mirasan, Hoechst S-201, Schistocide T-109, Lucanthone, and Wellcome 153C51. In conclusion, from 16 compounds taken at random, all of which are active on mature schistosome infections, 11 displayed prophylactic activity. This indicates a high sensitivity of the technique using peritoneal schistosomules.

Animals↗
PubMed1977

Effects of low-dose irradiation with x-rays and pi-mesons on embryos of two different mouse strains.

The effects of two different kinds of radiation (X-rays and negative pions) on embryonic development of mice was examined. The application of a known radiosensitizer (lucanthone) combined with 13.5 rd whole-body irradiation on day 8 of gestation showed enhanced teratogenic action compared to treatment with each of the agents alone. The extent of intensification varied both with mouse strain and treatment, indicating possible differences in repair capacity and LET-dependency of sensitization effects. Strain differences were found in the incidence and type of chemical and radiation-induced malformations, which may be explained by different developmental stages at the time of treatment.

Animals↗
PubMed1992

Drug-DNA sequence-dependent interactions analysed by electric linear dichroism.

The interactions between 20 drugs and a variety of synthetic DNA polymers and natural DNAs were studied by electric linear dichroism (ELD). All compounds tested, including several clinically used antitumour agents, are thought to exert their biological activities mainly by virtue of their abilities to bind to DNA. The selected drugs include intercalating agents with fused and unfused aromatic structures and several groove binders. To examine the role of base composition and base sequence in the binding of these drugs to DNA, ELD experiments were carried out with natural DNAs of widely differing base composition as well as with polynucleotides containing defined alternating and non-alternating repeating sequences, poly(dA).poly(dT), poly(dA-dT).poly(dA-dT),poly(dG).poly(dC) and poly(dG-dC).poly(dG-dC). Among intercalating agents, actinomycin D was found to be by far the most GC-selective. GC selectivity was also observed with an amsacrine-4-carboxamide derivative and to a lesser extent with methylene blue. In contrast, the binding of amsacrine and 9-aminoacridine was practically unaffected by varying the GC content of the DNAs. Ethidium bromide, proflavine, mitoxantrone, daunomycin and an ellipticine derivative were found to bind best to alternating purine-pyrimidine sequences regardless of their nature. ELD measurements provided evidence for non-specific intercalation of amiloride. A significant AT selectivity was observed with hycanthone and lucanthone. The triphenyl methane dye methyl green was found to exhibit positive and negative dichroism signals at AT and GC sites, respectively, showing that the mode of binding of a drug can change markedly with the DNA base composition. Among minor groove binders, the N-methylpyrrole carboxamide-containing antibiotics netropsin and distamycin bound to DNA with very pronounced AT specificity, as expected. More interestingly the dye Hoechst 33258, berenil and a thiazole-containing lexitropsin elicited negative reduced dichroism in the presence of GC-rich DNA which is totally inconsistent with a groove binding process. We postulate that these three drugs share with the trypanocide 4',6-diamidino-2-phenylindole (DAPI) the property of intercalating at GC-rich sites and binding to the minor groove of DNA at other sites. Replacement of guanines by inosines (i.e., removal of the protruding exocyclic C-2 amino group of guanine) restored minor groove binding of DAPI, Hoechst 33258 and berenil. Thus there are several cases where the mode of binding to DNA is directly dependent on the base composition of the polymer. Consequently the ELD technique appears uniquely valuable as a means of investigating the possibility of sequence-dependent recognition of DNA by drugs.

Base Sequence↗
PubMed1979

Qualitative and quantitative aspects of intercalator-induced DNA strand breaks.

The intercalating agents, adriamycin and ellipticine, were previously found to produce DNA strand breaks associated with DNA-protein crosslinks in mouse leukemia L1210 cells. The current work explores the nature of the agents that produce this effect and the quantitative relationship between the breaks and crosslinks. The protein-associated DNA breaks were produced by a wide variety of intercalators in addition to the above-mentioned compounds: actinomycin D, daunoycin, ethidium and lucanthone (miracil D). Treatment with several drugs that bind to DNA without intercalation, or that inhibit DNA synthesis without binding to DNA, did not cause DNA breaks. The strand break and crosslink frequencies were quantitated by means of alkaline elution methods. The strand break and crosslink frequencies were found to be within a factor of 2 of each other over a range of concentrations of adriamycin and ellipticine. It is proposed that intercalation-induced distortion of the DNA helix leads to strand scission by a nuclease which becomes bound to one terminus of the break so as to form a DNA-protein crosslink.

Alkaloids↗
PubMed1979

Structural modification study of bis(substituted aminoalkylamino)anthraquinones. An evaluation of the relationship of the [2-[(2-hydroxyethyl)amino]ethyl]amino side chain with antineoplastic activity.

Several anthraquinones containing the [2-[(2-hydroxyethyl)amino]ethyl]amino, the [2-(dimethylamino)ethyl]amino, and the 2-(dimethylamino)ethoxy groups were prepared. Preparation of a lucanthone analogue, a 7-chloroquinoline derivative, and derivatives of naphthoquinones containing the [2-[(2-hydroxyethyl)amino]ethyl]amino side chain and related amino-substituted side chains was also conducted. It was found that the antineoplastic activity of anthraquinones containing the [2-[(2-hydroxyethyl)amino]ethyl]amino side chain is superior to those containing the tertiary amino side chain. However, the presence of the [2-[(2-hydroxyethyl)amino]ethyl]amino chain is an important, but not a sufficient, factor for good antineoplastic activity, as indicated by the lack of significant biological activity of other ring systems containing this side chain.

Animals↗
PubMed1975

Mutagenicity testing of antischistosomal thioxanthenones and indazoles on yeast.

Two antischistosomal thioxanthenones, lucanthone and hycanthone, and four antischistosomal indazoles, IA-3, IA-4, IA-5, and IA-6, have been tested for mutagenicity on stationary phase cells of the yeast Saccharomyces cerevisiae. It was shown that, although there are some gaps in the data, hycanthone and IA-6 are mutagenic at pH 7.0, hycanthone is mutagenic at 5.9, and none of the other compounds is mutagenic at either pH. (Because mutagenicity of these compounds at pH 7.0 appears to be related to the presence of a methoxy group at position 5 of the polycyclic ring, it is possible that IA-4 will be mutagenic on yeast when it is tested at pH 7.0.) An excision-repair-deficient strain of yeast is no more sensitive than other strains. It was found from time-concentration studies on lethality that an inverse relation held: cells exposed to a mutagenic compound are more sensitive when time of exposure was varied and concentration of the compound was held constant, and cells exposed to a nonmutagenic compound are more sensitive when concentration is varied and time of exposure held constant. When the compounds were tested on growing cells of yeast in rich media, none of the compounds is mutagenic, although some are lethal. The kinetic behavior in reversion of yeast exposed to these compounds shows marked departures from similar reversion studies where yeast is exposed to radiation, implicating different physiological mechanisms for the alteration of responses of yeast cells exposed to the different mutagens.

Indazoles↗
PubMed1975

Hycanthone and its congeners as bacterial mutagens.

Hycanthone methanesulfonate (HCT) was shown to induce "forward" and "reverse" mutations in Salmonella typhimurium and Escherichia coli. Mutational effects of HCT on S. tyhhimurium TA1532 were concentration and time dependent. A comparison of mutagenic potency for TA1532 was made between HCT and the frame-shift mutagens quinacrine and ICR-191. An investigation of structure-activity relationships revealed the substituent in the 4-position of ring A to be critical for mutagenicity. Activity was found when this group was a hydroxymethyl (i.e., HCT) or an aldehyde (Win 25,315), but the analogues having a carboxyl group (Win 25,850) or methyl group (lucanthone) in this positionwere inactive. Removal of a single ethyl group from the side chain did not affect mutagenic activity inasmuch as the potency of desethyl HCT (Win 27,262) equaled that of HCT on a molar basis. A marginal activity was found with a sample of HCT sulfoxide (win 27,266), but this sample was found to contain traces of HCT. The HCT analogue with a terminal N-oxide in the side chain (Win 29,329) was inactive at the concentration tested.

Bacteria↗
PubMed1991

Schistosomiasis drug therapy and treatment considerations.

Schistosomiasis, a grave and debilitating disease of socioeconomic importance, is increasing in incidence despite concerted efforts to control and contain the disease in all the endemic areas. While a multipronged method of control using health education, sanitation and snail control has been used, chemotherapy and chemoprophylaxis play the most important and crucial role in containing/preventing the transmission of the disease. Schistosomicides such as antimonials were introduced, as early as the 1990s as the drugs of choice and continued to be used until the early 1960s. The antimonials were administered intravenously, and produced severe side effects; the various variables that determined their effects at the site of action made their application difficult and adversely affected their use in large scale chemotherapy. The antimonials were then replaced by hycanthone and lucanthone which were administered intramuscularly. These drugs produced immediate side effects such as hepatotoxicity and gastrointestinal disturbances, and were consequently withdrawn. It was then decided that the alternative was to produce synthetic drugs that could be administered orally. Niridazole, oxamniquine, and metrifonate were introduced as schistosomicidal agents, with drugs like oltipraz and amoscanate still at clinical trial phase. Therapeutic doses of drugs like hycanthone, niridazole and amoscanate have been found to cause many major side effects. A significant advance in the control of schistosomiasis chemotherapy is the introduction of a relatively safe, effective, broad spectrum oral helminthic agent, praziquantel. Studies have also shown that oxamniquine is as effective as praziquantel in eliminating intestinal S. mansoni infection, and metrifonate is as effective as praziquantel in eliminating urinary S. haematobium and S. mansoni infections. Praziquantel has been found to be effective in treating S. haematobium infections compared with metrifonate and more effective in treating S. mansoni infection when compared with oxamniquine. Because the drug is effective even when treating advanced hepatosplenic schistosomiasis, with few side effects, praziquantel is currently the drug of choice for the treatment of any kind of schistosomiasis. The only limitation is the cost which restricts its use in many developing countries. While effective, safe drugs for mass chemotherapy are being developed, the problem of therapeutic failure and drug resistance is being reported from certain developing countries. Under these circumstances, alternative drugs must be resorted to. Mass treatment, a crucial goal in the eventual control of schistosomiasis, awaits a well-tolerated and nontoxic drug that will ultimately prove to be effective where cure is definite. Until such a time, while eradication of the disease is a near impossibility, reducing the intensity of infection can ultimately reduce morbidity and even mortality.(ABSTRACT TRUNCATED AT 400 WORDS)

Humans↗
PubMed1971

Influence of parasite strain on chemotherapy of murine infections with Schistosoma mansoni.

The effectiveness of chemotherapy in human schistosomiasis varies from one area to another, and limited data from experimentally infected animals suggest inherent differences in the susceptibility of certain parasites to drugs. In the present study, groups of mice infected with each of several geographic strains of Schistosoma mansoni were treated with one of four selected drugs and parasiticidal effects were compared.Responses to treatment were generally similar among strains except in two trials involving a Puerto Rican strain that was unusually sensitive to hycanthone and relatively resistant to stibophen.Selective killing of male worms occurred consistently with lucanthone and hycanthone treatment. The use of portal perfusion rather than dissection to recover surviving worms appears to have been instrumental in allowing the relatively resistant female worms to be found, namely in the liver.The results of this study indicate that strain differences in susceptibility to drugs do occur in S. mansoni, and apparent refractoriness or unusual sensitivity encountered in the field should be evaluated in the laboratory.

Animals↗
PubMed1971

Chemotherapeutic studies on experimental Schistosoma mansoni infection of Mastomys natalensis.

Comparative chemotherapeutic studies on various well known or newly developed schistosomicidal agents have been carried out in Mastomys natalensis experimentally infected with Schistosoma mansoni. Hycanthone, lucanthone, niridazole, Mirasan, the experimental compounds HOE S616, HOE S683, HOE S688, and HOE S201, tartar emetic, stibophen, and stibocaptate acid have shown marked activity when administered in standard daily dosages for 5 consecutive days. Dehydroemetine and bis (p-rosaniline pamoate) proved to be ineffective. The mode of action and the dose-activity relationship of hycanthone methanesulfonate are discussed and compared with the results found for other antimonial and non-antimonial substances.

Animals↗
PubMed1980

Effect of dihydroxyanthraquinone and radiation on G2 progression.

The effect of dihydroxyanthraquinone (DHAQ), a potential anticancer chemotherapeutic agent, on the progression of Chinese hamster ovary cells into mitosis and on the division delay induced by ionizing radiation was studied using the mitotic selection procedure for cell cycle analysis. Following the addition of DHAQ, the number of mitotic cells selected from an asynchronous population remained unaltered for a refractory period and then decreased. This effect was concentration dependent with transition points between the S/G2 boundary at 10(-4) micrograms/ml and the G2/M boundary at greater than or equal to 10(2) micrograms/ml. The duration of the transient division delay was dependent upon the concentration of drug used and the duration of pulse exposure. When cells were treated with pulses of DHAQ in addition to X-irradiation, there was no change in the location of the radiation transition point. There was an increase in the duration of division delay compared to that produced by X-ray alone that was dependent upon the concentration and duration of drug treatment. The effect of DHAW is similar to that of other cancer chemotherapeutic agents (Adriamycin, bleomycin, and lucanthone), and the same cautions should therefore be considered when combining DHAQ and radiation for clinical use.

Animals↗