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PubMed1990

Mechlorethamine, vincristine, and procarbazine chemotherapy for recurrent high-grade glioma in adults: a phase II study.

We undertook a phase II study of combination chemotherapy with mechlorethamine (nitrogen mustard) 6 mg/m2 intravenously day 1 and day 8, vincristine 2 mg intravenously day 1 and day 8, and procarbazine 100 mg/m2 orally days 1 through 14 (MOP) in adults with recurrent high-grade glioma. There were 31 patients entered and 27 patients assessable for response. The median age was 49 years old. All patients had prior maximal radiotherapy, and eight had previous chemotherapy. Responses were determined based on clinical and computed tomographic (CT) scan/magnetic resonance imaging (MRI) criteria. The response rate (partial response [PR] plus objective qualitative response [OQR] plus complete response [CR]) was 52% with one CR. The response rate was higher in patients with anaplastic astrocytoma as compared with glioblastoma multiforme (P less than .05). The median duration of response was 42 weeks. Median survival for all assessable patients was 30 weeks, and for responders, it was 60 weeks. Response was correlated with ability to decrease dexamethasone doses and improved performance status. Toxicity was mainly hematologic with leukopenia being common. There was one treatment-related death from listeria meningitis, and two patients developed Pneumocystis carinii pneumonia. There were three episodes of neutropenic fever. We conclude that MOP is active and merits further investigation in adult high-grade glioma.

Adult↗
PubMed2002

Pathways of reductive fragmentation of heterocyclic nitroarylmethyl quaternary ammonium prodrugs of mechlorethamine.

Nitroarylmethyl quaternary (NMQ) ammonium salts have potential as prodrugs for enzymatic or radiolytic reduction to release amine effectors under hypoxia. Earlier studies demonstrated one-electron release of the cytotoxic amine mechlorethamine (HN2) from 4-nitroimidazolyl and 2-nitropyrrolyl NMQ prodrugs (but not from nitrobenzyl analogs) through intramolecular electron transfer. In this study we determined whether this is a general feature of heterocyclic NMQ prodrugs of HN2 and examined the reductive pathways in detail using pulse and steady-state radiolysis. The kinetics of radical fragmentation varied by more than four orders of magnitude, independently of the one-electron reduction potential, within the series of eight nitroheterocycles examined. In addition to the compounds identified previously, new 2-nitropyrrole and 3-nitrothiophene NMQ prodrugs were found to provide efficient HN2 release (G > 0.5 micromol/J in anoxic formate buffer). However, the nitrothiophene was sensitive to nucleophilic displacement of HN2, making it less promising. Product analysis by HPLC/mass spectrometry identified symmetrical dimers arising from benzyl-type radical intermediates but also demonstrated that these dimers are not reliable markers for the intramolecular fragmentation of the initial nitro radical anion. This study elucidated multiple competing pathways for reductive fragmentation of NMQ prodrugs and identified the preferred electron acceptors for use in the development of analogs that release more potent cytotoxins.

Antineoplastic Agents, Alkylating↗
PubMed1979

A 10-year experience with topical mechlorethamine for mycosis fungoides: comparison with patients treated by total-skin electron-beam radiation therapy.

A group of 243 patients with mycosis fungoides (MF) received treatment with topical applications of dilute aqueous solutions of mechlorethamine and/or systemic chemotherapy over the past 10 years. The likelihood of a complete and relapse-free remission and survival was found to correlate inversely to the magnitude of disease as denoted by a simple staging system. Although disease-free intervals of greater than 3 years have occurred thus far in 32 (13%) patients, the permanency of these remissions and the curability of disease remain uncertain because of the variability of disease progression characteristic of MF. Comparison of treatment results with those published on a large group of patients treated with total-skin electron-beam radiation therapy indicates that the chemotherapeutic approach to the treatment of MF is equally effective in promoting survival.

Administration, Topical↗
PubMed1990

[14C]mechlorethamine binding to proteins of the human keratinocyte.

Much mustard agent research has focused on mustard/DNA interactions. Mustard also interacts with proteins, however, and to reach the DNA any agent must first pass through the cytoplasm. We hypothesized that the cell's proteins would covalently bind mustard, and thereby limit its access to the DNA. Keratinocyte proteins were radiolabeled with [14C]mechlorethamine and separated by electrophoresis. The banding patterns that resulted were made visible on x-ray films, then compared with control patterns. A correspondence of almost one-to-one was observed, which supports the hypothesis that many cellular proteins are susceptible to mustard alkylation. It follows that some mustard symptoms probably result from effects on existing proteins.

Carbon Radioisotopes↗
PubMed1979

Differential protection of normal and malignant tissues against the cytotoxic effects of mechlorethamine.

The radioprotective drug, WR-2721 (S,2-[3-aminopropylamino]ethyl-phosphorothioic acid), has been studied in terms of its ability to (a) protect mice against mechlorethamine (HN2)-induced hematopoietic death, and (b) alter the ability of HN2 injections to induce growth delay in a solid tumor, the Line 1 lung carcinoma. When WR-2721 was injected ip 15 minutes before iv injections of HN2, it increased resistance to hematopoietic death by a factor of 2, and the protection declined with a half-life of 1.5-2.0 hours. Similar administration of both drugs failed to alter the responsiveness of the Line 1 lung carcinoma to HN2-induced growth delays, except when the HN2 was given within 15 minutes after WR-2721. This interaction of the two drugs, when given within 5-15 minutes of each other, does not appear to be true protection at the tumor site, but rather appears to result from HN2 inactivation in the blood. When HN2 is given 30-60 minutes after WR-2721, it is possible to obtain a twofold increase in the tumor delay without risking increased hematopoietic injury.

Amifostine↗
PubMed1987

Effects of PUVA and mechlorethamine treatment of psoriatic patients on epidermal Langerhans' cells.

Using OKT6 monoclonal antibody, we investigated the number of epidermal Langerhans' cells (LCs) in involved skin from patients with psoriasis, before and after mechlorethamine (HN2) or PUVA treatment. The number of LCs remained at about pretreatment number during three weeks of HN2 treatment alone, though they were reduced after 10 systemic PUVA treatments. Therefore, in contrast to PUVA which influences LCs, HN2 seems to have little effect on LCs. LCs in psoriatic plaques were, in number, 3-4 times less numerous than those in uninvolved, nontreated epidermis.

Antibodies, Monoclonal↗
PubMed1988

Comparison of total nodal irradiation versus combined sequence of mantle irradiation with mechlorethamine, vincristine, procarbazine, and prednisone in clinical stages I and II Hodgkin's disease: experience of the European Organization for Research and Treatment of Cancer.

The H5 study of supradiaphragmatic Hodgkin's disease in clinical stages I-II consisted of two controlled trials adapted to patients considered to have either favorable or unfavorable characteristics, based on prognostic factors identified in two former studies by the European Organization for Research and Treatment of Cancer. Of 494 patients, 257 who were classified as having unfavorable prognosis qualified for the more intensive treatment and consequently were spared a staging laparotomy. They were randomized either to total nodal irradiation (TNI) (132 patients) or to treatment with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) alternated with mantle irradiation (MOPP X 3-mantle irradiation-MOPP X 3; 3M) (125 patients). In complete responders (96%), the 6-year relapse-free survival was 77% in the TNI arm and 91% in the 3M arm (P = .02). Relapses in the initially involved and irradiated mantle area were less frequent in patients started on MOPP. The 6-year actuarial total survival (TS) (TNI, 82%, and 3M, 89%; P = .05) appeared to favor the 3M arm, but this difference disappeared when patients dying from causes unrelated to cancer were excluded from analysis. In men less than or equal to 40 years old, there was no difference in relapse-free survival, freedom from disease progression, or TS between the groups receiving TNI and 3M. Thus, TNI is a short and appealing treatment, especially because it preserves fertility. The same observation was true in women less than or equal to 40 years old. In addition, even irradiation less than TNI, which is meant to spare the ovaries, provided a TS similar to that for 3M.

Adult↗
PubMed1981

Successful treatment of actinic reticuloid induced by whole-body topical application of mechlorethamine.

A man suffering from actinic reticuloid for 2 years showed highly abnormal light sensitivity over a broad action spectrum. He has been successfully treated with daily whole-body topical applications of mechlorethamine, initially for 4 weeks and after a 2-month interruption, for 3 weeks. Gauzes moistened with the same solution were placed over lichenified areas for 10-15 min. His skin became normal pale and the lichenification decreased. After treatment his tolerance for daylight increased.

Administration, Topical↗
PubMedDate not supplied

Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) salvage of mechlorethamine, vincristine, prednisone, and procarbazine (MOPP)-resistant advanced Hodgkin's disease.

Thirty-nine patients with advanced Hodgkin's disease were treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Thirty-one of these patients had previously failed to respond to MOPP (mechlorethamine, vincristine, prednisone, and procarbazine) treatment (29 patients) or to CCVPP (lomustine, cyclophosphamide, vincristine, procarbazine, and prednisone) treatment (two patients). Twenty-seven patients were considered evaluable: eight (30%) achieved complete remission (CR), two (7%) achieved partial remission (PR), and 17 (63%) had no response. All of the complete responders are still in continuous unmaintained CR, while 14 of the 19 partial responders and nonresponders have died. The overall median survival was 21 months; it was 16 months for partial responders and nonresponders. The remaining eight patients had ABVD substituted to MOPP early in treatment, because of allergy to procarbazine: six patients achieved CR and two achieved PR. Our results are in keeping with the literature data and confirm the effectiveness of ABVD as primary and salvage treatment in advanced Hodgkin's disease.

Adult↗
PubMed1983

Randomized study for the treatment of adult advanced Hodgkin's disease: mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) versus lomustine, vinblastine, and prednisone.

Forty-seven patients with advanced Hodgkin's disease were entered in a prospective, randomized trial comparing MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) with a regimen containing lomustine (CCNU), vinblastine, and prednisone (CCNU-VP). Both groups were comparable for the variables of age, stage, substage (symptoms), histology, prior radiation, and sites of involvement. Seventy-two percent of CCNU-VP-treated patients achieved a pathologically documented complete remission (CR) compared to 41% of the MOPP-treated group. Two additional patients treated with MOPP had remission documented only clinically but have been long-term, disease-free survivors. There was a greater frequency of CR in the patients who had received previous irradiation when compared to patients with no prior irradiation. After a median follow-up of greater than 89 months, there is no statistical difference between the two treatment groups in survival (45% for MOPP and 60% for CCNU-VP). Further, no statistical difference in survival for the two treatment groups was noted when compared by histology, stage, or symptoms. The CCNU-VP combination was better tolerated with significantly less nausea and emesis. The alternative drug regimen of CCNU-VP appears to be as effective as MOPP in producing CR and long-term survival in patients with advanced Hodgkin's disease.

Adult↗
PubMed1984

Effects of mechlorethamine (HN2, nitrogen mustard) on UV-induced carcinogenesis in hairless mouse skin.

The influence of mechlorethamine (HN2, nitrogen mustard) on UV-induced carcinogenesis was examined in the hairless mouse skin in vivo. Noncarcinogenic amounts of topically applied HN2 and carcinogenic levels of UVB energy were used in the study. The HN2 applications significantly accelerated the appearance and growth of cutaneous tumors in this study. Thus HN2 acted as either a promoter or cocarcinogen for UV-induced cancer formation. Although the mechanism of this effect was not established, combinations of UVB radiation and HN2 topical therapy pointed to an increased incidence of cutaneous tumors in human skin.

Animals↗
PubMed1983

Histiocytosis X in two adults. Treatment with topical mechlorethamine.

Two adult patients with skin lesions typical of histiocytosis X were treated topically with mechlorethamine hydrochloride. In the patient whose disease was limited to the skin, a sustained remission was induced, but in the patient with extensive systemic disease, cutaneous remission lasted only six weeks.

Administration, Topical↗
PubMed1983

Radiation as salvage therapy for patients with Hodgkin's disease relapsing after MOPP (mechlorethamine, vincristine, prednisone, and procarbazine) chemotherapy.

Six patients with Hodgkin's disease who failed MOPP (mechlorethamine, vincristine, prednisone, and procarbazine) chemotherapy, with recurrences confined to lymph node areas, are reported. All patients were treated with tumoricidal doses of irradiation in mantle, inverted Y, or whole-abdominal fields. All six patients achieved complete remission, with minimal toxicity. Disease-free survival ranged from 3 to 38 months, with four patients remaining in complete remission at 9, 15, 27, and 38 months. Radiation therapy should be considered in patients failing MOPP chemotherapy with lymph node disease.

Drug Therapy, Combination↗
PubMed1994

Modulation of humoral response in rats by levamisole, mechlorethamine and sodium diethyldithiocarbamate.

The effects of levamisole (LMS) (2.5 mg/kg), mechlorethamine (MCHT) (5 or 600 micrograms/kg) and sodium diethyldithiocarbamate (DTC) (20 mg/kg) on primary humoral response of SRBC immunized rats were investigated. Each drug mentioned potentiates the primary humoral response to SRBC by increasing the number of plaque forming cells (PFC) and the level of anti-SRBC antibodies. Comparatively the strongest effect reflected in the increased quantity of PFC occurs after a single administration of the drugs, 48 h after antigen stimulation. The effect of DTC is twice lower than that of LMS or MCHT (5 micrograms/kg). Moreover, accelerated production of IgG (7S anti-SRBC antibodies) is a result of a single administration of LMS and MCHT (5 micrograms/kg) 72 h or 96 h after immunization or five days' DTC treatment at 24 hours intervals. MCHT administered at a dose of 600 micrograms/kg suppresses humoral response of the immunized rats both after a single dosage and five days' treatment at 24 hours intervals.

Animals↗
PubMed2001

Hypoxia-selective antitumor agents. 16. Nitroarylmethyl quaternary salts as bioreductive prodrugs of the alkylating agent mechlorethamine.

Nitrobenzyl quaternary salts of nitrogen mustards have been previously reported as hypoxia-selective cytotoxins. In this paper we describe the synthesis and evaluation of a series of heterocyclic analogues, including pyrrole, imidazole, thiophene, and pyrazole examples, chosen to cover a range of one-electron reduction potentials (from -277 to -511 mV) and substitution patterns. All quaternary salt compounds were less toxic in vitro than mechlorethamine, and all were more toxic under hypoxic than aerobic conditions, although the differentials were highly variable within the series. The most promising analogue, imidazole 2, demonstrated DNA cross-linking selectively in hypoxic RIF-1 cells, and was active in vivo in combination with radiation or cisplatin. However, 2 also produced unpredictable toxicity in vivo, suggestive of nonspecific nitrogen mustard release, and this has restricted further development of these compounds as hypoxia-selective cytotoxins.

Animals↗