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At least 19 recordsLinked to original sources
PubMed1975

Mechlorethamine desensitization in therapy for mycosis fungoides. Topical desensitization to mechlorethamine (nitrogen mustard) contact hypersensitivity.

Five patients with mycosis fungoides who had developed contact dermatitis to a nitrogen mustard, mechlorethamine hydrochloride, even in low concentrations (1 to 5 mg/100 ml), received daily total-body applications of extremely dilute solutions (0.01 to 0.1 mg/100 ml) of mechlorethamine. The concentrations of the drug were approximately doubled weekly if the patient could tolerate it, or they were raised more slowly if the patient could not. Attempts to desensitize one patient were discontinued since he was unable to tolerate a greater concentration than 1.0 mg/100 ml after trying for one year. Another patient was able to tolerate a concentration of 3 mg/100 ml after three months, at which time his skin had completely cleared and treatment was stopped. Three other patients were desensitized during a period of 8 to 13 months to the point of tolerating the full therapeutic concentration used in our clinic (20 mg/100 ml) without experiencing dermatitis or pruritus.

Administration, Topical↗
PubMed1999

A prospective study of cutaneous intolerance to topical mechlorethamine therapy in patients with cutaneous T-cell lymphomas. French Study Group of Cutaneous Lymphomas.

OBJECTIVE: To study the exact frequency and the histological features of cutaneous intolerance to mechlorethamine (CIM) hydrochloride therapy in patients with cutaneous T-cell lymphomas, including Langerhans cell histiocytosis. DESIGN: A multicenter prospective study was conducted from January 1, 1994, to May 31, 1996, in 12 different hospitals in France. PATIENTS: Of the 52 patients with cutaneous T-cell lymphomas or Langerhans cell histiocytosis, 35 were men and 17 were women, aged 18 to 87 years. Of the 52 patients, 35 had mycosis fungoides, 8 had nonepidermotropic cutaneous lymphoma, 7 had lymphomatoid papulosis, 1 had Sézary syndrome, and 1 had Langerhans cell histiocytosis. METHODS: Patients were treated with topical applications of a 0.02% aqueous solution of mechlorethamine. The diagnosis of CIM was determined by the presence of erythema and pruritus. Patients who developed CIM underwent closed patch testing with three 10-fold dilutions of 0.02% mechlorethamine solution. A positive patch test result was the presence of erythema and pruritus, a weak result was the presence of simple erythema without pruritus, and a negative result was the absence of erythema and pruritus. Skin biopsy specimens from patients with positive patch test results were obtained in patients who developed CIM. The biopsy specimens were reviewed, and the results determined by 2 pathologists (E.T. and J.W.). The histopathological findings were classified in 3 categories: (1) spongiotic dermatitis, (2) irritant dermatitis, and (3) insignificant or normal. In September 1998, the referring physicians were contacted if mechlorethamine therapy had been continued in patients with CIM. RESULTS: Of the 52 patients, 43 were evaluated for tolerance to mechlorethamine therapy. Of the 43 patients, CIM developed in 23, from 4 days to 9 months after the initiation of mechlorethamine therapy. Of those 23 patients, CIM developed within 3 months in 21 and within 1 month in 13. Closed patch tests were performed in 21 of the 23 patients who developed CIM. The results of the patch test were positive in 12, weak in 4, and negative in 5. Of these 21 patients, 14 skin biopsy specimens were obtained in 14 different patients who had positive or weak patch test results. The specimens showed histological features that were consistent with spongiotic dermatitis in 9 patients, irritant dermatitis in 2, and insignificant or normal in 3. All 9 patients with histological features of spongiotic dermatitis discontinued mechlorethamine therapy. All 5 patients without histological features of spongiotic dermatitis were able to resume mechlorethamine therapy. These results do not correlate with those of previous study results. CONCLUSIONS: Mechlorethamine therapy is a cost-effective and easily administered treatment for cutaneous T-cell lymphomas. Our study shows that allergic dermatitis caused by mechlorethamine therapy is an early and frequent adverse reaction in patients with cutaneous T-cell lymphomas. The most common histological feature of patients with CIM is spongiotic dermatitis.

Administration, Cutaneous↗
PubMed2003

Topical mechlorethamine restores autoimmune-arrested follicular activity in mice with an alopecia areata-like disease by targeting infiltrated lymphocytes.

Alopecia areata is an autoimmune disease targeted at hair follicles with infiltrated T lymphocytes probably playing an important role in the pathogenesis. It was reported in 1985 that mechlorethamine was effective on alopecia areata patients. This has never been confirmed since. The aims of the study were to investigate the effects of mechlorethamine on balding C3H/HeJ mice affected with an alopecia-areata-like disease and to study the underlying mechanisms. Mice were treated on half of the dorsal skin with mechlorethamine and the contralateral side was treated with the vehicle ointment. After 10 wk of mechlorethamine therapy, a full pelage of hair covered the treated side in all the mice and was maintained during the study, whereas the vehicle-treated sides showed either no change or continued hair loss. Immunohistochemistry revealed that infiltrated CD4+ and CD8+ lymphocytes were eliminated from the treated side. In vitro cell viability assay showed that lymphocytes were much more sensitive to the cytotoxic effects of mechlorethamine than skin and hair follicular cells. RNase protection assay and real-time reverse transcription polymerase chain reaction showed that tumor necrosis factor alpha/beta, interleukin-12, and interferon-gamma were inhibited by mechlorethamine upon successful treatment. Our findings support that mechlorethamine restores follicular activity by selectively targeting infiltrated lymphocytes in vivo in alopecia-areata-affected mice.

Alkylating Agents↗
PubMed1985

PUVA therapy prevents sensitization to mechlorethamine in patients with psoriasis.

Two groups of 20 patients with psoriasis were treated with mechlorethamine applied topically (group A) or with PUVA combined with mechlorethamine (group B). In group B mechlorethamine was started after six PUVA treatments. Results showed a significant decrease of the incidence of contact dermatitis in group B (30%) compared with group A (75%). Allergic dermatitis, demonstrated by a positive patch test to mechlorethamine with an histology of eczema, was observed in 55% of patients in group A and 20% in group B. The incidence of irritant dermatitis was not significantly different in the two groups. Allergic dermatitis was observed later in group B: after an average of 32.2 applications of mechlorethamine compared with 25 applications in group A. Possible mechanisms responsible for these results are reduction of epidermal Langerhans cells by PUVA therapy and induction of antigen-specific suppressor T cells. Patients living far from a specialized centre might be treated initially with PUVA therapy then with mechlorethamine alone, at home. This schedule may reduce the incidence of contact dermatitis to mechlorethamine.

Adult↗
PubMed1983

Psoriasis therapy. The effect of UV radiation on sensitization to mechlorethamine.

A study was performed to determine the effect of UV-B radiation on the sensitization of patients to topically applied mechlorethamine hydrochloride. Patients with widespread psoriasis were randomized into two groups. One group was given six daily treatments of one minimal erythemal dose (MErD) prior to starting daily applications of a 0.02% mechlorethamine ointment and, thereafter, one MErD weekly; the other group was given daily applications of mechlorethamine but received no UV-B. The improvement of psoriasis was monitored by a severity score system and patients were treated for 30 days, or until contact dermatitis occurred. The addition of UV-B to topical applications of mechlorethamine reduced the incidence of allergic contact dermatitis to mechlorethamine from 64% to 22%. In those sensitized to mechlorethamine, the time required for sensitization to develop was increased from 14 to 23 days by UV-B therapy.

Administration, Topical↗
PubMedDate not supplied

Dominant lethal mutations induced in mouse spermatogonia by mechlorethamine, procarbazine and vincristine administered in 2-drug and 3-drug combinations.

Male mice were treated with mechlorethamine (2.0 mg/kg), procarbazine (100 mg/kg) and vincristine (0.67 mg/kg) alone, or in 2-drug and 3-drug combinations. 5 weeks later and continuing for 5-8 weeks, embryos fertilized by spermatozoa that were derived from drug-treated spermatogonia were evaluated for drug-induced dominant lethal mutations. Significant mutagenesis was detected for mechlorethamine alone, for 2-drug combinations including mechlorethamine and for 3-drug combinations. Combinations where mechlorethamine was given first were mutagenic whereas combinations where mechlorethamine was not given first were not. Some combinations were more cytotoxic to the germinal epithelium than others. The data suggest that mutagenesis by this combination of drugs which is used extensively in treating Hodgkin's disease is due primarily to the mechlorethamine and that the frequency of mutation-induction may be a function of the order of administration.

Animals↗
PubMed1999

Anomalous cross-linking by mechlorethamine of DNA duplexes containing C-C mismatch pairs.

Nitrogen mustards such as mechlorethamine have previously been shown to covalently cross-link DNA through the N7 position of the two guanine bases of a d[GXC].d[GYC] duplex sequence, a so-called 1,3 G-G-cross-link, when X-Y = C-G or T-A. Here, we report the formation of a new mechlorethamine cross-link with the d[GXC].d[GYC] fragment when X-Y is a C-C mismatch pair. Mechlorethamine cross-links this fragment preferentially between the two mismatched cytosine bases, rather than between the guanine bases. The cross-link also forms when one or both of the guanine bases of the d[GCC].d[GCC] fragment are replaced by N7-deazaguanine, and, more generally, forms with any C-C mismatch, regardless of the flanking base pairs. Piperidine cleavage of the cross-link species containing the d[GCC].d[GCC] sequence gives DNA fragments consistent with alkylation at the mismatched cytosine bases. We also provide evidence that the cross-link reaction occurs between the N3 atoms of the two cytosine bases by showing that the formation of the C-C cross-link is pH dependent for both mechlorethamine and chlorambucil. Dimethyl sulfate (DMS) probing of the cross-linked d[GCC].d[GCC] fragment showed that the major groove of the guanine adjacent to the C-C mismatch is still accessible to DMS. In contrast, the known minor groove binder Hoechst 33258 inhibits the cross-link formation with a C-C mismatch pair flanked by A-T base pairs. These results suggest that the C-C mismatch is cross-linked by mechlorethamine in the minor groove. Since C-C pairs may be involved in unusual secondary structures formed by the trinucleotide repeat sequence d[CCG]n, and associated with triplet repeat expansion diseases, mechlorethamine may serve as a useful probe for these structures.

Alkylating Agents↗
PubMed1995

Effect of mechlorethamine on SRBC-induced secondary antibody response in mice.

The effect of low-dose mechlorethamine (5 micrograms/kg) on secondary humoral response to sheep red blood cells (SRBC), depending on time of exposure to the drug in relation to priming and challenge was studied in Balb/c mice. It was found that mechlorethamine in a dose of 5 micrograms/kg stimulated primary humoral response to SRBC resulting in the increased number of the plaque forming cells (PFC) and hemagglutinin titre (19S + 7S). However, this effect waned 10 days after immunization. On the other hand, the same mechlorethamine dose potentiated secondary humoral response to SRBC and increased the number of PFC and anti-SRBC hemagglutinin titres (notably 7S), which was due to the challenging antigenic stimulus. In each immunization, mechlorethamine administration prolonged the potentiating effect of the drug on anti-SRBC hemagglutinin titre. When mechlorethamine was administered to the mice only after priming, the number of PFC increased, but anti-SRBC hemagglutinin titre (7S) remained unchanged. This was likely due to the fact that mechlorethamine administered after priming increases the number of long-lived lymphocytes B, which in turn affect secondary humoral response.

Adjuvants, Immunologic↗
PubMed1977

Failure to induce tolerance to mechlorethamine hydrochloride.

In view of the contradictory results reported in the literature regarding induction of specific immunologic tolerance to mechlorethamine hydrochloride (HN2), the problem was reinvestigated using a "tolerogenic" schedule that had been reported to be effective. Mechlorethamine hydrochloride, 200 microgram, intravenously, was given weekly for five weeks before beginning topical therapy with it. In the test group, five of 13 patients (11 with mycosis fungoides and two with psoriasis) became contact sensitized to mechlorethamine. In another patient, what was probably a contact urticarial reaction developed. In the control group, five of 13 patients (12 with mycosis fungoides, one with parapsoriasis) became contact sensitized to mechlorethamine. Thus, 38% of the patients in both groups became contact sensitized to mechlorethamine. It is concluded that this tolerogenic schedule, just as others previously tried, was not effective in inducing specific tolerance to mechlorethamine.

Dermatitis, Contact↗
PubMed1983

Ointment-based mechlorethamine treatment for mycosis fungoides.

The treatment of skin disease with topical mechlorethamine has been restricted because of the frequent development of contact dermatitis. A series of 43 patients with mycosis fungoides in Stages 1A (17), IB (22), II (2), and III (2) were treated with an ointment-based mechlorethamine, prepared by an anhydrous method. Complete clearing occurred in 26 patients over a 42-month evaluation period. The incidence of contact dermatitis was very low. Only 1 of 31 patients exposed to mechlorethamine for the first time, and only 3 of 12 patients with a history of previous hypersensitivity to mechlorethamine, developed contact dermatitis to the ointment-based mechlorethamine.

Administration, Topical↗
PubMed1984

Protection of murine L1210 leukemia and bone marrow progenitor cells against mechlorethamine and inhibition of choline uptake as a structure-activity relationship of 2-dimethylaminoethanol and its analogues.

The structure-activity relationships of 2-dimethylaminoethanol and its analogues as protectors against mechlorethamine cytotoxicity and as inhibitors of choline uptake were evaluated. Of a series of inhibitors and protectors, 2-dimethylaminoethanol was the most potent inhibitor of choline uptake and the most potent protector of both hematopoietic progenitor cells and murine L1210 leukemia cells. Two analogues that exhibited both potent protection and inhibition were 1-dimethylamino-2-propanol and 2-ethylmethylaminoethanol. 2-Di-n-butylaminoethanol, while protecting against mechlorethamine cytotoxicity, was not an inhibitor of choline uptake. 2-n-Butylmethylaminoethanol, while an inhibitor of choline uptake, was not a protector against mechlorethamine cytotoxicity. Addition of 2-dimethylaminoethanol to mechlorethamine in a mole ratio of 1000:1 did not improve survival of tumor-bearing mice beyond that of mice treated with mechlorethamine alone.

Animals↗
PubMed1998

Reduction of nitroarylmethyl quaternary ammonium prodrugs of mechlorethamine by radiation.

Nitroarylmethyl quaternary ammonium nitrogen mustards are bioreductive drugs designed to release mechlorethamine, when reduced metabolically, via fragmentation of the initial nitro radical anion to a benzylic-type radical. This proposed mechanism (termed Type I) is analogous to the well-known reductive fragmentation of 2-nitrobenzyl halides. The lead nitroarylmethyl quaternary mustard SN 25246 (NSC 656581), which contains a 2-nitrobenzyl electron acceptor, was shown previously to release mechlorethamine in hypoxic cell cultures and to be a highly selective hypoxic cytotoxin. In the present work the mechanism of reductive release of mechlorethamine from nitroarylmethyl quaternary prodrugs was investigated by steady-state radiolysis with product analysis by high-performance liquid chromatography. SN 25246 releases mechlorethamine in high yield upon reduction, but several reducing equivalents are required (Type II mechanisms). Investigation of other nitroarylmethyl units identified two heterocyclic analogues, the 1-methyl-4-nitro-5-imidazolyl derivative SN 25341 and the 1-methyl-5-nitro-2-pyrrolyl derivative SN 26581, which have a reduction stoichiometry of about one reducing equivalent and which release mechlorethamine efficiently. The other products from reduction of SN 25341 are also consistent with Type I fragmentation, via intramolecular electron transfer, to give the 1-methyl-4-nitroimidazole-5-CH2. radical. The sensitivity of the 4-nitroimidazole and 5-nitropyrrole nitroarylmethyl quaternary mustards to Type I reductive fragmentation suggests that these electron acceptor units may be well suited to development of prodrugs which release tertiary amine effectors after metabolic or radiolytic reduction in hypoxic regions of tumors.

Antineoplastic Agents↗
PubMed1977

The treatment of mycosis fungoides: adjuvant topical mechlorethamine after electron beam therapy.

The feasibility of employing adjuvant topical mechlorethamine after electron beam therapy in the treatment of patients with mycosis fungoides is demonstrated. Patients treated with a planned adjuvant topical mechlorethamine schedule had a median disease-free interval of 25 months compared to 17 months for the group treated with electron beam therapy alone. Projected relapse-free survivals are slightly better in the adjuvant group--37% versus 29%. Patients receiving adjuvant topical mechlorethamine after the electron beam were observed to have a low incidence of contact allergy to the medication. The topical medication can be continued if a contact allergy develops by using a planned desensitization program. We currently treat all mycosis fungoides patients with electron beam therapy, randomizing half to receive adjuvant topical mechlorethamine.

Administration, Topical↗
PubMed1982

Tetraalkylammonium ions: protection of murine L1210 leukemia and bone marrow progenitor cells in vitro against mechlorethamine cytotoxicity and inhibition of the choline transport system.

In the series of tetraalkylammonium ions from tetramethylammonium to tetra-n-heptylammonium, tetra-n-pentylammonium ion was a potent protector of both murine L1210 leukemia and bone marrow progenitor cells against mechlorethamine cytotoxicity. It was also a non-competitive inhibitor of choline uptake. Phosphonium analogs of the tetraalkylammonium ions were equal to their corresponding tetraalkylammonium ions in their protection against mechlorethamine cytotoxicity and in their inhibition of choline uptake. Treatment of tumor bearing L1210 leukemia mice with the combination of tetra-n-pentylammonium ion and mechlorethamine resulted in no major improvement in survival of the tumor-bearing mice compared to mechlorethamine treatment alone.

Animals↗
PubMed1980

Modification of the 4-(p-nitrobenzyl) pyridine assay for measurement of melphalan and mechlorethamine in plasma.

A sensitive, reproducible spectrophotometric assay for mechlorethamine and melphalan was developed through modifications in the use of 4-(p-nitrobenzyl) pyridine as the chromogenic reagent. Key factors that led to enhanced color development and consistency of results were: (1) protein precipitation with 4 degrees C perchloric acid; (2) control of the pH of the reaction with acetate buffer; (3) precise timing of color development in alkali; and (4) sample reading at the appropriate wavelength. The modifications allowed measurement of mechlorethamine and melphalan levels in perfusate samples obtained from isolated rat liver perfusions. Half-lives calculated from perfusate decay curves after addition of mechlorethamine at 50 microgram/ml and 10 microgram/ml were 15.9 min and 15.0 min respectively. The perfusate half-life after addition of melphalan at 5 microgram/ml was 44.2 min. Plasma levels of mechlorethamine were not detectable by this assay after intrapleural administration of 15 mg to one patient but were detectable after intravenous administration of 20 mg to a second patient.

Animals↗
PubMed2005

Analysis of the nitrogen mustard mechlorethamine in topical pharmaceutical preparations by high-performance liquid chromatography.

Mechlorethamine in topical pharmaceutical formulations was derivatized with benzenethiol to form the disubstitution product and analyzed by normal-phase HPLC on silica gel using dibutyl phthalate as an internal standard. The derivatization reaction, purification, and isolation were conveniently performed in a single test tube. Analyses were successfully performed on three types of ointment formulations: anhydrous hydrophobic petrolatum-based ointments, anhydrous hydrophilic ointments, and hydrous hydrophilic ointments. Precision for the analysis of mechlorethamine standard or mechlorethamine in ointments ranged from 0.08 to 0.52% RSD (n = 6). Recoveries from ointments spiked with 0.02% mechlorethamine hydrochloride were 98.4-100.4%. The chromatograms were clean, showing minimal or no interference from ointment excipients or reagents.

Administration, Topical↗
PubMed1995

Effects of levamisole, DTC and low-dose mechlorethamine on humoral response of SRBC-immunized rabbits exposed to cold stress.

The experiments were carried out on normothermal rabbits and rabbits exposed to cold stress (hypothermia). The animals of the latter group were submerged in ice-water for 20 s and then placed in a freezer at -15 degrees C for 8 min until their body temperature dropped by 3 degrees C. Both the normothermal and hypothermal rabbits were immunized i.p. with 3 ml of 10% sheep red blood cells (SRBC). Levamisole (2 mg/kg), DTC (sodium diethyldithiocarbamate, 20 mg/kg) or mechlorethamine (mustine; 5 micrograms/kg) were injected i.v. three times at 24-h intervals. The number of PFC, total (19S + 7S) and 2-mercapthoethanol resistant (7S) serum haemagglutination titres were determined. It was found that, in normothermal rabbits, all three agents potentiated the number of plaque-forming cells (PFC); the impact of DTC was the strongest, while the weakest influence was observed for mechlorethamine. Furthermore, DTC increased anti-SRBC haemagglutinin titre, whereas mechlorethamine did not. Levamisole, on the other hand, reduced total serum haemagglutinin titre. Cold stress reduced humoral response to SRBC, which was reflected in the decreased number of PFC and serum haemagglutination titres (19S + 7S and 7S). Each agent showed a different way of action. Pretreatment with DTC prevented the immunosuppression caused by cold stress, while levamisole and mechlorethamine only reduced the immunosuppressive effect.

Adjuvants, Immunologic↗