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At least 19 recordsLinked to original sources
PubMed1990

DNA-directed alkylating agents. 1. Structure-activity relationships for acridine-linked aniline mustards: consequences of varying the reactivity of the mustard.

A series of DNA-targeted aniline mustards have been prepared, and their chemical reactivity and in vitro and in vivo cytotoxicity have been evaluated and compared with that of the corresponding simple aniline mustards. The alkylating groups were anchored to the DNA-intercalating 9-aminoacridine chromophore by an alkyl chain of fixed length attached at the mustard 4-position through a link group X, while the corresponding simple mustards possessed an electronically identical small group at this position. The link group was varied to provide a series of compounds of similar geometry but widely differing mustard reactivity. Variation in biological activity should then largely be a consequence of this varying reactivity. Rates of mustard hydrolysis in the two series related only to the electronic properties of the link group, with attachment of the intercalating chromophore having no effect. The cytotoxicities of the simple mustards correlated well with group electronic properties (with a 200-300-fold range in IC50S). The corresponding DNA-targeted mustards were much more potent (up to 100-fold), but their IC50 values varied much less with linker group electronic properties. Most of the DNA-targeted mustards showed in vivo antitumor activity, being both more active and more dose-potent than either the corresponding untargeted mustards and chlorambucil. These results show that targeting alkylating agents to DNA by attachment to DNA-affinic units may be a useful strategy.

Alkylating Agents↗
PubMed1984

Comparative genotoxicity of nitrogen mustard and nor-nitrogen mustard.

Nitrogen mustard and nor-nitrogen mustard were investigated in Salmonella typhimurium and human lymphocytes for genotoxicity. Point mutations were assessed using the plate test, the conventional spot test and a method in which the substances were not in direct contact with the microorganisms. Both compounds were active, but nor-nitrogen mustard was far more potent than nitrogen mustard in all bacterial systems. Cytogenetic experiments with human lymphocytes revealed that both compounds induced a dose dependent increase in chromosomal aberrations and sister chromatid exchanges, but that nitrogen mustard was 10 times more potent than nor-nitrogen mustard. Thus, the spectrum of activity for nor-nitrogen mustard and nitrogen mustard differ. Nor-nitrogen mustard was more effective in inducing point mutation damage than nitrogen mustard and a reversal of potency was found for cytogenetic damage. These results indicate that although these two substances induce the same type of DNA lesions the amounts of the different DNA adducts vary.

Chromosome Aberrations↗
PubMedDate not supplied

Biological fate of sulfur mustard, 1,1'-thiobis(2-chloroethane). Urinary excretion profiles of hydrolysis products and beta-lyase metabolites of sulfur mustard after cutaneous application in rats.

The urinary excretion profiles of some metabolites of sulfur mustard were determined by gas chromatography/mass spectrometry after cutaneous application of sulfur mustard in rats. Excretion profiles of the individual metabolites thiodiglycol and thiodiglycol sulfoxide, derived from the hydrolysis of sulfur mustard, were determined in different groups of three rats. Concentrations of thiodiglycol detected increased up to 10 fold after treatment of the urine with hydrochloric acid, presumably because of the excretion of acid-labile esters of thiodiglycol. Free thiodiglycol, free plus esterified thiodiglycol, and thiodiglycol sulfoxide excreted over 8 days accounted for less than 0.3%, 1-1.5%, and 3.4-4.3%, respectively, of the applied dose of sulfur mustard. In a further study, a modified analytical method was applied to determine these hydrolysis products and their acid-labile esters as the single analyte thiodiglycol, after treatment with acidic titanium trichloride. The excretion profile of the combined hydrolysis products was compared with the excretion profile of a different group of metabolites of sulfur mustard derived from the glutathione/beta-lyase pathway. These were also reduced to a common analyte, 1,1'-sulfonylbis-[2-(methylthio)ethane], after similar treatment with titanium trichloride. Urinary excretion of hydrolysis products determined in 4 rats over 8 days accounted for 3.7-13.6% of an applied cutaneous dose of sulfur mustard. Urinary excretion of beta-lyase metabolites accounted for 2.5-5.3% of the applied dose in the same group of rats. The excretion of beta-lyase products showed a much sharper decline than was observed for the hydrolysis products of sulfur mustard.

Administration, Cutaneous↗
PubMedDate not supplied

Mustard allergy: three cases of systemic reaction to ingestion of mustard sauce.

Very few cases of hypersensitivity due to ingestion of mustard have been described in the literature, although this spice enjoys widespread use. We present three cases of anaphylactic reactions to ingestion of a small amount of mustard sauce. In our patients we performed skin prick tests with mustard and with the rest of the vegetables belonging to the Cruciferae family. We also performed skin prick tests with common pneumoallergens. We measured specific serum IgE to mustard using the CAP System (Pharmacia). Oral challenges with the other vegetables of the Cruciferae family were performed in the patients with no evidence of previous tolerance. Skin prick tests and specific serum IgE determinations to mustard were positive in all three patients. The tests with the rest of the vegetables belonging to the same family were negative. In conclusion, we consider that skin prick tests and the measurement of specific serum IgE to mustard are good methods for the diagnosis of mustard hypersensitivity. We did not detect cross-sensitivity with other vegetables of the same family or with pneumoallergens.

Adolescent↗
PubMed1985

Comparative study of antiproliferative effects of chlorpromazine, 7,8-dioxochlorpromazine, amantadine-N-mustard, rutin-N-mustard and alpha, beta and gamma interferon on K-562 cells in vitro.

The effects of rutin-N-mustard, amantadine-N-mustard, chlorpromazine and human interferon types alpha, beta and gamma (IFN-alpha, -beta and -gamma) were studied on the DNA, RNA and protein synthesis of K-562 cells. Monocyte-mediated cytotoxicity and immune spleen cell activity were examined in the presence of the same compounds (except for IFN-beta). The natural killer (NK) cell activity was tested in the presence of the two chlorpromazine compounds and the two N-mustard derivatives. Only 7,8-dioxochlorpromazine exerted an inhibitory effect on DNA synthesis. The protein synthesis of the cells was inhibited in the presence of IFN-alpha, -beta and -gamma. 7,8-Dioxochlorpromazine exerted some inhibition on both NK and immune spleen cell activity, while monocyte-mediated cytolysis was not altered. IFN-alpha, -beta and -gamma activated the cytolytic activity of monocytes and the NK activity in control experiments. Chlorpromazine, rutin-N-mustard and amantadine-N-mustard were ineffective in both tests in vitro. Rutin-N-mustard, 7,8-dioxochlorpromazine and the interferons may be assumed to have quite different antiproliferative mechanisms of actions.

Amantadine↗
PubMed1997

Protective effect of povidone-iodine ointment against skin lesions induced by sulphur and nitrogen mustards and by non-mustard vesicants.

Mustard gas (sulphur mustard, SM) is a powerful vesicant employed as a chemical weapon. The present study demonstrates the effect of povidone iodine (PI) ointment against skin toxicity caused by SM. Gross and histopathological examinations showed that application of PI up to 20 min following exposure to the vesicant resulted in marked skin protection. The shorter the interval between exposure and treatment the better was the protection achieved. PI was also effective against other mustards such as carboxybutyl chloroethyl sulphide (CBCS) and mechlorethamine. The fact that PI protected the skin against agents which cannot be oxidized such as iodoacetic acid, divinylsulphone and cantharidine showed that the antidotal effect of PI was unrelated to oxidation of the nitrogen and sulphur atoms of the mustards. PI ointment is proposed as an efficient protective agent against skin toxicity caused by mustards and other alkylators.

Animals↗
PubMed1986

Stabilities of 7-alkylguanosines and 7-deoxyguanosines formed by phosphoramide mustard and nitrogen mustard.

7-Alkylguanosine and 7-alkyldeoxyguanosine were prepared from phosphoramide mustard and nitrogen mustard in nonaqueous conditions. The guanosine products were N-(2-chloroethyl)-N-[2-(7-guanosinyl)ethyl] phosphorodiamidic acid, and N-(2-chloroethyl)-N-[2-(7-guanosinyl)ethyl]methylamine, respectively. These were also formed in aqueous reactions but they rapidly underwent secondary reactions. The half-life of the phosphoramide mustard-guanosine adduct was 3.1 h (37 degrees C, pH 7.4) and that of the nitrogen mustard adduct 1 h (25 degrees C, pH 7.4), as determined by HPLC. The half-lives of the respective adducts for imidazole ring-opening were 9.5 h and 0.78 h (37 degrees C, pH 7.4). The respective deoxyguanosine derivatives depurinated with half-lives of 8.5 h and 1.6 h (25 degrees C, pH 4.2). The mustard adducts are notably more labile than simple alkyl substituted guanosines and deoxyguanosines.

Alkylation↗
PubMed1985

Irreversible inhibition of calcium uptake in synaptosomes by quinacrine mustard: relationship to labeling sites of quinacrine mustard.

The sites of interaction of quinacrine with synaptic membranes were labeled with quinacrine mustard. Quinacrine mustard had an inhibitory effect on depolarization-induced calcium uptake by synaptosomes similar to that of quinacrine. The inhibition of depolarization-induced calcium uptake by quinacrine was reduced by 70% after washing, whereas that by quinacrine mustard was not affected. Fluorescence electrophoretograms of the quinacrine mustard-treated synaptic membranes showed that quinacrine mustard specifically labeled two proteins, with corresponding molecular weights of about 37,000 and 32,000.

Animals↗
PubMed1997

Surgical treatment of skin lesions induced by sulfur mustard ("mustard gas")--an experimental study in the guinea pig.

Sulfur mustard has been known as a chemical warfare agent since 1915 and its biological effects, e.g. acting as an alkylating agent reacting with nucleophiles in proteins and nucleic acids, are well known. Still, there is today no specific antidote against or treatment of sulfur mustard induced cutaneous lesions. Recently, a technique of treating thermal burns with early surgical excision followed by skin grafting has been established. The present study was undertaken to evaluate, if a similar technique could be of value in the treatment of sulfur mustard lesions. Under anaesthesia, guinea pigs were exposed to sulfur mustard vapour, followed six hours later by excision of the exposed skin segment. In animals where the skin defect was primary sutured, healing time was significantly shorter and increase in body mass greater compared to conservatively treated controls. No such differences were found if excision was followed by full thickness skin grafting. Further studies in other species are suggested to clarify the possible role of surgical excision of sulfur mustard skin lesions, followed by skin transplantation, in humans.

Animals↗
PubMed1998

Comparative mutational spectra of the nitrogen mustard chlorambucil and its half-mustard analogue in Chinese hamster AS52 cells.

Nitrogen mustards play an important role in current cancer chemotherapy. The most effective antitumour agents are those carrying two alkylating functions, probably through their ability to form interstrand cross-links in DNA. Such lesions appear to create more of a block in DNA replication and are more difficult to repair than are most monoadducts. Although there were early reports that monofunctional drugs were more mutagenic than the bifunctional drugs, this has not been formally proved using structurally related drugs in a mutagenicity assay capable of detecting a range of different events. We have studied both the mutagenic potency and spectrum of events caused by treatment with the clinical agent, chlorambucil, compared with its half-mustard analogue, in Chinese hamster ovary (CHO)-AS52 cells. Although both drugs caused comparable increases in mutation frequency at doses killing 90% of cells (from around 9x10-6 to around 9x10-5 mutant cells), the nature of events differed significantly between the drugs. By far the majority of mutations caused by the half-mustard were transversion mutations, and almost all of these could be interpreted in relation to the DNA adducts that are known to be formed. In contrast, the majority of chlorambucil-induced mutations were major deletions, and point mutations were only identified from a few clones. Parallel micronucleus assays verified that chlorambucil has a stronger ability to break chromosomes than the half-mustard. These two drugs are thought to form similar monoadducts, but only the full mustard can form interstrand cross-links. The data suggest that DNA cross-links, although only a minor fraction of the total lesions, dominate the mutagenic spectrum and lead to gross changes at the chromosome level that can not be readily associated with individual lesions produced by the drug.

Animals↗
PubMed1979

[Treatment of psoriasis vulgaris with external sulfur mustard gas with particular reference to its potential carcinogenic risk. III. Clinical and experimental studies on the extent of percutaneous and inhalational uptake of sulfur mustard gas].

Concerning the often discussed carcinogenic risk of psoriasis treatment with 0.005% S-mustard-vaseline (so-called Russian Ointment) -- especially by inhalation -- 19 patients were treated with a radioactive labeled S-mustard-ointment and examined. The patients' whole bodies were inuncted for 1--2 days with about 50 g of radioactive S-mustard vaseline (U14C, 3 muCi/g). Afterwards the radioactivity was determined in the patients' expired air, blood, urine, and in their surrounding air. In three patients punch biopsy material from normal and psoriatic skin was assayed for radioactivity after combustion. In the skin, radioactivity distinctly decreased from the epidermis (13.1 pCi/mg) to the subcutis (0.77 pCi/mg) without significant differences between normal skin and psoriatic lesions as confirmed by autoradiography. In all samples of air, body fluids and tissue, definitive amounts of radioactivity were found, which, however, were far below the US-American MAK-values. Between skin surface and shirt, the values varied from 1.5 to 13.7 nCi/20 l air, at a distance of 2 meters by 0.3 nCi/100 l air, in the breath by 0.5 nCi/20 l. The radioactivity decreased to 1/10 of the maximum values after 1--2 hours. In blood the activity was at the limit of detection and was parallelled by the activity of the urine. Generally, 1--7% of the radioactivity applied to the skin was eliminated with the urine within one week. Thus, the carcinogenic risk may be very low in the external S-mustard therapy of psoriasis and other skin diseases.

Air↗
PubMed1993

Hypoxia-selective antitumor agents. 7. Metal complexes of aliphatic mustards as a new class of hypoxia-selective cytotoxins. Synthesis and evaluation of cobalt(III) complexes of bidentate mustards.

Nitrogen mustards coordinated to Co(III) are potential hypoxia-selective cytotoxins, since one-electron reduction to the Co(II) complexes greatly labilizes the Co-N bonds, causing the release of activated aliphatic mustards which can act as diffusible cytotoxins. Two series of Co(III) complexes of the bidentate bisalkylating nitrogen mustard ligands N,N'-bis(2-chloroethyl)-ethylenediamine (BCE) and N,N-bis(2-chloroethyl)ethylenediamine (DCE) have been synthesized and evaluated for their hypoxia-selective cytotoxicity against AA8 cells in vitro. The complexes also bear two 3-alkylpentane-2,4-dionato (acac) auxiliary ligands; cyclic voltammetry studies show that variation of the alkyl group in the auxiliary ligands alters the reduction potentials of the complexes (within a series) over a range of about 150 mV. In both series, the patterns of cytotoxicities of the cobalt complexes were broadly similar to those of the respective free ligands, suggesting that the cytotoxicity of these compounds is due to release of the free ligands. The nonsymmetrical ligand DCE and its cobalt complexes were 1 order of magnitude more cytotoxic than the corresponding BCE compounds. Although the unsubstituted acac/DCE complex showed no hypoxic selectivity against repair-deficient UV4 cells in a stirred suspension culture assay, the methyl and ethyl analogues showed substantial selectivity. The results may indicate a narrow range of acceptable reduction potential, with an optimum close to that for the methyl analogue (E1/2 = -305 mV). The methyl analogue also shows hypoxic selectivity against repair-proficient cell lines (e.g., AA8 and EMT6) and has high activity against EMT6 cells in intact spheroids, suggesting that the released DCE is capable of back-diffusion from the hypoxic core of the spheroid. This work shows that metal complexes of nitrogen mustards have significant hypoxia-selective cytotoxicity toward mammalian cells in cell culture and are a new general class of hypoxia-selective cytotoxins.

Animals↗
PubMed1997

Biological fate of sulphur mustard: identification of valine and histidine adducts in haemoglobin from casualties of sulphur mustard poisoning.

1. Analytical methods were developed for the detection of N-terminal valine and histidine adducts in haemoglobin alkylated with sulphur mustard. 2. N-(2-hydroxyethylthioethyl)-N-terminal valine was selectively cleaved from globin with the Edman reagent pentafluorophenyl isothiocyanate. The resulting thiohydantoin derivative was analysed by high resolution gc-ms using negative ion chemical ionization. An alternative procedure, involving acid hydrolysis of globin to its constituent amino acids and conversion of the adduct to its di-TBDMS derivative, was less sensitive. 3. N-(2-hydroxyethylthioethyl)histidine was analysed, after acid hydrolysis of globin, as its fluorenylmethyloxycarbonyl derivative by lc-ms-ms using electrospray ionisation and selected reaction monitoring. 4. N-(2-hydroxyethylthioethyl)valine and (2-hydroxyethylthioethyl)histidine were detected in globin isolated from a rat treated percutaneously with sulphur mustard, and in globin from five blood samples collected from human casualties of sulphur mustard poisoning. The adducts are proposed as biological markers of sulphur mustard poisoning. in addition to urinary metabolites and DNA adducts.

Alkylating Agents↗
PubMed1993

Biological fate of sulphur mustard (1,1'-thiobis(2-chloroethane)): uptake, distribution and retention of 35S in skin and in blood after cutaneous application of 35S-sulphur mustard in rat and comparison with human blood in vitro.

1. During the 6-h occluded cutaneous application of 35S-sulphur mustard vapour to rat, most of the dose, approximately 75%, passed through the skin and was systemically-distributed. Up to 25% of the 35S was retained in the skin, up to 30% was excreted in the urine and 5-8% was present in the blood, by the end of the application. 2. 35S initially declined rapidly in skin and then more slowly with a half-life of approximately 7.4 days. Some of the early loss was as sulphur mustard vapour from a possible depot of this compound which was larger with increase in dose. There was some apparent continuing uptake from such a depot into the systemic circulation. 3. The decline of 35S in blood was much slower than that from skin. About one-fifth of the original post-exposure level in the blood still present 6 weeks later. 4. The 35S in blood was mainly in the red cell contents as reaction products of haemoglobin with sulphur mustard. Its persistence in the systemic circulation, after an initial rapid decline due to its removal from the plasma, reflected the 65 day life span of these cells. Significant levels of 35S were found in the plasma only for a few days (t1/2 = 2.4 days). 5. Uptake and subsequent distribution of 35S in rat and human blood in vitro during gradual exposure to 35S-sulphur mustard using a novel method were similar. 35S in the red cells was associated mainly with the haemoglobin protein, but slightly greater binding with human, rather than with rat, plasma components was indicated.

Administration, Cutaneous↗
PubMed1978

Quantitation by gas chromatography-chemical ionization mass spectrometry of cyclophosphamide, phosphoramide mustard, and nornitrogen mustard in the plasma and urine of patients receiving cyclophosphamide therapy.

Unambiguous and sensitive methods based on gas chromatography-chemical ionization mass spectrometry have been developed to quantitate cyclophosphamide and two alkylating and cytotoxic metabolites, phosphoramide mustard and nornitrogen mustard. The levels of these materials have been determined in the plasma and urine of five patients receiving cyclophosphamide, 60 or 75 mg/kg i.v. Peak plasma levels of phosphoramide mustard of 50 to 100 nmoles/ml were found at 3 hr after cyclophosphamide administration. Variable levels of nornitrogen mustard were found in the plasma. This product may be arising in part from the decomposition of other metabolites during sample storage and preparation.

Adolescent↗
PubMed2003

Mode of cell death induced in Chinese hamster cells by sequence-selective DNA minor groove binding nitrogen mustards: comparison with untargeted mustards and with Hoechst 33342.

The clinical antitumor efficacy of nitrogen mustards such as chlorambucil may relate to their ability to cause programmed cell death (apoptosis), probably through their DNA cross-linking properties. In contrast, bisbenzimidazoles such as Hoechst 33342 interact noncovalently with the minor groove of DNA, and appear to cause apoptosis in a fundamentally different way, which may involve the inhibition of topoisomerase (topo) I enzymes. A series of DNA minor groove binding nitrogen mustards with selective DNA affinity and in vivo antitumor activity in animal models was studied. Although two examples of such compounds proved to inhibit topo I enzymes in vitro, they were equally toxic towards topo I-proficient and- deficient strains of yeast, suggesting that topo I inhibition was not involved in cell killing. Flow cytometric analysis of Chinese hamster cells highlighted the differences in the propensity to cause apoptosis by chlorambucil compared with Hoechst 33342, revealing two distinct apoptotic populations in cells treated with the latter drug. Unexpectedly, the bisbenzimidazole mustards showed a novel peak of apoptotic activity, distinct from that shown by either parent drug. Exploring these different mechanisms of apoptosis may provide new directions for the development of antitumor drugs.

Animals↗
PubMed2001

Chlorophyllin protects cells from the cytostatic and cytotoxic effects of quinacrine mustard but not of nitrogen mustard.

Chlorophyllin (CHL), the sodium and copper salt of chlorophyll, is capable of inhibiting the mutagenic activity of many chemical compounds. Several mechanisms have been advanced to explain the antimutagenic activity of CHL, including its antioxidant properties and its ability to form complexes with mutagens. The present study was designed to reveal whether the heterocyclic aromatic nature of a potential mutagen is essential to its sensitivity to CHL. Toward this end, the inhibitory effect of CHL on two compounds of similar chemical reactivity (mustards), that either embodied an aromatic structure (quinacrine mustard; QM) or did not (nitrogen mustard; NM), were compared. Human leukemic HL-60 and breast carcinoma MCF-7 cells were treated with QM or NM in the absence or presence of various concentrations of CHL. Both QM and NM when administered for 1-2 h at micromolar concentrations exerted similar effects; both arrested cells in G2 phase of the cell cycle, induced apoptosis and reduced the clonogenicity of MCF-7 cells. The simultaneous addition of 0.22 M CHL to cultures receiving QM virtually abolished the QM-induced inhibition of cell growth and clonogenicity. In contrast, CHL had no effect on reducing the cytostatic or cytotoxic activity of NM. CHL alone, at a concentration of 0.22 M, had minimal effect on growth of HL-60 cells slightly perturbing their progression through G2. The results are consistent with the model that explains the inhibition of the activity of mutagens or antitumor drugs with aromatic structures by CHL as mediated by its ability to sequester these molecules within heterologous mutagen:CHL complexes that are maintained by stacking interactions. Therefore, excess of chlorophyll in the diet, by sequestering aromatic mutagens (or antitumor drugs with a heterocyclic structure, if taken orally), may inhibit their accessibility to cells, thereby reducing their activity.

Antimutagenic Agents↗