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PubMed1997

Low risk of secondary leukemias after chemotherapy without mechlorethamine in childhood Hodgkin's disease. German-Austrian Pediatric Hodgkin's Disease Group.

BACKGROUND: In the last two decades, it has become evident that secondary leukemias after Hodgkin's disease (HD) are mainly caused by the treatment with alkylating agents, especially mechlorethamine. Since 1978, the German-Austrian trials for childhood HD have used combined chemoradiotherapy without mechlorethamine. PATIENTS AND METHODS: The risk of secondary hematologic malignancies (SHM) was assessed in the total cohort of 667 children treated in four consecutive German-Austrian trials between 1978 and 1990. Primary chemotherapy for stages IA/B and IIA consisted of two cycles of vincristine, procarbazine, prednisone, and doxorubicin (OPPA) or OPA (without procarbazine) and, for more advanced stages, of two cycles of OPPA or OPA plus two, four, or six cycles of COPP or COMP (C, cyclophosphamide; M, methotrexate). Radiotherapy was given in the first study to extended fields, and in later trials to involved fields only. In 591 patients, only primary therapy was given; 76 patients (11%) needed additional salvage therapy. The actuarial survival rate at 15 years is 94%. RESULTS: SHM developed in 5 of 667 patients: four acute myeloid leukemias (AMLs) and one myelodysplastic syndrome (MDS). The estimated cumulative risk for SHM at 15 years is 1.1% (95% CI, 0.0% to 2.2%). Salvage therapy was a significant risk factor for SHM (relative risk, 7.25; P = .03), whereas age, sex, stage of HD, splenectomy, and amount of alkylating agents were not. CONCLUSION: The observed risk of SHM is smaller than in other studies (adults and children) in which chemotherapy with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) was given. This difference can be attributed to the lower cumulative doses of alkylating agents, the absence of mechlorethamine in the chemotherapy, and the small number of patients who needed salvage therapy in the presented cohort. In general, differences in the incidence of SHM after HD reflect complex differences between treatment strategies.

Adolescent↗

PubMed2001

The influence of mechlorethamine on the activity of ecto-ATPase of rat lymphocytes.

Mechlorethamine, is an immunomodulator widely used in therapy although its effect on plasma membrane - bound enzymes is unclear. In rats with an inflammatory state, an increased activity of ecto-ATPase was observed both in the B and T subpopulations of lymphocytes. A single administration of mechlorethamine (simultaneously with carrageenin - inflammation factor), either in immunomodulating (5microgram/kg) or cytotoxic (600microgram/kg) dose, decrease the enzymatic activity in both subpopulations but to higher degree in the case of cytotoxic dose. In in vitro studies, after administering mechlorethamine, a diminution of inhibiting potential of the inhibitors blocking the nucleophilic site of proteins was noticed. This confirms the hypothesis that mechlorethamine attacks the catalytic part of the ecto-enzyme containing a nucleophylic group. Classical inhibitors of apyrase - Hg(2+), cerythrosin B and suramine - did not cause any significant change in the activity of ecto-ATPase, what confirms the fact that these enzymes belong to different groups.

Adenosine Triphosphatases↗

PubMed1984

[Effect of mechlorethamine in idiopathic nephrotic syndrome in childhood].

Mechlorethamine has been assessed in 28 patients with idiopathic nephrotic syndrome previously treated with prednisone only. One patient was cortico-resistant (CR), 22 cortico-dependent (CD) and 5 patients had frequent relapses (FR). FR patients had not histological examination and CR patient had a global focal sclerosis (GFS). Among CD patients, 12 had minimal change nephropathy (MCN) and 10 had a diffuse mesangial proliferation (DMP). After prednisone treatment was started, 0.1 mg/kg/d of mechlorethamine for four days was administered iv, in hospital and repeated one month later. After mechlorethamine treatment, GFS evolution was unchanged. Among FR, all the patients improved, 3 with complete remission and 2 with infrequent relapses. MNC improved in 66.6% and DMP in 40%, with the best evolution in immunofluorescence negative patients. Among early side effects, we found gastrointestinal disorders in 11 cases (39.2%) and leukopenia in 8 (28.2%), that required discontinuation of treatment in only 2 cases. We have not assessed gonadal toxicity. We comment the evolution after treatment of the different histological patterns, comparing with other nitrogen mustards and we conclude that mechlorethamine is useful in FR and CD idiopathic nephrotic syndrome corresponding to MCN or DMP with negative inmunofluorescence. Results with other nitrogen mustards, especially chlorambucil, are better.

Child↗

PubMed1981

Thiamine protection of murine L1210 leukemia cells against mechlorethamine cytotoxicity and its relation to the choline uptake system.

Thiamine is an inhibitor of choline transport by murine L1210 leukemia cells and a protector of these cells from growth inhibition by mechlorethamine in vitro. Combination chemotherapy of tumor bearing mice with thiamine and mechlorethamine increased the mechlorethamine dosage required for a 50 to 60 percent increase in survival time but did not improve survival over that obtained with mechlorethamine alone.

Animals↗

PubMed2005

Treatment of early-stage mycosis fungoides with twice-weekly applications of mechlorethamine and topical corticosteroids: a prospective study.

OBJECTIVE: To determine if a therapeutic regimen of twice-weekly applications of mechlorethamine hydrochloride and betamethasone dipropionate cream is effective in the treatment of early-stage mycosis fungoides while increasing cutaneous tolerance. DESIGN: Prospective nonrandomized study conducted from November 1999 to November 2002. SETTING: Eleven university or hospital dermatology departments in France. PATIENTS: Sixty-four consecutive patients with newly diagnosed early-stage mycosis fungoides (stage IA, n = 33; stage IB, n = 26; stage IIA, n = 5). INTERVENTIONS: Patients were treated with twice-weekly applications of a 0.02% aqueous solution of mechlorethamine followed by an application of betamethasone cream during a 6-month period. MAIN OUTCOME MEASURES: The primary end point was the rate of complete response during the treatment. Secondary end points were mean delay to achieve complete response, rate of severe cutaneous reactions of intolerance, and rate of relapse after achieving complete response. RESULTS: Thirty-seven patients (58%) had a complete response after a mean +/- SD treatment duration of 3.6 +/- 2.5 months: 20 (61%) of 33 patients with stage IA disease, 15 (58%) of 26 patients with stage IB disease, and 2 (40%) of 5 patients with stage IIA disease. Eighteen patients (28%) developed severe cutaneous reactions of intolerance that necessitated treatment discontinuation. Relapse was observed in 17 patients (46%) after a mean +/- SD time of 7.7 +/- 6.5 months. CONCLUSIONS: A regimen of twice-weekly applications of mechlorethamine and betamethasone cream is an effective treatment for early-stage mycosis fungoides. The decreased frequency of applications provides an advantage to the patient by being easy to use with limited adverse effects.

Administration, Topical↗

PubMed1980

Accidental intramuscular injection of mechlorethamine.

A 55-year-old man with chronic, active diffuse psoriasis was accidentally given 30 mg of mechlorethmine deep into the buttock muscles. About 5 hours after the intramuscular (IM) mechlorethamine injection, 1/6 M sodium thiosulfate was infused around the intramuscular site. Although systemic responses to the mechlorethamine developed, the expected muscular and adjacent skin destruction did not occur. Instead, IM mechlorethamine induced only minimal local tenderness.

Antidotes↗

PubMed1986

Reversible mechlorethamine-associated hearing loss in a patient with Hodgkin's disease.

Mechlorethamine, when administered in massive doses (0.6-1.5 mg/kg) to cancer patients in several early studies, caused severe irreversible hearing loss. There have been no reports of ototoxicity with doses of 0.4 mg/kg or less. The authors describe a 36-year-old man who developed profound sensorineural hearing loss during his first cycle of MOPP chemotherapy for Hodgkin's disease. Cyclophosphamide was substituted for mechlorethamine in subsequent cycles and his hearing deficit resolved. This is the first reported case of reversible ototoxicity associated with currently recommended doses of mechlorethamine.

Adult↗

PubMed2001

DNA interstrand crosslink formation by mechlorethamine at a cytosine-cytosine mismatch pair: kinetics and sequence dependence.

Expansion of the triplet repeat DNA sequence d[CGG]n.d[CCG]n is a characteristic of Fragile X syndrome, a human neurodegenerative disease. Stable intrastrand conformations formed by both d[CGG]n and d[CCG]n, and involving G-G and C-C mismatch pairs, respectively, are believed to be of importance in the development of the disease. We have shown previously that C-C mismatch pairs can be crosslinked covalently by mechlorethamine, a nitrogen mustard alkylating agent, and hence this reaction may be of value as a probe for conformers of d[CCG]n. To characterize the mechlorethamine C-C crosslink reaction further, here we report the kinetics and sequence dependence of formation of the crosslink species, using a series of model duplexes. The rate of reaction depends on the base sequence proximal to the C-C mismatch pair. Hence, in 19mer duplexes containing a central d[M4M3M2M1Cn1n2n3n4].d[N4N3N2N1Cm1m2m3m4] sequence, where M-m and N-n are complementary base pairs, the amount of crosslink increased with increasing G-C content of the eight base pairs neighboring the C-C mismatch and with the proximity of the G-C pairs to the C-C mismatch. Molecular dynamics simulations of the solvated duplexes provided an explanation of these data. Hence, for a C-C pair flanked by G-C base pairs the mismatched cytosine bases remain stacked within the duplex, but for a C-C pair flanked by A-T base pairs, the simulations suggested local opening of the duplex around the C-C pair, making it a less effective target for mechlorethamine.

Alkylating Agents↗

PubMed1994

Tetracycline compared with mechlorethamine in the treatment of malignant pleural effusions. A randomized trial.

Pleural sclerosis after tube thoracostomy was performed in 40 patients with malignant pleural effusions. The patients were randomly allocated to intrapleural therapy with tetracycline or mechlorethamine. Follow up was obtained on each patient to determine if a symptomatic effusion recurred. The response was classified as a complete or partial response and failure. (Complete response: complete lack of reaccumulation of pleural fluid for at least 60 days. Partial response: small pleural effusion asymptomatic not requiring further treatment for at least 60 days. Failure: all other cases). Tetracycline produced complete or partial control of the effusion in 16 of 20 trials for a duration of 6.1 +/- 4.1 months (range 2-14 months). Mechlorethamine produced control of the effusion in 12 of 20 trials for a duration of 4.4 +/- 1 months (range 2-8 months). These findings indicate that intracavitary tetracycline is a more effective treatment than intracavitary mechlorethamine for the control of neoplastic pleural effusion.

Adult↗

PubMed2002

Evaluation of a 1-h exposure time to mechlorethamine in patients undergoing topical treatment.

BACKGROUND: Mechlorethamine is frequently used in the treatment of cutaneous lymphoma, but its application is limited in 30-80% of cases because of cutaneous intolerance. Reducing the concentration to avoid this side-effect has been only modestly successful. OBJECTIVES: To investigate whether a shorter application period could reduce the frequency of intolerance. METHODS: In an open prospective study in 39 patients with cutaneous T-cell lymphoma or parapsoriasis, mechlorethamine was applied according to the usual practices of the participating physicians (number of weekly applications, treatment confined to lesions or performed over the entire body) and then washed off after 1 h in all cases. RESULTS: Cutaneous intolerance was observed in 19 of 39 patients (49%). Six of these patients showed allergic contact dermatitis to mechlorethamine after a mean period of 9.3 weeks, while the other 13 developed irritant contact dermatitis after a longer period. Cutaneous intolerance did not differ significantly according to the number of applications per week or the extent of body area treated. The therapeutic response rate was 69%, and no difference in therapeutic efficacy was noted between daily and intermittent applications. CONCLUSIONS: Comparison with published studies showed no significant difference in the number of cases of cutaneous intolerance after short-term application, although their occurrence was delayed. Therapeutic response was decreased appreciably by short-term application as compared with results in the literature.

Administration, Topical↗

PubMed2001

Extrahelical cytosine bases in DNA duplexes containing d[GCC](n).d[GCC](n) repeats: detection by a mechlorethamine crosslinking reaction.

The cytosine-cytosine (C-C) pair is one of the least stable DNA mismatch pairs. The bases of the C-C mismatch are only weakly hydrogen bonded, and previous work has shown that, in certain sequence contexts, they can become unstacked from the core helix, and adopt an 'extrahelical' location. Here, using DNA duplexes with d[GCC](n).d[GCC](n) fragments containing C-C mismatches in a 1,4 bp relationship, we show that cytosine bases of different formal mismatch pairs can be crosslinked by mechlorethamine. For example, in the duplex d[CTCTCGCCGCCGCCGTATC].d[GATACGCCGCCGCCGAGAG], where underlined cytosine bases are present as the formal C-C mismatch pairs C(7)-C(32), C(10)-C(29) and C(13)-C(26), we show that two mechlorethamine crosslinks form between C(13) and C(29) and between C(10) and C(32), in addition to crosslinks at C(7)-C(32), C(10)-C(29) and C(13)-C(26) (we have reported previously the crosslinking of formal C-C pairs by mechlorethamine). We interpret the formation of the C(13)-C(29) and C(10)-C(32) crosslinks as evidence of an extrahelical location of the crosslinkable cytosines. Such extrahelical cytosine bases have been observed previously for a single C-C mismatch pair (in the so-called E-motif conformation). In the E-motif, the extrahelical cytosines are folded back towards the 5'-end of the duplex, consistent with our crosslinking data, and also consistent with the absence of C(7)-C(29) and C(10)-C(26) crosslinks in the current work. Hence, our data provide evidence for an extended E-motif DNA (eE-DNA) conformation in short d[GCC](n).d[GCC](n) repeat fragments, and raise the possibility that such structures might occur in much longer d[GCC](n).d[GCC](n) repeat tracts.

Base Pair Mismatch↗

PubMed1976

Distinctive effects of mechlorethamine (NSC-762), cyclophosphamide (NSC-26271), and BCNU (NSC-409962) on transcription in Ehrlich cells.

Comparisons have been made between mechlorethamine, cyclophosphamide (CP), and BCNU as to the effects of chemotherapeutic drug levels on the transcription of RNA in vivo in Ehrlich cells. Mechlorethamine causes a dose-dependent depression in the synthesis of large Hn RNA transcripts in the nucleus and in the amount of large polysomal mRNA in the cytoplasm without apparent disturbance of polyadenylation and transport. Because of compensating increases in smaller Hn RNA and mRNA chains there is no inhibition of total RNA synthesis. CP seems to accelerate total Hn RNA and mRNA formation but inhibits polyadenylation. CP also produces an excess of short chains with only a minor depression of the synthesis of longer transcripts and messages. BCNU inhibits both RNA synthesis and polyadenylation but without disturbance of the size distribution of the polynucleotide chains. The results with mechlorethamine, in particular, are not easily explained on the basis of premature chain termination at the sites of DNA alkylation.

Adenosine Triphosphate↗

PubMed1986

Proton magnetic resonance (PMR) spectroscopic determination of mechlorethamine hydrochloride for injection in commercial unit doses.

A simple PMR spectroscopic method was developed for the quantitative determination of mechlorethamine hydrochloride for injection in commercial unit doses. Deuterium oxide was used as the PMR solvent and tert-butyl alcohol served as the internal standard. The mean +/- SD% recovery value of mechlorethamine hydrochloride from synthetic formulations was 99.5 +/- 0.83, with a coefficient of variation of 0.83%. The mean content of mechlorethamine hydrochloride in a group of ten commercial unit doses was 99.3% by the PMR method and 99.4% by the titrimetric method of U. S. P. XX.

Chemical Phenomena↗

PubMed1982

The treatment of mycosis fungoides with ointment-based mechlorethamine.

The use of topical mechlorethamine hydrochloride in the treatment of skin disease has been restricted because of the frequent development of contact dermatitis. A series of 24 patients with mycosis fungoides in stages 1A (eight patients), 1B (15 patients), and 2 (one patient) were treated with ointment-based mechlorethamine, prepared by an anhydrous method. This preparation was therapeutically effective. Complete clearing occurred in 15 of 18 patients with active disease over evaluation periods of up to 27 months, and one patient had partial clearing. Two patients showed a partial relapse during their evaluation periods. The incidence of contact dermatitis was very low: 8% in individuals with a history of hypersensitivity to mechlorethamine and 0% in patients being exposed to the medication for the first time. This new preparation has been shown to be effective therapy for mycosis fungoides. Patient use is associated with minimal side effects.

Administration, Topical↗

PubMed1981

Cain's quinolinium (NSC 176319): protection of murine L1210 leukemia cells and bone marrow progenitor cells against mechlorethamine cytotoxicity and its application to combination chemotherapy.

Cain's Quinolinium; quinolinium, 6-amino-1-methyl-4[[[[[[(1-methyl-pyridinium-4-yl)amino]phenyl]amino]carbonyl]phenyl]amino] (NSC 176319), is a chemotherapeutic agent, which is equally cytotoxic in vitro to both murine L1210 leukemia cells and bone marrow progenitor cells. At non-toxic concentrations it equally protects L1210 cells and bone marrow progenitor cells against mechlorethamine cytotoxicity. However, treatment of murine L1210 leukemia bearing mice with the combination of Cain's Quinolinium and mechlorethamine at a mole ratio of 1:1 resulted in 100% long term survivors compared to 50% with Cain's Quinolinium alone or 0% with mechlorethamine alone.

Animals↗

PubMed1976

Intravenous desensitization to mechlorethamine in patients with psoriasis.

Eight patients with psoriasis who had developed contact allergy to mechlorethamine hydrochloride (nitrogen mustard) were subjected to a regimen of intravenous infusion of small amounts of the drug in an attempt to produce desensitization. Although three of eight developed negative patch tests and were presumed to be desensitized, only one patient was able to use the drug therapeutically, and then only for a period of eight months, after which allergy recurred. The other two patients whose allergic contact dermatitis was abolished by the infusions were unable to use mechlorethamine therapeutically because of pruritus. Seven patients experienced some adverse reaction to the infusion. Intravenous desensitization of psoriatic patients who are allergic to mechlorethamine was not successful enough as a useful clinical procedure to allow them to once again use the drug therapeutically.

Administration, Topical↗

PubMed1998

Covalent sequestration of the nitrogen mustard mechlorethamine by metallothionein.

The research reported here demonstrates covalent binding to the metal-binding protein metallothionein (MT) by the therapeutic nitrogen mustard mechlorethamine. The most surprising aspect of this interaction is the selectivity of the alkylating agent for specific residues of MT. A combination of MS and proteolytic and enzymatic methods was used to deduce specific locations of mechlorethamine alkylation. These experiments indicated that alkylation occurs predominantly in the carboxyl domain of MT, with one molecule of mechlorethamine covalently cross-linking two cysteine residues. Electrospray MS revealed the retention of all seven metal ions in the cross-linked MT/mechlorethamine adducts, highlighting the uniqueness of this protein. Computerized docking experiments supported the hypothesis that selective binding precedes selective alkylation, and the structure of the drug indicates the minimal structural requirements for this binding. These results support the idea that MT overexpressed in tumor cells contributes to the inactivation of anticancer drugs.

Alkylating Agents↗

PubMed1977

Topical mechlorethamine. Cutaneous changes in patients with mycosis fungoides after its administration.

Six patients with mycosis fungoides were treated with topical mechlorethamine hydrochloride for periods of two to four years. Clinical and histological studies for radiomimetic and radiodermatitis-like effects failed to demonstrate any abnormalities. The only observed changes were generalized hyperpigmentation of the skin and melanin-containing melanophages in the papillary dermis. We consider that the long-term use of topical mechlorethamine may be a safe form of therapy, but that a continuous indefinite follow-up of patients on this medication should be mandatory.

Administration, Topical↗