Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “NITROGEN MUSTARDS”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 91 records · Page 5Linked to original sources
PubMed1990

DNA adenine adducts induced by nitrogen mustards and their role in transcription termination in vitro.

Previous studies have demonstrated that three cancer chemotherapeutic compounds of the nitrogen mustard class, melphalan (L-PAM), nitrogen mustard (HN2) and chlorambucil (CBC), each generated DNA lesions that prematurely terminate in vitro transcription. Sites of these lesions were inconsistent with sites of N7 guanine monoadducts formed by these compounds, and in the cases of L-PAM and CBC were suggestive of adenine lesions. The present study is an attempt to identify and characterize nitrogen mustard-induced non-N7 guanine DNA adducts, and in particular adenine DNA adducts, and to assess their role in drug-induced in vitro transcription termination. Data from studies using a modified Maxam-Gilbert DNA sequencing technique demonstrate that L-PAM and CBC, but not HN2, generate heat-labile, alkaline-stabilized adenine adducts at nearly every adenine in a region of a defined DNA template examined. Comparison of sites of L-PAM- and CBC-induced adenine adducts to known sites of drug-induced transcription termination in the same DNA template show that L-PAM- and CBC-induced transcription termination is associated not with drug lesions at single adenines, but rather with drug-induced adducts at neighboring adenines. Additional in vitro transcription studies using a small DNA molecule generated by polymerase chain reaction-mediated DNA amplification demonstrate that none of the transcription-terminating lesions induced by L-PAM and CBC in this molecule are interstrand in nature. These results suggest that some, but not all, nitrogen mustard compounds can generate heat-labile adenine lesions in DNA, and that bifunctional nitrogen mustards that can form heat-labile adenine adducts also form adducts consistent with intrastrand adenine-adenine crosslinks. These adducts at pairs of adenines in turn appear to be responsible for L-PAM- and CBC-induced transcription termination in vitro.

Amino Acid Sequence↗
PubMed1995

Nitrogen mustard inhibits transcription and translation in a cell free system.

Nitrogen mustard and its derivatives such as cyclophosphamide, chlorambucil and melphalan are widely used anti-cancer agents, despite their non-specific reaction mechanism. In this study, the effect of alkylation by nitrogen mustard of DNA and RNA (coding for a single protein) was investigated using both a translation system and a coupled transcription/translation system. When alkylated DNA was used as the template for coupled transcription and translation, a single translation product corresponding to the 62 kDa luciferase protein was synthesised. Production of the translated product encoded by this template was inhibited by mustard concentrations as low as 10 nM, and 50% inhibition occurred with 30 nM mustard. A primer extension assay employed to verify alkylation sites on the DNA revealed that all guanine residues on the DNA template are susceptible to alkylation by nitrogen mustard. Similarly, when alkylated RNA was used as the template for protein synthesis, the amount of the 62 kDa luciferase protein decreased with increasing mustard concentration and a range of truncated polypeptides was synthesised. Under these conditions 50% inhibition of translation occurred with approximately 300 nM mustard (i.e. approximately 10 times that required for similar inhibition using an alkylated DNA template). Furthermore, a gel mobility shift assay revealed that mustard alkylation of the RNA template results in the formation of a more stable retarded RNA complex. The functional activity of the luciferase protein decreased with alkylation of both the DNA and RNA templates, with a half-life of loss of activity of 1.1 h for DNA exposed to 50 nM mustard, and 0.5 h for RNA exposed to 50 microM mustard. The data presented support the notion that DNA is a critical molecule in the mode of action of mustards.

Alkylating Agents↗
PubMedDate not supplied

Synthesis and alkylation activity of a nitrogen mustard agent to penetrate the blood-brain barrier.

Nitrogen mustard agents are widely used for the clinical treatment of cancers. A nitrogen mustard (N-mustard) agent was synthesized utilizing nicotinic acid as the carrier of the alkylating substituent (-OCH2CH2N(CH2CH2Cl)2) that forms an ester group (R-C(O)-OR) on a heterocyclic ring. The N-mustard agent is a solid at room temperature and is stable for more than 6 weeks when stored at -10 degrees C. To determine the kinetics of alkylation activity a nucleophilic primary amine compound (4-chloroaniline) was placed in aqueous solution with the mustard agent at physiological pH 7.4 (pH of blood) and 37 degrees C. The alkylation reaction was found to be second-order with rate equation: rate = k2[N-mustard][Nu], where Nu = nucleophile and k2 = 0.0415 L/(mol x min). Pharmacological descriptors calculated showed values indicating a strong potential of penetrating the blood-brain barrier. The partition coefficient (Log P) of the mustard agent is 1.95 compared with 0.58 for nicotinic acid. Values of descriptors such as dipole, polar surface area, Log BB, molar refractivity, parachor, and violations of Rule of 5 were found to be 5.057 Debye, 42.44 A2, 0.662, 72.7 cm3, 607.7 cm3, and 0.0 for the N-mustard agent. Value of polar surface area for the mustard agent (42.44 A2) predicts that >90% of any amount present in the intestinal tract will be absorbed.

Algorithms↗
PubMed1980

Potential anticancer agents. XX. 2. Quantitative structure--activity relationships (QSAR) in aromatic nitrogen mustards area.

Quantitative structure--activity relationships have been fomulated for 27 aromatic nitrogen mustards derived from benzoic acids (9 monosubstituted and 18 disubstituted derivatives). Their toxicity (LD50) and antitumor activity against Jensen sarcoma were correlated with hydrolysis rate (log k66) lipophilicity constants (pi) and steric parameters (MDT). The chemical reactivity of the nitrogen mustard moiety (expressed as log k66) seems to be of main importance in determining the biological properties of these derivatives. The favorable effect of ortho-substitution was pointed out. Generally these results are in good agreement with those obtained by HANSCH et al. [7] on a different series of nitrogen mustards.

Animals↗
PubMed1985

Sensitivity of murine B- and T-lymphocytes to oxazaphosphorine and non-oxazaphosphorine nitrogen mustards.

The relative sensitivities of murine B- and T-lymphocytes to the oxazaphosphorine nitrogen mustards, cyclophosphamide and ASTA Z 7557, and to the non-oxazaphosphorine nitrogen mustards, melphalan and chlorambucil, in vivo, were determined. B- and T-lymphocytes were defined by selective mitogen-induced proliferation. Lipopolysaccharide (LPS)-induced B-lymphocytes were approximately twice as sensitive to the cytotoxic effects of cyclophosphamide and ASTA Z 7557 as were phytohemagglutinin (PHA)- and concanavalin A (Con A)-induced T-lymphocytes. LPS-induced B-lymphocytes and PHA-induced T-lymphocytes were approximately equisensitive to the cytotoxic action of melphalan and chlorambucil, but the former were somewhat more sensitive to these agents than were Con A-induced T-lymphocytes. The relative sensitivities of murine B- and T-lymphocytes to ASTA Z 7557 and the non-oxazaphosphorine metabolite of cyclophosphamide, phosphoramide mustard, ex vivo, were also determined. LPS-induced B-lymphocytes were approximately twice as sensitive to the cytotoxic action of ASTA Z 7557 as were PHA- and Con A-induced T-lymphocytes. The three mitogen-induced lymphocyte populations were approximately equisensitive to the cytotoxic action of phosphoramide mustard. These observations suggest that the differential effect of cyclophosphamide on murine B- and T-lymphocytes is uniquely exhibited by oxazaphosphorine nitrogen mustards. Furthermore, the results suggest that 4-hydroxycyclophosphamide is the cyclophosphamide metabolite that mediates the differential immunotoxic effect of the parent compound.

Animals↗
PubMed1988

Protection of Ehrlich ascites tumor cells against the antiproliferative effect of mechlorethamine (nitrogen mustard) by 5-N,N-dimethylamiloride.

5-N,N-Dimethylamiloride protects Ehrlich ascites tumor cells against the antiproliferative effect of nitrogen mustard. The drug reduces the frequency of DNA interstrand cross-links introduced by nitrogen mustard. Cells with a defective choline carrier are not protected against nitrogen mustard by dimethylamiloride. As nitrogen mustard is taken up by the choline carrier, it is concluded that the recently reported inhibition of the choline transport system by amiloride and its dimethyl derivatives (W. Doppler et al., Biochem. Pharmacol., 36: 1645-1649, 1987) is responsible for the protection against the alkylating agent.

Amiloride↗
PubMed1964

EFFECT OF DEXAMETHASONE AND NITROGEN MUSTARD ON THE PRODUCTION OF RHEUMATOID FACTOR IN RHEUMATOID ARTHRITIS.

The effect of dexamethasone and nitrogen mustard on the production of rheumatoid factor, as measured by sensitized sheep cell and latex agglutination tests, was studied in 19 patients with classical rheumatoid arthritis. Dexamethasone was given orally in a daily dose of 6-8 mg. which was slowly reduced after a two-week period. Nitrogen mustard was infused in the usual therapeutic dose of 0.3 mg./kg. The level of circulating rheumatoid factor decreased, following administration of each agent, after a latent period of 10 days. The effect was most marked at around 30 days. Dexamethasone was more potent than nitrogen mustard. Both drugs together caused transient disappearance of rheumatoid factor in one patient.It is concluded that dexamethasone and nitrogen mustard have the capacity to suppress the formation of the macroglobulins associated with rheumatoid arthritis.

Adolescent↗
PubMed2005

Overexpression of GSTA2 protects against cell cycle arrest and apoptosis induced by the DNA inter-strand crosslinking nitrogen mustard, mechlorethamine.

The effectiveness of bifunctional alkylating nitrogen mustard compounds in chemotherapy is related to their ability to form DNA inter-strand crosslinks. Patients exposed to DNA inter-strand crosslinking (ICL) agents subsequently experience an elevated incidence of myelodysplastic syndromes (MDS) and MDS related acute myeloid leukemia. Fanconi's anemia (FA) patients are deficient in the repair of crosslink DNA damage and they experience a high incidence of MDS. These observations indicate that hematopoietic cells are specific target for the transforming effects of DNA crosslinking damage. Changes in transcript levels were characterized in human hematopoietic cells occurring in response to the nitrogen mustard, mechlorethamine (HN2), but not in response to monofunctional analogs. Only modest changes in a few gene transcripts were detected in HL60 cells exposed to levels of HN2 tittered to maximal dose that caused growth suppression with minimal cell death and allowed eventual resumption of normal cell growth. Under conditions of transient growth suppression, a subset of glutathione-S-transferase (GST) isoenzyme genes was consistently upregulated three to fourfold by HN2, but not by monofunctional analogs. Subsequent efforts to confirm the changes detected by microarray analyses revealed an unexpected dependence on treatment conditions. The GST alpha class A2 subfamily member transcripts were upregulated 24 h after a 1 h exposure to HN2 that caused an extensive, but transient block in late S/G2 cell cycle phase, but were minimally altered with continuous exposure. The 1-h exposure to HN2 caused a transient late S/G2 cell cycle arrest in both the HL-60 cell line and the Colo 320HSR human colon cancer cell line. Overexpression of GSTA2 by transient transfection protected Colo 320HSR cells against both cycle arrest and apoptosis following exposure to HN2. Overexpression of GSTA2 in Colo 320HSR cells induced after exposure to HN2 did not alter cycle arrest or apoptosis. The results indicate that human GSTA2 facilitates the protection of cells from HN2 damage and not repair. Our results are consistent with the possibility that GSTA2 polymorphisms, variable isoenzyme expression, and variable induced expression may be factors in the pathogenesis of MDS.

Antineoplastic Agents, Alkylating↗
PubMed1968

Mycosis fungoides. Topical use of nitrogen mustard in recurrent cases.

The management of the patient with mycosis fungoides requires a variety of therapeutic modalities depending on the stage of the disease. Topically applied nitrogen mustard in the early stages of the disease has a beneficital palliative effect. The effects of nitrogen mustard paintings in the later course of the disease have not been previously reported. In the present study, topically applied nitrogen mustard solution was used to control recurrences of mycosis fungoides following electron beam therapy in 11 patients. Each patient received whole body applications of freshly prepared 10 mg per 50 ml solution of mechlorethamine hydrochloride (a nitrogen mustard) in water daily for seven days. In all patients pruritus disappeared within the first week and ulcers and plaques improved or disappeared in two to four weeks. The seven-day courses of mechlorethamine paintings were repeated as recurrences were noted. Mycosis fungoides was controlled by this therapy for periods ranging up to 15 months. Absence of systemic toxicity, a low incidence of cutaneous irritation and application of the treatments at home make topical nitrogen mustard a useful adjunct in the management of the late stages of mycosis fungoides.

Adult↗
PubMed1978

Use of nitrogen mustard N-oxide for the fixation of electron microscopic tissues.

Nitrogen mustard N-oxide was tried for the fixation of tissue for electron microscopy. A fixative consisting of 1% nitrogen mustard N-oxide, 1% glutaraldehyde and 1% paraformaldehyde buffered at pH 7.4 followed by 1% OsO4 buffered at pH 7.4 was found useful for the tissues examined: thyroid, anterior pituitary, adrenal gland and oviduct of mice. If the tissues are fixed and the sections are stained with uranyl acetate and lead acetate doubly, the follicle colloid, colloid droplets, and secretory granules containing thyroglobulin in the thyroid become higher in electron density. The cisterna of the maturing face of the Golgi apparatus, secretory granules, ribosomes, nucleolus and chromatin in the cells examined are extremely electron dense. Tubular elements of smooth endoplasmic reticulum in the adrenal cortical cell and microtubules in all the cells examined are also well preserved. The fixative containing nitrogen mustard N-oxide is useful also for cytochemistry. Using tissue fixed by this method and stained en bloc by uranyl acetate, the noradrenaline and adrenaline cells in the adrenal medulla are clearly distinguished by light microscopy.

Adrenal Medulla↗
PubMed1982

Second cutaneous malignancies in patients with mycosis fungoides treated with topical nitrogen mustard.

Previous reports of skin cancer occurring in mycosis fungoides patients who have been treated with topical nitrogen mustard have been of carcinomas occurring predominantly on sun-exposed skin. Four of twenty-nine mycosis fungoides patients in our clinic treated with topical nitrogen mustard developed six skin cancers on sun-protected skin. Four lesions were squamous cell carcinomas and two were basal cell carcinomas. Few other risk factors for the development of skin cancer were present in our patients. These cases support the hypothesis that topical nitrogen mustard is a carcinogen or tumor promote and emphasize the need for careful examination of the skin of patients treated with topical nitrogen mustard.

Administration, Topical↗
PubMed1987

The induction of aneuploidy by nitrogen mustard in a human lymphoblastoid cell line.

We report that the presence of an extra Y chromosome can be used as a marker for the induction of aneuploidy (mitotic non-disjunction) in a human lymphoblastoid cell line. This endpoint is easily visualized in metaphase chromosome preparations after staining with quinacrine mustard. The induction of cells with two Y chromosomes by nitrogen mustard (NM) was examined. Exposure to 150 ng/ml nitrogen mustard induced a 6-fold increase in aneuploid frequency relative to untreated control levels; maximal induction of aneuploidy was observed 2 days after treatment. Lower concentrations of nitrogen mustard (36 and 75 ng/ml) induced smaller increases in aneuploid frequency, with maximal induction observed 1 day after treatment. This system has the potential to be used as an assay for the induction of aneuploidy in cultured human cells.

Aneuploidy↗
PubMed1960

Influence of pH on the toxicity of nitrogen mustard.

The experiments reported here demonstrate the unexpected finding that, in mice, the pH of nitrogen mustard solution at the time it is injected into the animal appears to determine the toxicity of the material. At certain doses, highly acid solutions of nitrogen mustard show no toxic effects, while alkaline solutions at the same dose are invariably lethal. From further experiments on the antitumor activity of acid solutions of nitrogen mustard, it is cojpcluded that the toxic effect is separable from the antitumor effect.

Animals↗
PubMed2000

Sensitivity to nitrogen mustard relates to the ability of processing DNA damage in Chinese hamster ovary cells.

The hallmark of the excision repair pathways is the removal of DNA adducts by excision of the damaged nucleotides. In the course of repair, transient DNA strand breaks occur, which can be measured by the Comet assay. We have investigated the processing of DNA damage, mediated by nitrogen mustard, in wild-type AA8 Chinese hamster ovary cells, and in UV5, UV20 and UV41 DNA repair deficient cell lines. Whereas DNA repair could not be detected by unscheduled DNA synthesis at nitrogen mustard doses below 10 microM, processing of nitrogen mustard-mediated DNA damage was observed by the Comet assay at a 100-times lower concentration. Wild-type Chinese hamster ovary AA8 cells were able to process nitrogen mustard-mediated DNA damage within 4-24 hr depending on the dose of nitrogen mustard (0.1-10 microM). None of the repair-deficient cell lines was able to completely process the DNA damage induced by 10 microM nitrogen mustard. At nitrogen mustard doses that conferred 10% colony forming ability, the repair-deficient cells had an altered processing of nitrogen mustard-mediated DNA damage: In the AA8, UV20, and UV41 cells, the amplitude of strand breaks peaked early (within 4 hr), the level of strand breaks in the nitrogen mustard exposed UV20 and UV41 cells did not return to the baseline of the unexposed reference culture, and the peak in strand breaks in the UV5 cell line occurred after 4 hr. Our results indicate that the single cell gel electrophoresis (Comet) assay is suitable for assessing repair capability of DNA alkylations.

Alkylating Agents↗
PubMedDate not supplied

[Nitrogen mustard fixes the Z-conformation in poly[d(G-C)]poly[d(G-C)] and DNA].

The reactions of poly(dG-dC).poly(dG-dC) and (dG-dC)10 insert in the plasmid pGC20 with N-methyl-bis(2-chloroethyl)-amine (nitrogen mustard, HN-2) have been studied. It is shown that nitrogen mustard does not induce the B----Z transition in poly(dG-dC).poly(dG-dC), but produces fixation of the polynucleotide Z-conformation once this exists. In the case of pGC20 plasmid DNA, nitrogen mustard also fixes Z-form of the (dG-dC)-insert. The rate constant of the reaction of nitrogen mustard with guanine in the polynucleotide (k = 9,0.10(-3) min-1) is about one-third of that for the fixation of Z-form of the (dG-dC)-insert in the plasmid (k1 = 2,8.10(-2) min-1) which is attributed to a greater rate of formation of diguanyl derivative in the opposite DNA chains. It is suggested that nitrogen mustard is capable of fixing the Z-form DNA not only in vitro, but also in vivo.

Circular Dichroism↗
PubMed1982

Failure of periodic ultraviolet radiation treatments to prevent sensitization to nitrogen mustard: a case report.

We have reported that prior ultraviolet radiation (UVR) exposure significantly delayed development of contact sensitivity to nitrogen mustard (Halprin et al., 1981). We felt that this effect was due to disruption of functional Langerhans cells in skin by UVR and suggested that periodic UVR treatments might prevent sensitization to the mustard. We now report on a patient with mycosis fungoides whose epidermal Langerhans cell count was monitored with the ATP-ase stain in order to determine when such 'booster" UVR therapy was to be given. Our attempts to interfere with Langerhans cell function in this manner failed to prevent delayed contact sensitivity to nitrogen mustard and may have been partly responsible for the development of contact urticaria to nitrogen mustard after 28 days of use. Whether the reaction was a delayed, cell-mediated reaction, or an antibody mediated reaction is not clear, but the use of UVR did fail to prevent contact sensitivity to the nitrogen mustard in our patient.

Cell Count↗
PubMed1977

Inverse relationship between splenomegaly and stem cell compartment size in mice treated with nitrogen mustard.

Following the administration of similar doses of nitrogen mustard (4 mg/kg) to different strains of mice, wide variations in the subsequent degree of splenomegaly were observed, implying strain differences in the role of the spleen in the compensatory erythropoietic response to haematopoietic stress. This investigation was undertaken to determine whether or not these differences were related to the size of the haematopoietic stem cell compartment size in the various strains of mice. Groups of 4 different strains of mice (Swiss Webster, A/J, C57BL/6J and CS1/ASH) were injected i.v. with nitrogen mustard (4 mg/kg body weight) and autopsied at regular intervals up to 20 d post-injection. At autopsy, the wet weight of the spleen was determined. Subsequently, groups of the same 4 strains of mice were exposed to single doses of wholebody gamma-irradiation in the range of 500-900 rads. 9 d after gamma-irradiation the mice were autopsied, their spleens removed, and the number of endogenous spleen colonies determined. The greatest degree of splenomegaly was observed in the C57BL/6J mice. The Swiss Webster mice showed no splenomegaly during the time period studied. There existed a linear inverse relationship between the maximum degree of splenomegaly observed and the dose of wholebody gamma-irradiation required to completely eliminate endogenous spleen colonies. This data is in accord with the hypothesis that there exists an inverse relationship between the extent of splenomegaly observed following haematopoietic stress and the haematopoietic stem cell compartment size.

Animals↗
PubMed2006

Effect of nitrogen mustard, a vesicant agent, on lymphocyte energy metabolism.

BACKGROUND: The vesicant agents sulfur and nitrogen mustards, which contain chloroethyl groups, are potent inhibitors of DNA synthesis and cell growth, likely changing the utilization of anaerobic glycolysis for energy generation. METHODS: To investigate the effect of nitrogen mustard on cellular energy metabolism, lymphocytes treated with increasing doses of mechlorethamine (HN2), a nitrogen mustard and an analogue of sulfur mustard, were incubated with radiolabeled glucose. The rates of aerobic and anaerobic glycolysis were then determined. RESULTS: Glycogen consumption was significantly higher in cells treated with HN2 in a dose-dependent manner compared to untreated cells. Similarly, the amount of end-product lactate was increased, but CO2 was reduced in HN2-treated cells. CONCLUSIONS: Lymphocytes normally use aerobic glycolysis under aerobic conditions, but energy metabolism predominantly involved anaerobic glycolysis after severe intoxication with mustard agent.

Adult↗