Mechlorethamine Research Articles

The radiation therapy of early stage cutaneous T-cell lymphoma

Results of different radiotherapy schedules used for early stage (T1-2, N0-1, M0) cutaneous T-cell lymphoma (CTCL) are compared in a series of 45 patients (22 patients treated with high dose total skin electron beam therapy (TSEB) with curative intent, 18 patients treated with palliative radiotherapy, and 5 patients treated with high dose local electron beam). At 3, 5, and 10 years after diagnosis the high dose TSEB treatment group had a probability of overall survival of 91%, 86%, and 75%, respectively, compared with 94%, 88%, and 88% for the palliative treatment group. The complete response (CR) rate for the high dose TSEB treatment group was 82% ( 18 22 ), compared with a 57% ( 4 7 ) complete response rate for seven patients in the palliative group who received low dose TSEB (<25 Gy in 6–7 weeks) followed by daily application of topical mechlorethamine hydrochloride (HN2). However, the probability of continued remission at 3, 5, and 10 years was 44%, 44%, and 33%, respectively, for the high dose TSEB group and 25%, 25%, and 0%, respectively, for the low dose TSEB + HN2 group. The median disease-free survival was 17.5 months for the high dose TSEB group versus 5.5 months for the low dose TSEB + HN2 group. The five patients who were treated with high doses of local electrons to a single local field had an overall survival rate of 80%, a median survival rate of 64 months, and a median length of continued remission of 31 months. These results indicate that high-dose electron beam can result in long-term disease-free survival in patients with localized and limited extent skin involvement with cutaneous T-cell lymphoma.

Can MOPP be replaced in the treatment of advanced Hodgkin's disease?

MOPP (mechlorethamine, vincristine, procarbazine, prednisone) was the first successful regimen for the treatment of Hodgkin's disease. It has the longest period of follow-up and is best studied as to its benefits and acute and long-term side effects. The acute toxicity of the side effects, including nausea and/or vomiting, hair loss, and myelosuppression, may have been reason to modify doses of nitrogen mustard, an agent whose dose intensity may be critical in achieving long-term benefits. The substitution of chlorambucil and vinblastine in the ChlVPP (chlorambucil, vinblastine, procarbazine, prednisone) program has relieved all of these acute toxicities, except myelosuppression. The long-term toxicity of sterility, especially in males, and myelodysplasia is most likely due to alkylating-agent toxicity and would not be influenced by the various MOPP variants, such as MVPP (mechlorethamine, vinblastine, procarbazine, prednisone), ChlVPP, and COPP (chlorambucil-vincristine, procarbazine, prednisone). Doxorubicin-containing regimens, such as ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and ABDIC (doxorubicin, bleomycin, dacarbazine, lomustine, prednisone), have been second-line treatments that have significant antitumor effect and, as such, have resulted in few, if any, long-term cures in most series. ABVD has been incorporated into alternating MOPP/ABVD schemes or in hybrids that attempt to offer all active agents, such as MOPP/ABV. The initial experience has been encouraging with high and durable complete remissions (CRs). MOPP/ABVD x 12(1) and MOPP-2/ABVD-2(2) have been compared with MOPP alone with a significant superiority for the alternating regimens. Other randomized trials have not shown any superiority for the alternating program. The Cancer and Leukemia Group B (CALGB) has compared MOPP with MOPP/ABVD given with a third arm of ABVD alone. The complete response and time-to-treatment failure rates for MOPP/ABVD and ABVD alone were superior to those for MOPP. Significant modifications of MOPP doses may explain the differences, since only 20% of patients were receiving full doses of nitrogen mustard by the sixth dose. ABVD has unique toxicity, and myelodysplasia and sterility are not seen. Pulmonary fibrosis with radiation and bleomycin is unique to ABVD, as shown in the ABVD experience at the NCl (Milan). Can ABVD be improved? The demonstrated single-dose activity of etoposide in Hodgkin's disease has prompted its inclusion in second-line programs, such as EVA (etoposide, vincristine or vinblastine, doxorubicin). The second-line response rates in the St Bartholomew's (London, England) series (where vincristine was used) was 11 of 19 patients (58%);3 in the ongoing CALGB trial of EVA (vinblastine combination), the response rate is 67%. (ABSTRACT TRUNCATED AT 400 WORDS)

Oral and parenteral therapy with saperconazole (R 66905) of invasive aspergillosis in normal and immunocompromised animals

Saperconazole (R 66905) is a broad-spectrum antifungal triazole with potent in vitro activity against Aspergillus spp. A total of 279 strains were tested in brain heart infusion broth. Development of the Aspergillus spp. was completely inhibited at 0.1 and 1 microgram of saperconazole per ml for 80.3 and 99.6% of the strains, respectively. Normal and immunocompromised guinea pigs were infected intravenously with Aspergillus fumigatus and treated orally, intravenously, or intraperitoneally with saperconazole or intraperitoneally with amphotericin B. Leukopenia, neutropenia, lymphocytosis, and monocytosis were obtained with mechlorethamine hydrochloride; leukopenia, neutrophilia, and lymphopenia were obtained with cyclophosphamide. Saperconazole was dissolved for oral treatment in polyethylene glycol and for parenteral treatment in cyclodextrins. Amphotericin B was given parenterally as Fungizone (E.R. Squibb & Sons). Treatment was given once daily for 14 days. An early starting treatment was efficacious, but the activity of saperconazole was maintained even when the onset of the treatment was delayed to the moribund state. The activity of saperconazole was not altered in immunocompromised animals. Saperconazole was clearly superior to amphotericin B and free of side effects. The oral and parenteral formulations of saperconazole were equipotent. The systemic activity of saperconazole in guinea pigs was confirmed in invasive aspergillosis in pigeons.

Nosocomial Amphotericin B

Fungal diseases are relative newcomers among infectious diseases. Even though the major endemic mycoses, coccidioidomycosis, blastomycosis, See also p 2533. and histoplasmosis, were recognized around the turn of the 20th century, they remained medical curiosities until just after World War II. Our understanding of these extremely common infections continued to expand until, by the middle 1950s, both coccidioidomycosis and histoplasmosis became well understood, and only the natural history of the much more uncommon blastomycosis remained poorly charted. Simultaneously with our expanding understanding of diseases caused by these usually pathogenic fungi, infections caused by fungi of low natural invasiveness began to appear in special patient populations. Recognition of life-threatening illnesses caused by these saprophytic fungi closely followed the advent of the modern era of cancer chemotherapy. From the introduction of mechlorethamine hydrochloride (nitrogen mustard) into clinical practice, an ever increasing torrent of new, more and more potent antineoplastic agents appeared, ushering

Late Complications of Curative Treatment in Hodgkin's Disease

SELECTED CASE CANCER therapy has transformed Hodgkin's disease (HD) from a uniformly fatal to a largely curable disorder. Although most long-term survivors enjoy a normal quality and length of life, complications related to curative treatment can be quite diverse (Figure), as illustrated in the following case report. A 29-year-old woman who presented with mediastinal stage II-B nodular sclerosing HD in 1978 received urgent chest irradiation due to symptoms of superior vena caval obstruction. Findings from subsequent staging laparotomy were normal, and she was treated with total nodal irradiation (49 Gy) using an expanded mediastinal port. She obtained a clinical complete remission complicated by chronic pulmonary fibrosis, soft-tissue fibrosis, and elevated levels of thyroid-stimulating hormone (TSH). In 1979 she developed pleuritic chest pain, a perihilar mass, and pleural effusion consistent with recurrent HD. Following six cycles of mechlorethamine hydrochloride (Mustargen), vincristine sulfate (Oncovin), procarbazine, and prednisone (MOPP), complicated by febrile neutropenia,

PUVA Treatment of Erythrodermic and Plaque-Type Mycosis Fungoides

Since our preliminary report of psoralen plus long-wave ultraviolet A (PUVA) therapy in ten patients with erythroderma-type or plaque-type mycosis fungoides (MF), we have treated 38 patients with biopsy-proved MF. Approximately one third, mostly patients with erythroderma, received PUVA as primary therapy; the remainder had recurrent disease following electron beam irradiation or topical mechlorethamine (Mustargen) hydrochloride. Follow-up data are presented in 29 patients who completed an initial course of PUVA given two to three times weekly. A complete clinical response was observed in ten patients with plaque-type MF and seven with erythroderma without Sézary syndrome. The PUVA therapy was palliative for patients with advanced disease, in combination with other therapies. The mean observation period was approximately five years. Despite maintenance PUVA, most patients relapsed between ten and twenty months and were treated with another intensive course. Long-term maintenance therapy with PUVA was necessary to control the disease.

Histiocytosis X

• A 76-year-old man developed a generalized orangered nodular eruption associated with constitutional symptoms. A biopsy specimen of a nodule revealed an extensive infiltration of histiocytes with relatively abundant cytoplasm and folded nuclei. Electron microscopy showed Langerhans' cell granules, which confirmed the diagnosis of histiocytosis X. Results of immunohistochemical studies revealed a pattern of antigen expression usually found in histiocytosis X, including la, T6, and S100. Analysis of the DNA content of the cells with flow cytometry revealed an aneuploid peak. The patient responded partially to topical mechlorethamine hydrochloride therapy. (<i>Arch Dermatol</i>1986;122:446-450)

Guidelines for Handling Parenteral Antineoplastics-Reply

ABSTRACT In Reply.— As staff scientist to the Council on Scientific Affairs, I researched and prepared the report entitled Guidelines for Handling Parenteral Antineoplastics. Randall and Constable are concerned that readers might infer from the introduction to this report that combined chemotherapy and radiation may lead to a higher risk of secondary nonlymphocytic leukemia than chemotherapy alone. Careful reading of the text shows that we did not imply that risks were higher. The statement that patients received radiation therapy was included in an attempt to describe further the therapeutic intervention. Randall and Constable are correct in that not all patients in one of our references (Am J Med 1983; 75:449-454) received radiation in addition to MOPP therapy (Mustargen [mechlorethamine hydrochloride], Oncovin [vincristine sulfate], procarbazine, and prednisone).However, I strongly object to the language of the last paragraph of their letter. This is an attempt to embroil this report in the controversial

Clonogenic response of cells of murine intestinal crypts to 12 cytotoxic drugs.

The in situ response of clonogenic cells in murine intestinal crypts to graded doses of 12 clinically used cytotoxic drugs has been measured by the crypt microcolony assay. For the alkylating agents mechlorethamine hydrochloride and BCNU, survival curves down to three logs of crypt depletion could be obtained. However, with isopropyl methane sulphonate only one log of depletion was measurable, and for a fourth alkylating agent, cyclophosphamide, no crypt killing occurred before other toxicities resulted in death of the animal in less than 3-4 days. This is the major constraint on the use of the microcolony assay with cytotoxic drugs. Of four antibiotics, survival curves were obtainable for adriamycin, bleomycin and mitomycin C, but not for actinomycin D. 5-Fluorouracil gave only a limited degree of crypt kill. Of three S-phase-specific drugs, hydroxyurea and vincristine resulted in little or no crypt depletion, but there was dose-dependent crypt depletion after methotrexate. The complexities of applying cellular-kinetic classifications of cytotoxic drugs to in situ endpoints are discussed.

Alkylating agent resistance: in vitro studies with human cell lines.

Development of in vitro resistance to HN2 (also called mustargen or mechlorethamine hydrochloride), N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU), and cisplatin [cis-diamminedichloroplatinum(II)] was achieved in two human cell lines, the Raji/Burkitt lymphoma and a squamous cell carcinoma of the tongue. A 10- to 20-fold increase in resistance relative to the parental line was achieved in 3-4 months of continuous selection pressure. At this time, further increase in selection pressure resulted in cell death, while removal of drug led to rapid loss of resistance. However, by holding selection pressure constant over 8-12 months, semistable clones ranging in resistance up to 8- to 12-fold were obtained. The half-life for resistance loss upon removal of drug was 2-3 months. In the presence of intermittent low concentrations of the alkylating agent, resistance has been maintained in excess of 9 months. With one exception, the growth kinetics of the resistant clones were slightly slower than those of the parental lines. Cross-resistance studies were performed against HN2, BCNU, cisplatin, phenylalanine mustard, and hydroperoxycyclophosphamide. There was, in general, a lack of cross-resistance. We conclude that stable resistance to alkylating agents is produced with difficulty. We propose that these semistable cloned human tumor lines represent clinically relevant models for the study of alkylating agent resistance and that the cross-resistance patterns among these cells have important therapeutic and mechanistic implications.

Permeability of latex and polyvinyl chloride gloves to 20 antineoplastic drugs

Permeability of latex and polyvinyl chloride (PVC) gloves to 20 injectable antineoplastic drugs was studied. Four types of gloves were evaluated: latex surgical gloves, latex examination gloves, and PVC gloves in two thicknesses. Each glove material was exposed to each drug for 90 minutes, and permeation was tested using a mutagenicity assay. Individual fingertips of thin PVC gloves and latex surgical gloves were tested for permeability at five time points (2-30 minutes) using a doxorubicin coloration assay. All drugs permeated the thin PVC gloves. Latex surgical gloves were definitely permeable to two drugs (carmustine and thiotepa) and exhibited borderline permeability to mechlorethamine hydrochloride. The thick PVC gloves were definitely permeable to four drugs (carmustine, thiotepa, mechlorethamine hydrochloride, and daunorubicin hydrochloride) and exhibited borderline permeability to two drugs (doxorubicin and mercaptopurine). The latex examination gloves were permeable to carmustine, thiotepa, mechlorethamine hydrochloride, and cyclophosphamide. Doxorubicin permeation of individual fingertips of thin PVC gloves varied in time and amount. Doxorubicin did not permeate the latex surgical glove material, but testing with thiotepa showed that individual fingertips of this material also varied in permeability. Glove thickness was a major determinant of permeability; latex surgical gloves were the least permeable and thin PVC gloves the most permeable to the antineoplastic drugs tested. Within individual gloves and glove types, time and amount of permeation were not uniform.

Response of Mycosis Fungoides to Topical Chemotherapy With Mechlorethamine

Seventy-six patients with mycosis fungoides (MF) were given topical mechlorethamine hydrochloride therapy. Allergic contact hypersensitivity reactions to the drug developed in 51 patients (67.1%). Sixty-four patients of the original 76 continued therapy, with 43 (67.2%) achieving a complete remission and 12 (18.8%) achieving a partial remission. Stage I disease responded significantly better than did subsequent, more severe disease stages. The median times to complete remission were 5.6 months, 32.3 months, and 22.3 months for stage I, II, and III disease, respectively. The conditions of patients with contact sensitivity did not respond better than those of patients without contact sensitivity. Patients with substage A disease did not respond better patients with substage B disease. These findings are encouraging and indicate that the use of topically applied mechlorethamine for early-stage MF should be continued, despite the development of contact dermatitis to the drug.

Dichloroethyl carbamoyl ester of delta-9-tetrahydrocannabinol. Chemical synthesis and biological testing and evaluation as a potentially site-specific anti-tumor agent.

A novel compound, Delta-9-Tetrahydrocannabinol Nitrogen Mustard (THC-mustard), was chemically synthesized and characterized. The rationale was to target a known anti-tumor agent, nitrogen mustard, to tumor cells with "THC Receptors" and/or "Estrogen Receptors". A microtest in vitro bioassay was designed and developed to compare the ID50 of the drug in cell culture against various tumor cell types. The ID50's of the THC-mustard were determined against several tumor cell types in culture, compared with Mechlorethamine HCl, Delta-9-Tetrahydrocannabinol (THC), and an equimolar mixture of THC and nitrogen mustard. A preliminary toxicity study by the NCI of the THC-mustard (in vivo) in Swiss male mice bearing the P388 tumor (1 dose X 1 day) by the I.P. route was also carried out. A description of the rationale, chemical synthesis and characterization, bioassay, and results is herewith presented.

Death of intestinal crypts and of their constituent cells after treatment by chemotherapeutic drugs.

The number and spatial distribution of necrotic cells in the jejunal crypts of mice, has been measured after treatment by each of 6 cytotoxic drugs. At the LD10/8 day dose of each drug, the majority of necrotic cells were found below position 9 and numbers per crypt were similar for all drugs (approximately 8). These findings resemble those for radiation. However, major differences between agents were found in the calculated numbers of the microcolony-forming units (MFU) that determine overall crypt survival or ablation after high doses of cytotoxic agent. Numbers of MFU as assayed by radiation were approximately 80 per crypt, but only 2 when assayed by mechlorethamine hydrochloride, adriamycin and 5-fluorouracil, and 7 using BCNU. No crypts were destroyed by either cyclophosphamide or actinomycin D, despite the appearance of numerous necrotic cells in the lower part of the crypt. We conclude that in drug-treated intestine, necrotic cells may arise from a non-MFU compartment and the incidence and distributions of such cells are likely to be poor indicators of the response of the MFU.

Combined moderate dose electron beam radiotherapy and topical chemotherapy for cutaneous t-cell lymphoma

Between October, 1978 and June, 1979, nine patients with biopsy-proven cutaneous T-Cell lymphoma were treated with combined total-skin electron beam radiation (TSEB) and topical chemotherapy. TSEB was administered using 3.8 MeV electron and dual exposure technique. All patients received skin dose of 400 rad once weekly to a total dose of 2000 to 2400 rad followed by topical chemotherapy with mechlorethamine hydrochloride (HN2) ∗ two to four weeks after completion of radiation. A complete response followed TSEB in seven of nine patients, but a relapse of disease activity has subsequently occurred within the first year for all the patients despite adjunct therapy, except for one patient who remains disease free for more than 21 months. Generalized severe erythema developed during or shortly after completion of radiation in six of nine patients, with blistering at the overlapping treatment fields and body folds in four patients. In addition four patients developed diffuse permanent telangiectasia of skin and one patient developed linear sclerosis, telangiectasis and painful ischemic ulceration on the fingertips two years after completion of electron beam therapy. Most patients had evidence of mild depression of lymphocyte responsiveness to Phytohemagglutinin after TSEB. Our conclusion is that the short-term benefits and convenience of this particular technique do not justify the acute and chronic toxicity encountered.

Topographic variations in the clonogenic response of intestinal crypts to cytotoxic treatments.

In the intestinal crypt microcolony assay, a "surviving fraction" of whole crypts is calculated conventionally by dividing the number of regenerating crypts three to four days after treatment by the number of crypts in untreated animals, both measured around a complete intestinal circumference in transverse sections of gut. We show that in relation to the mesenteric attachment of the gut, crypts in different regions of this circumference differ in their survival characteristics after radiation or mechlorethamine hydrochloride ("HN2"). Crypts associated with Peyer's patches are resistant to both agents (large initial shoulder, shallow slope). The mode of administration of HN2 (IP vs. IV) influences the shape of the crypt survival curve. Differences in size of shoulder and slope affect the estimate of numbers of microcolony-forming cells per crypt (A). For radiation, this number can vary sevenfold, depending on the region of circumference chosen for analysis. Different agents of assay result in radically different values for A.

Histiocytosis X in Two Adults

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.

Psoriasis Therapy

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.

Unusual Local Cutaneous Reaction to Dacarbazine

Dacarbazine is widely used in the systemic treatment of malignant melanoma and Hodgkin's disease. While side effects of nausea, vomiting, and bone marrow depression are well recognized, adverse skin reactions are less common. We report a localized skin reaction to the intravenous (IV) administration of dacarbazine that histologically resembled a fixed drug reaction. Report of a Case A 19-year-old man was hospitalized in September 1980 for recurrent Hodgkin's disease, manifested by severe peripheral lymphadenopathy. In the hospital he began treatment on a regimen of mechlorethamine hydrochloride, procarbazine hydrochloride, prednisone, doxorubicin hydrochloride, bleomycin sulfate, vinblastine sulfate, and dacarbazine chemotherapy. He had previously been treated with mechlorethamine, vincristine, prednisone, and procarbazine chemotherapy, which had produced a complete remission, but paralytic ileus had developed secondary to vincristine-caused autonomic neuropathy. He had never received dacarbazine before September 1980. Four hundred milligrams of dacarbazine, diluted in 1 dL of a 5% glucose-and-water solution, was

The Hydrolysis of Spirohydantoin Mustard

Spirohydantoin mustard (I) is a rationally designed antitumor agent with substantial in vivo activity against intracranially implanted tumors in mice. However, hydrolysis of I was much faster than that of mechlorethamine hydrochloride or melphalan, two parenterally administered mustards. The hydrolysis products of I were identified by GC-MS of their silylated derivatives. The decomposition of I (at 25° in 10% dimethylacetamide at pH 4–6), as monitored by GLC was pseudo first-order. The half-life of I ranged from 20min at pH 4.0 to 14min at pH 6.0. Nonionic surfactants enhanced the stability of I, but this effect was diminished at lower pH, presumably due to decreased solubility of I in the micelle as more drug was protonated. Several dilute parenterally suitable solvents exhibited no marked effect on the hydrolysis of I. The drug was most stable in a 10% fat emulsion system where the time for 10% decomposition of I was 49 ± 5min. Plots of the concentration of I versus time were linear indicating the disappearance was zero order in the 10% fat emulsion system.