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PubMed1994

Toxic effects of mechlorethamine on mammalian respiratory mucociliary epithelium in primary culture.

Mechlorethamine (HN2) is an alkylating agent usually used in cancer chemotherapy. Nevertheless, HN2 is extremely toxic and its use is accompanied by severe side-effects that may cause lung complications. Many studies report the morphological and biochemical modifications induced by sulfur mustard (SM) but no report has been published concerning the toxic effects of HN2 on the ultrastructural and functional activity of surface respiratory epithelial cells. This study was performed on rabbit tracheal epithelium (RTE) cells in primary culture. The functional activity of the culture was evaluated by measuring the ciliary beating frequency (CBF) of the ciliated cells using a videomicroscopic method, and the culture growth was determined by an image analysis system. The morphological aspects of the cells were analyzed by light, scanning electron, and transmission electron microscopy. An important inhibition of cell growth was observed associated with a detachment of the outgrowth cells. Morphological changes were expressed by vacuolization, increases in the intercellular spaces, and by disorganization of the cytoskeleton associated with a specific attack of the ciliated cells that show ciliary blebbing. The sudden CBF inhibition is more likely due to the detachment and the death of the ciliated cells than to a specific ciliotoxic effect of HN2. All these observations demonstrated the high sensitivity of respiratory epithelial cells to HN2 and showed that HN2-induced injuries were irreversible, and time- and dose-dependent.

Animals↗
PubMed1991

Protective effect of O-phenanthroline against mechlorethamine toxicity in the rat liver slice system and in the guinea pig skin.

The effect of O-phenanthroline (OP) on mechlorethamine hydrochloride (HN2) toxicity was studied in in vitro and in vivo experiments. Incubation of HN2 with the in vitro rat liver slice system resulted in leakage of alanine aminotransferase (ALT) in a time-dependent manner. Exposure of the slices to HN2 for 4 h caused 79.2% ALT leakage. In the presence of OP enzyme leakage was reduced to 28.7%. OP-induced protection was shown to be dose dependent. Other metal chelators such as dithiothreitol (DTT) and EDTA (ethylenediaminetetraacetic acid) had a weak effect on HN2 cytotoxicity. The protective activity of OP was also demonstrated in in vivo skin toxicity studies in the guinea pig. The ulcerative effect of topically applied HN2 was inhibited by OP even when applied 10 min following the alkylator. Histology of NH2-treated skin showed epidermal ulceration associated with a covering layer of encrusted exudate. However, only a slight diffuse acanthosis of the epidermal layer was observed when OP was applied for 10 min after the vesicant. It is suggested that OP may be used for the prevention of tissue damage caused by antineoplastic treatment with nitrogen mustard. It might also be employed in military medicine as an antidote to the chemical weapon sulfur mustard.

Animals↗
PubMed1992

Hepatocyte toxicity of mechlorethamine and other alkylating anticancer drugs. Role of lipid peroxidation.

The alkylating anticancer drugs, mechlorethamine (HN2), chlorambucil, cyclophosphamide, carmustine and lomustine readily induced cytotoxicity in isolated rat hepatocytes. Hepatocyte glutathione (GSH) was depleted rapidly following addition of the drugs. Lipid peroxidation ensued following GSH depletion and before cytotoxicity occurred. Furthermore, cytotoxicity was delayed by the antioxidants butylated hydroxyanisole (BHA) and alpha-tocopherol, the ferric iron chelator desferoxamine or the radical trap 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) even when added 10 min later. HN2 was much less toxic to hepatocytes under nitrogen and caused much less lipid peroxidation than under aerobic conditions. Cytotoxicity induced by HN2 was also prevented by choline, suggesting that a choline carrier is responsible for HN2 uptake in the hepatocytes. Various sulfur compounds acted as antidotes for HN2 cytotoxicity. Thiosulfate was still effective when added 30 min after HN2. Depletion of GSH in the hepatocytes markedly increased their susceptibility to HN2. However, BHA, desferoxamine or TEMPO protected these hepatocytes from HN2. This suggests that antioxidants could prove useful in preventing the increased risk of hepatotoxicity if GSH-depleting agents are used to overcome tumor resistance to nitrogen mustards.

Alkylating Agents↗
PubMed1996

The in vivo and in vitro effects of an alkylating agent, mechlorethamine, on IL-6 production in mice and the role of macrophages.

Alkylating agents, cyclophosphamide (CY) and the related compound mechlorethamine (NM), significantly increase in vivo the blood level of IL-6 but not of IL-1. Since in vitro CY is inactive we have used in our experiments NM, a compound structurally and functionally related to phosphoramide mustard, the natural biologically active metabolite of CY. Thioglycollate or oil-induced peritonal macrophages (Mf) of four different mouse strains treated with NM produce significantly more IL-6 than the non-treated cells. In contrast, under these conditions, the production of IL-1, TNF alpha and NO/NO2 radicals is not affected. The NM-induced elevated production of IL-6 by Mf could not be further increased by the treatment of cells with LPS, which may suggest that both agonists stimulate the same signalling pathway. The antineoplastic activity of the alkylating agents like CY or NM is usually attributed to the interstrand cross-linking of the DNA of the dividing cells. Our experiments can be tentatively interpreted as the induced overplus of IL-6 can also contribute to the stimulation of the cytotoxic NK-cells.

Alkylating Agents↗
PubMed1988

Topical mechlorethamine therapy for early stage mycosis fungoides.

One hundred seventeen patients with mycosis fungoides were treated with topical mechlorethamine hydrochloride. The probability of achieving a clinically apparent remission within 2 years of therapy was 75.8% in patients with stage I disease, 44.6% in patients with stage II disease, and 48.6% in patients with stage III disease. Patients with stage I disease achieved complete remission sooner (median, 6.5 months) than patients with stage II (median, 41.1 months) or stage III (median, 39.1 months) disease. The median time to relapse was 44.5 months. Sixty-eight patients (58.1%) developed a delayed hypersensitivity reaction, but only one patient had to discontinue therapy as a consequence. No appreciable differences were seen in the probability to achieve complete remission or time to complete remission as stratified by gender, substage, or the development of a delayed hypersensitivity reaction. Survival analysis revealed that the probability of surviving at 5 years was 89% for all patients. These findings compare favorably with results with other treatments for early stage mycosis fungoides.

Administration, Topical↗
PubMed1989

Long-term efficacy, curative potential, and carcinogenicity of topical mechlorethamine chemotherapy in cutaneous T cell lymphoma.

Complete responses lasting from 4 to 14 years were documented in 65 of 331 (20%) patients with cutaneous T cell lymphoma treated with topical mechlorethamine (HN2) between 1968 and 1982. Such long-lasting remissions occurred most often, but not invariably, in patients with patch or plaque phase mycosis fungoides without palpable lymphadenopathy (stage Ia or Ib). The likelihood of a continuous remission was enhanced by initiation of treatment before an unequivocal pathologic diagnosis. Despite the long-lasting responses in these patients, however, relapses have been documented in 11 (17%) of these patients, and all relapses occurred within 8 years of discontinuing maintenance topical chemotherapy. Thus, in our experience, a continuous remission lasting 8 or more years provides evidence that cutaneous T cell lymphoma can be eradicated by aggressive topical chemotherapy. This circumstance was observed in 35 patients, representing a cure rate of at least 11% overall. In addition, when compared with the general population of the United States, patients who received topical HN2 were at an 8.6-fold and a 1.8-fold increased risk for the development of squamous cell carcinoma and enhanced for Hodgkin's disease and colon cancer but not for systemic cancers known to be induced by systemic administration of alkylating drugs. These results compare favorably with experiences with topical HN2 chemotherapy at other centers but raise questions about the risks associated with long-term administration for maintenance of remissions.

Administration, Cutaneous↗
PubMed1996

Hypoxia-selective antitumor agents. 12. Nitrobenzyl quaternary salts as bioreductive prodrugs of the alkylating agent mechlorethamine.

A series of benzene-substituted analogues of the novel hypoxia-selective cytotoxin N,N-bis(2-chloroethyl)-N-methyl-N-(2-nitrobenzyl)ammonium chloride (3a), together with three corresponding tetrahydroisoquinolinium "cyclic" analogues 21a-23a and two naphthalene derivatives (19a and 20a), have been prepared and evaluated for cytotoxicity in cultured mammalian tumor cells under aerobic and hypoxic conditions. The parent compound 3a has a one-electron reduction potential of -358 mV and undergoes reductively-induced fragmentation to release the nitrogen mustard mechlorethamine. The compounds were prepared by halogenation (SOCl2) of the corresponding quaternary diols, which in turn were synthesized from N-methyldiethalnolamine and substituted nitrobenzyl chlorides. The reduction potentials of the benzene-substituted compounds were generally well-predicted by Hammett substituent relationships. All of the compounds were much more toxic toward repair-deficient UV4 cells than the corresponding wild-type AA8 cells, as expected if the active cytotoxic species as a DNA alkylating agent. They were also more toxic toward the human cell lines EMT6 and FME compared to AA8, but the reasons for this are not known. Analogues of 3a substituted in the phenyl ring with electron-donating substituents provided compounds with widely differing selectivities for hypoxic AA8 cells, ranging from no selectivity for the 3-Me compound 9a to 3000-fold (at least as great as that of the parent 3a) for the 4-OMe compound 14a. The naphthalene derivatives 19a and 20a and the tetrahydroisoquinolinium compounds 21a-23a showed no hypoxic selectivity. Selective chemical reduction of 22a and 23a with nickel boride resulted in isolation of the corresponding stable amino derivatives, indicating that reduction of these compounds does not result in fragmentation. The reason(s) for the marked differences in hypoxic selectivity of the nitrobenzyl quaternary mustards is unknown, but may reflect differences in radical chemistry, cell uptake, or sensitivity to enzymatic reduction.

Animals↗
PubMed1998

The prognostic significance of delayed hypersensitivity to dinitrochlorobenzene and mechlorethamine hydrochloride in cutaneous T cell lymphoma.

Recent studies suggest that cells elaborating type 1 cytokines are important mediators of anti-tumor cell-mediated immunity in cutaneous T cell lymphoma. Type 1 cell-mediated immune responsiveness was assessed in 276 patients with cutaneous T cell lymphoma (mycosis fungoides and Sézary syndrome) using 2,4-dinitrochlorobenzene (DNCB) skin testing as part of the initial evaluation. The overall rate of sensitization after one and two DNCB challenges was 32% and 67%, respectively, which is much decreased compared with the expected rate of more than 95% for normal individuals. Moreover, the frequency of DNCB sensitization and allergic contact dermatitis to topically applied mechlorethamine decreased with advancing stage of disease. In addition to the expected strong correlation with stage, we observed that patients who were DNCB test positive were significantly less likely to experience disease progression and had a better overall prognosis compared with DNCB-negative patients. These results support the concept that cell-mediated responses are important in cutaneous T cell lymphoma, and that augmentation of these responses would be therapeutically beneficial.

Administration, Topical↗
PubMed1996

Mechlorethamine-induced enhancement of radiation sensitivity of guanine.

This study describes and characterizes the interactions of nitrogen mustard mechlorethamine (HN2) with guanine and the radiation sensitivity of guanine in the presence of HN2. Briefly, in an equimolar solution (0.5 mmol dm-3) the pH-dependence (pH 3.0-12.0) and time-dependence (0-36 h) of alkylation of guanine at room temperature were determined using a reverse-phase high-performance liquid chromatography (hplc) column. Based on the hplc peak areas of the product and intact guanine, the optimal pH for alkylation was determined to be 8.0. Similarly, the optimal time required for alkylation was 10 h. Two products, i.e. alkylated guanines, were detected (10:1, peak areas measured at 260 nm) and purified. Structural studies of the products were performed by direct insertion probe-electron impact mass spectrometry. These products were identified as N-(2-chloroethyl)-N-[2-(7-guanyl)ethyl]-methylamine (product 2). At optimal conditions, samples of either guanine or an equimolar solution of guanine and HN2 were 60Co irradiated (gamma-ray) at 25 Gy min-1 at doses up to 400 Gy. Both sets of samples were analysed by hplc. In each case, the sole radiation product observed and characterized was 8-hydroxy-guanine. Dose-yield plots were linear and showed that HN2 enhanced the radiation sensitivity of guanine. This increase in radiation sensitivity is attributed to the differences in electrophilic properties between nitrogen mustard and guanine.

Chromatography, High Pressure Liquid↗
PubMed2000

The in vivo genetic activity profile of the monofunctional nitrogen mustard 2-chloroethylamine differs drastically from its bifunctional counterpart mechlorethamine.

The property of forming crosslinks within DNA is seen as the major cause of the high carcinogenic, genotoxic and anti-neoplastic potency of bifunctional nitrogen mustards. To further investigate the importance for genotoxicity of a second reactive group in a molecule, the genetic activity profiles of the bifunctional nitrogen mustard mechlorethamine (MEC) and its monofunctional counterpart 2-chloroethylamine (CEA) were compared, using several in vivo end points in Drosophila. When post-meiotic male germ cells were alkylated by CEA and then transferred to nucleotide excision repair (NER)-proficient oocytes, no more than up to 4-fold increased forward mutation frequencies were induced. With oocytes deficient for XPG (DmXPG), frequencies were enhanced up to 50 times. For MEC mutation frequencies increased up to 40 times the background, whereas only a low hypermutability was observed when DmXPG were used instead of wild-type females, indicating that nitrogen mustard-induced monoadducts, in contrast to crosslinks, are efficiently repaired by the NER system. Specific locus mutations generated in the vermilion gene by CEA under NER(-) conditions were almost exclusively base pair substitutions (93%). The high proportion of mutations at guanine positions indicates a strong contribution of N7-alkylguanine to the mutational spectrum. MEC induced 64% deletions and other DNA rearrangements in crosses of males with DmXPG females. The small portion of point mutations (36%) was further reduced to approximately 20% with NER(+) females. Inactivation of NER had no potentiating effect on clastogenic events (chromosome loss) induced by CEA, which is in sharp contrast to the strongly enhanced forward mutation frequencies measured with DmXPG females. The weak genotoxic effectiveness of CEA under NER(+) conditions is clearly due to efficient error-free repair of monoalkyl adducts. These results further support the concept that bifunctional nitrogen mustards exert their mutagenic activity through formation of DNA crosslinks and that DNA monoadducts make only a minor contribution to their genotoxic activity.

Animals↗
PubMed2000

Protection from cytotoxic effects induced by the nitrogen mustard mechlorethamine on human bronchial epithelial cells in vitro.

The present study was undertaken to find potent molecules against the toxicity of nitrogen mustard mechlorethamine (HN2) on respiratory epithelial cells, using a human bronchial epithelial cell line (16HBE14o-) as an in vitro model. The compounds examined included inhibitors of poly(ADP-ribose) polymerase (PARP), sulfhydryl-group donors as nucleophiles, and iron chelators and inhibitors of lipid peroxidation as antioxidants. Their effectiveness was determined upon observance of metabolic dysfunction induced by HN2 following a 4-h exposure, using (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) reduction and ATP-level assays as indicators. Moreover, the fluorescent probe, monobromobimane (mBBr), and 2',7'-dichlorofluorescin-diacetate (H2DCF-DA) were used to assess intracellular sulfhydryl and peroxide level modifications by flow cytometry, respectively, following a 3-h exposure. At last, cell death was assessed by flow cytometry using the propidium iodide (PI)-dye-exclusion assay following 24-h exposure. PARP inhibitors (niacinamide, 3-aminobenzamide, 6(5H)-phenanthridinone), and two sulfhydryl-group donors (N-acetylcysteine, WR-1065) were found to be effective in preventing HN2-induced metabolic dysfunction when added in immediate or delayed treatment with HN2. Only N-acetylcysteine, however, was found to prevent cell death induced by HN2, though it must be present at the time of the HN2 challenge. Flow cytometric measurements of intracellular sulfhydryl levels strongly suggested that N-acetylcysteine and WR-1065 are preventive in alkylation of cellular compounds, mainly by direct extracellular interaction with HN2. PARP inhibitors prevent secondary deleterious effects induced by HN2, considering metabolism dysfunction as the endpoint. Elsewhere, the oxidative stress appears to be a side effect in HN2 toxicity only upon considering the inefficiency of several antioxidants.

Adenosine Triphosphate↗
PubMed1984

Nitrogen mustard (mechlorethamine) and UVB photocarcinogenesis: a dose response effect.

The effects of UVB energy and nitrogen mustard (mechlorethamine, HN2) on tumor formation in the hairless mouse skin was examined. Twice weekly applications of HN2 produced tumors in 34% of the mice. In addition, the HN2 treatments plus UVB radiation resulted in a significant acceleration in tumor formation as compared to either carcinogenic stimulus alone. The twice weekly application of HN2 plus UVB exposure was more tumorigenic than UVB plus HN2 applied once a week. Thus a positive carcinogenic dose response was noted. No tumor-suppressing effects were detected in this study.

Animals↗
PubMed1979

Topical mechlorethamine for psoriasis. An attempt to avoid the development of sensitization by the use of a topical tolerogenic schedule.

The topical application of mechlorethamine is associated with a high incidence of irritant contact dermatitis. An attempt was made to avoid this complication by the use of a topical tolerogenic schedule. Seven of ten patients developed contact dermatitis to the medication after they had completed the schedule, The use of this medication in its present form is unlikely to be practical value in the treatment of psoriasis.

Administration, Topical↗
PubMed1977

Topical mechlorethamine therapy for mycosis fungoides.

Patients with limited skin involvement by mycosis fungoides were treated with daily topical mechlorethamine. Seven of thirteen patients had a complete remission of diseases. Six of these seven experienced a contact dermatitis and four underwent a successful topical desensitization programme. The possible beneficial therapeutic effects of developing a contact allergy are discussed.

Administration, Topical↗
PubMed1985

Effects of mechlorethamine on lysosomal enzyme release from HeLa and 3T3 cells.

The growth of the established malignant HeLa cells was much more inhibited by mechlorethamine (HN2) than that of the nonmalignant 3T3 cells. An initial growth inhibition was followed by complete inhibition even if HN2 was removed from the culture medium. Significant cell death did not occur during the first 24 h of HN2 treatment, but well later on. Incubation with 2.5 micrograms/ml HN2 caused increased release of lysosomal enzymes into the medium and decreased intracellular enzyme activities after a latency period of at least 6 h. The lysosomes from HeLa cells did not seem to be more fragile than those from 3T3 cells. Incubation with 0.25 micrograms/ml HN2 did not alter the intra- or extracellular enzyme levels the first 24 h, but well later on even after refeeding with medium without HN2. This study indicates that lysosomal enzymes are not involved in the genesis of the process leading to cell inactivation by HN2, but may well be correlated with the cytotoxic effects leading to cell death.

Cell Division↗
PubMed1991

Air embolism of the brain in rabbits pretreated with mechlorethamine.

Infusion of 400 microliters air into the left internal carotid artery of five anesthetized rabbits caused transient pial arteriole air embolism, an immediate 41.9 +/- 0.8% dilatation of the embolized vessels, suppression of the cortical somatosensory evoked response to 29.4 +/- 2.7% of baseline, and a progressive decline in ipsilateral cerebral blood flow (measured by hydrogen clearance) to 46 +/- 4.1% of baseline after 2 hours. These values were significantly different from those at baseline and from the responses of 10 control rabbits given equivalent intracarotid saline infusions. Twelve other rabbits were made leukopenic by treatment with 1.5 mg/kg i.v. mechlorethamine 72 hours prior to study. Mean +/- SEM leukocyte count decreased from 6,320 +/- 73/mm3 to 1,890 +/- 66/mm3 without any change in the leukocyte differential or erythrocyte and platelet counts. Intracarotid infusion of saline into seven of the leukopenic rabbits caused no changes. In the other five leukopenic rabbits, infusion of 400 microliters air caused air embolism but did not produce the anticipated declines in cerebral blood flow or the cortical somatosensory evoked response, both of which remained indistinguishable from baseline values and responses in the seven saline-treated leukopenic controls. Similarly, air-embolized arterioles showed nonsignificant dilatation in leukopenic rabbits. Our data suggest that the decreases in both cerebral blood flow and brain function seen after air embolism require the presence of leukocytes.

Animals↗