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PubMed1986

[Treatment of Hodgkin's disease by chemotherapy with MOPP alone. Long-term results].

Between 1967 and 1978, 152 Algerian patients (31 children and 121 adults) with Hodgkin's disease were treated with the mechlorethamine, vincristine, procarbazine, prednisone combination (MOPP) alone and without radiotherapy. They were separated without lymphography into limited stage (n = 37) and extensive (n = 115) stage. The high initial failure rate (54%) was principally due to inadequate symptomatic treatment and to the patients' low socio-economic status. The complete remission rate was 45% (54% for limited stages; 42% for extensive stages) and significantly higher in women (58%) than in men (37%). In 20/23 cases relapses occurred during the first 4 years of complete remission; however, the final relapse was observed during the 12th year of complete remission. The actuarial relapse rate at 15 years was 48%. The long-term (10-15 years) life expectancy was 31% overall and 70% in cases with complete remission. Prognosis was significantly better in patients with limited forms and/or without systemic symptoms.

Adolescent↗
PubMed1986

The lack of effects of alkylating agents on mammalian cell membranes.

The importance of cell membrane components as target sites for the action of 2,3,5-tris(ethyleneimino)-benzoquinone (Trenimon), mechlorethamine hydrochloride (HN2) and tris(2-chloroethyl) amine hydrochloride (HN3) was investigated. Uptake of 2-aminoisobutyric acid (AIBA) was studied under nonsaturating conditions where the transport system was rate-limiting for the uptake. Uptake of AIBA into L5178Y leukaemic cells was either inhibited or stimulated, depending on the type of the drug, the drug concentration and the length of incubation. Treatment of human erythrocytes with 10(-3) M HN3 produced new high-molecular-weight protein bands on SDS-polyacrylamide gel electrophoresis. Conversely, HN3 had no effect on L5178Y cell membrane proteins. Neither HN2 nor Trenimon produced any detectable changes in membrane proteins of L5178Y cells or human erythrocytes. None of the three drugs at concentrations and incubation conditions which inhibited cell replication changed the stoichiometry or dissociation constant of concanavalin A (Con A) binding sites on L5178Y cells. Trenimon at highly toxic concentrations had no effect on the fluidity of phospholipid membranes or of membranes of Ehrlich ascites tumour cells as analysed by ESR spin-label methods. The results presented here do not support the hypothesis that cell membranes are the primary target sites for alkylating drugs.

Alkylating Agents↗
PubMed1988

The effect of leukocyte depletion on smoke inhalation injury in sheep.

Leukocytes and the production of oxygen radicals and proteolytic enzymes have been implicated in the pathogenesis of lung injury after smoke inhalation. We investigated the mechanism responsible for this form of pulmonary damage in chronically prepared sheep previously made leukopenic with intra-arterial infusions of nitrogen mustard (mechlorethamine hydrochloride). A control air insufflated group (sham: n = 6), a cotton smoke insufflated group (smoke: n = 12), and a leukopenic cotton smoke insufflation group (smoked + depleted: n = 6) were compared. Although both smoke insufflation groups had equivalent smoke exposure, which was indexed by carboxyhemoglobin, the smoked + depleted group had significant attenuation in the increases in pulmonary artery pressure, pulmonary vascular resistance, and pulmonary lymph flow. The PaO2 to FiO2 ratio (P:F) did not fall to the same extent, nor was there a fall in PaO2. The production of oxygen radicals, which was measured as plasma-conjugated dienes, and the consumption of antiprotease, as measured by alpha 2-macroglobulin levels in lung lymph, were not changed in the smoked + depleted group, whereas it was elevated in the smoked group. We conclude that circulating leukocytes and the release of oxygen radicals and proteolytic enzymes contribute to the lung injury, pulmonary microvascular permeability increase, and pulmonary edema seen after smoke inhalation.

Animals↗
PubMed1987

Selective enhancement by menadiol of in vitro drug activity in human lymphatic neoplasms.

The effect of menadiol (vitamin K3) on fresh specimens of human lymphatic neoplasms (HLN) was tested by means of the differential staining cytotoxicity assay. Menadiol was tested alone and in combination with standard antineoplastic agents. Drug effects were then compared with the effects of the same drugs in normal human lymphocytes and in fresh specimens of human non-small cell lung cancer. By itself, menadiol was moderately toxic to HLN, but not to normal lymphocytes or non-small cell lung cancer. Menadiol, menadione, and two structurally related congeners were equitoxic to HLN cells, but sodium metabisulfite (present in menadiol solutions as a preservative) was nontoxic. Menadiol increased the cytotoxic effects of a number of standard agents in HLN but not in normal lymphocytes. Cell survival times with mechlorethamine, vincristine, and dexamethasone were converted from a range characteristic of drug resistance (ie, range observed in relapsed patients) to a range characteristic of drug sensitivity (ie, range observed in untreated patients) in the presence of menadiol. These effects occurred at a concentration (2.0 micrograms/ml; 4.7 microM) of menadiol which is probably clinically achievable and which did not deplete intracellular glutathione. Menadiol should receive clinical testing as a chemosensitizing agent in HLN.

Antineoplastic Agents↗
PubMed1987

PUVA treatment of erythrodermic and plaque-type mycosis fungoides. Ten-year follow-up study.

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.

Adult↗
PubMed1986

Induction of plasminogen activator by alkylating agents in a repair defective human glioblastoma cell strain.

Alkylating agents, mechlorethamine and N-methyl-N'-nitro-N-nitrosoguanidine, induce the production of plasminogen activator in U-87MG cells, an alkylation DNA repair deficient (Mer-) human glioblastoma strain. Enzyme induction was not observed, however, in U-178MG and SH-101 cells, alkylation repair proficient (Mer+) glioblastoma strains, or in HeLa cells, which reactivated and supported well the growth of alkylation damaged adenovirus 3. In the alkylation repair defective U-87MG strain, enhanced production of plasminogen activator occurred in a narrow concentration range of treatment with either alkylating agent, causing a 20 to 50% inhibition of [3H]thymidine incorporation. Maximum plasminogen activator induction was observed between 32 and 48 h after alkylation treatment and the levels of enzyme produced were 5 to 10 times those of untreated control levels. This alkylation dependent enzyme induction required protein synthesis for it did not occur in the presence of cycloheximide. It was hence concluded that plasminogen activator induction in alkylation repair deficient human cells is caused by unrepaired DNA damage and that it may represent an eukaryotic SOS-like function. In addition, plasminogen activator induction may be useful as a sensitive assay for the identification of alkylation repair defective human tumors for which the susceptibility to alkylation chemotherapy should be expected to increase.

Alkylating Agents↗
PubMed1979

An improved method for analyzing survival data from combination chemotherapy experiments.

In this paper, we present a new method for analyzing survival data from combination chemotherapy experiments. The analysis consists of relating survival to the dosage level of each drug in the combination and using response surface techniques to determine the importance of drug interactions and to estimate optimal doses. A combination experiment using cyclophosphamide, mechlorethamine, and mitomycin C in early L1210 leukemia, advanced L1210 leukemia, and advanced P388 leukemia is used to illustrate the analyses. A therapeutic synergism has been shown. As a result of the various drug interactions, the predicted optimal dose of mitomycin C is found to be zero. This result was duplicated in each tumor system studied.

Animals↗
PubMed1984

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.

Animals↗
PubMed1980

Normalized light reactions in mycosis fungoides patients after complete remission of skin lesions.

Eleven mycosis fungoides patients were phototested on apparently normal skin before treatment with mechlorethamine, topically in 8 patients and with methoxsypsoralen followed by longwave ultraviolet light (PUVA) in 3 patients. Abnormal photosensitivity to UVB was seen before treatment in 4, to UVA in 4, and to visible light in one patient. The abnormal photosensitivity to all wavelength regions was normalized after complete remission of the cutaneous lesions. Two of the PUVA-treated patients demonstrated that special care should be taken during the initial phase of this treatment because of the light sensitivity, especially on lesional skin.

Aged↗
PubMed1982

Cyclic delivery of MOPP and ABVD combinations in Stage IV Hodgkin's disease: rationale, background studies, and recent results.

This paper summarizes the experience achieved at the Cancer Institute of Milan with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy in various stages of Hodgkin's disease, with special emphasis on the cyclic delivery of mechlorethamine, vincristine, prednisone, and procarbazine (MOPP) and ABVD in the primary treatment of stage IV disease. Six cycles of ABVD yielded a complete remission (CR) rate (71%) similar to that of MOPP (63%). ABVD combined with radiotherapy in 153 patients with stage IIB, IIIA, or IIIB disease was superior to MOPP plus radiotherapy in the CR induction (94% vs 79%, P less than 0.01), particularly in the presence of nodular sclerosis histology (P less than 0.03) and B symptoms (P = 0.01), as well as in the relapse-free survival of patients with pathologic stage IIIA disease (ABVD, 100%; MOPP, 68%; P = 0.02). Total survival was similar between the two treatment groups, but, compared to MOPP, ABVD chemotherapy was associated with a lower incidence of delayed toxic effects such as azoospermia, prolonged amenorrhea, and cancerigenesis. ABVD induced CR in 59% of 54 patients resistant to MOPP; 37.5% of the complete responders remain alive and disease-free at 5 years. The cyclic delivery of MOPP and ABVD was significantly superior to that of MOPP alone in terms of CR (92% vs 71%; P = 0.02), freedom from disease progression (70% vs 37%; P less than 0.0001), and relapse-free survival (77% vs 47%; P less than 0.01) at 5 years. Toxic effects were similar between the two treatment groups, but there was a higher incidence of vomiting and alopecia following ABVD chemotherapy; in the group given MOPP alone, one patient who had previously failed extensive irradiation developed acute nonlymphocytic leukemia. ABVD is confirmed to be an effective regimen that is non-cross-resistant to MOPP and devoid of late morbidity. Therefore, its administration, when alternated monthly with MOPP, offers the possibility to improve the cure rate of Hodgkin's disease.

Adult↗
PubMed1982

Chemotherapy strategies to improve the control of Hodgkin's disease: the Richard and Hinda Rosenthal Foundation Award Lecture.

The paper reviews new chemotherapy strategies for intermediate and advanced stages of Hodgkin's disease as well as the implications of recent biological concepts and mathematical models which appear useful in the interpretation and design of new treatments. The development and the application of the Adriamycin-bleomycin-vinblastine-dacarbazine (ABVD) combination was based on critical reevaluation of benefits and limits of the mechlorethamine-vincristine-procarbazine-prednisone (MOPP) combination. The attempts to develop non-cross-resistant regimens, such as ABVD, arose intuitively at first from the desire to improve salvage treatment in MOPP-refractory patients; more recently, a theoretical framework for this approach has been proposed by Goldie and Coldman (Cancer Treat. Rep., 63: 1727-1733, 1979). The 5-year results achieved with different forms of salvage chemotherapy and with the cyclic delivery of non-cross-resistant combinations (MOPP and ABVD) can be explained largely by the assumption that drug-resistant mutants represent a major limiting factor in the cure of Hodgkin's disease, as well as of other neoplasms, by chemotherapy. The initial results from a prospective randomized trial indicate that the administration as front-line therapy of non-cross-resistant regimens is a logical and powerful strategic approach and therefore that it may constitute an important avenue of clinical research. Recent observations also emphasized the problem of the quality of life, since the administration of multidrug combinations not including alkylating agents and/or procarbazine appears to be associated with a decreased incidence of carcinogenesis and sterility. The departure from the standard practice of utilizing a single multidrug regimen for chemotherapy of Hodgkin's disease should be supported by sound research and controlled studies built on drug combinations of known efficacy and toxicity.

Antineoplastic Agents↗
PubMed1976

Chemotherapy versus chemoimmunotherapy of head and neck cancer: report of a randomized study.

Thirty-four patients with recurrent squamous cell carcinoma of the head and neck were randomized to receive the five-drug chemotherapy regimen BACON (bleomycin, adriamycin, CCNU, vincristine [Oncovin], and mechlorethamine [nitrogen mustard]; 14 patients) or the same regimen plus bacillus Calmette-Gu erin (BCG) by scarification (20 patients). The majority of both patient groups had received prior surgery and radiation. The patients treated with BACON plus BCG experienced a significantly longer survival (P = 0.014) than those treated with BACON alone. There were five drug-related deaths, and eight other patients required hospitalization for treatment of drug-related morbidity.

Adult↗
PubMed1984

Glutathione metabolism as a determinant of therapeutic efficacy: a review.

Glutathione, as the chief nonprotein intracellular sulfhydryl, affects the efficacy and interactions of a variety of antineoplastic interventions, mainly through nucleophilic thioether formation or oxidation-reduction reactions. Thus, glutathione plays a role in the detoxification and repair of cellular injury by such diverse agents as mechlorethamine, melphalan, cyclophosphamide, nitrosoureas, 6-thiopurine, 4'-(9-acridinylamino)methanesulfon-m-anisidide, the quinone antibiotics (including Adriamycin, daunorubicin, and mitomycin C), the sesquiterpene lactones (such as vernolepin), and other sulfhydryl-reactive diterpenes (like jatrophone). Glutathione may play a similar role in host and tumor cell responses to radiation, hyperthermia, and the reactive reduction products of oxygen secreted by inflammatory cells. Further, glutathione participates in the formation of toxic metabolites of such chemotherapeutics as azathioprine and bleomycin and may affect the cellular uptake of other agents, such as methotrexate. It seems likely that alterations in glutathione metabolism of tumor or host as a result of one therapeutic intervention may affect the outcome of concurrent treatments. Knowledge of these interactions may be useful in designing combination therapy for neoplastic disease.

Aminoacridines↗
PubMed1976

Eight-drug combination chemotherapy (MOPP and ABDV) and local radiotherapy for advanced Hodgkin's Disease.

Thirty-seven patients with advanced Hodgkin's disease have been treated for greater than or equal to 3 months with a protocol consisting of alternate monthly courses of MOPP (mechlorethamine, Oncovin [vincristine], procarbazine, and prednisone) and ABDV (adriamycin, bleomycin, DTIC, and vinblastine) with local radiotherapy (RT) to areas of originally bulky disease. This therapy produced CR in 19 of 19 previously untreated patients (100%), eight of nine previously treated with RT (89%), and six of nine previously treated with RT and MOPP (67%). The remaining patients are all PRs tending toward CR status. The median time to CR was 3.0 months. The median time in remission to date for the previously untreated patients is 8+ months (2+-14+). After an induction period of eight cycles of chemotherapy patients are maintained on alternate-month treatment continuing the alternating sequence. During this phase three patients have experienced reappearance of disease (one recurrence, one possible second primary lymphoma, and one recurrence in a patient whose original diagnosis is in doubt). The regimen has been well tolerated. All patients were treated as outpatients. Alopecia and neurotoxicity were mild and myelosuppression was moderate. Clinically significant cardiopulmonary toxicity has been limited to mild radiation pneumonitis in one patient and bleomycin pneumonitis which cleared during prednisone in a second patient.

Adolescent↗
PubMed1984

Use of an in vitro technique to detect mutations induced by antineoplastic drugs in mouse germ cells.

Male mice were given graded doses of procarbazine or mechlorethamine in the presence or absence of prednisolone. Eight to 24 days later, these mice were mated with untreated females and the resulting zygotes were cultured in vitro from the two-cell stage to an early implantation stage. The frequency of successful embryonic development in these embryos was less than the frequency in embryos sired by untreated control animals. The reduced frequency reflects the induction of mutagenic lesions in the germinal epithelium by the drugs and their transmission by the spermatozoa to the oocyte.

Animals↗
PubMed1983

Altered hepatic functions and microsomal activity in perfused rat liver by hyperthermia combined with alkylating agents.

Livers of fasted rats were perfused for one hour in the presence of cyclophosphamide (CP), mechlorethamine (HN2), or melphalan (L-PAM) at 37 degrees and 42 degrees C. Hepatic biosynthetic function was assessed by determining gluconeogenesis from lactate, ureogenesis from NH4Cl, and O2 consumption. Antipyrine (AP) metabolism was employed to assess microsomal mixed function oxygenase enzyme activity at elevated temperatures. The t 1/2 of AP increased 2.8-fold in a temperature-dependent manner between 37 degrees and 43 degrees C. In the presence of biosynthetic substrates, the t 1/2 of AP increased 1.8-fold between 37 degrees and 43 degrees C. CP activation was suppressed (27% at 125 micrograms/ml, 49% at 500 micrograms/ml) at 42 degrees C. The presence of biosynthetic substrates significantly attenuated the suppression of CP activation by hyperthermia. A dose-dependent decrease in biosynthetic function occurred in the presence of CP at 37 degrees and 42 degrees C suggesting hepatotoxicity and/or competition for biochemical intermediates. The t 1/2 of HN2 at 50 micrograms/ml was slightly decreased by 11% at 42 degrees C (19.6 min vs. 17.4 min). The half-lives of 10 micrograms/ml HN2 and 5 micrograms/ml L-PAM were not altered at 42 degrees C (17.1 min vs. 16.4 min and 44.6 min vs. 44.1 min, respectively). The adverse effects of HN2 and L-PAM on hepatic biosynthetic functions were minimal suggesting that alkylating agents not requiring metabolism by the liver would be most useful for hepatic thermochemotherapy. The data indicate that hyperthermia depresses hepatic microsomal drug metabolizing enzyme function and alters the perfusate pharmacokinetics of alkylating agents. Moreover, manipulation of the hepatic biochemical environment may modify the adverse effects of hyperthermia on microsomal activity.

Alkylating Agents↗
PubMed1976

Recovery of cells from induced, potentially lethal damage.

The recovery of mammalian cells after a variety of treatments is, in part, governed by the cells' ability to deal with repairable, but potentially lethal, lessions. Kinetics of such recovery show a T1/2 of 10-20 hours after ultraviolet (UV) irradiation and 1.5-2.5 hours after X-irradiation. Recovery after exposure to mechlorethamine and bleomycin (BLM) is similar to X-ray recovery; after methylmethane sulfonate, recovery has components similar to X-ray and UV recovery. The sequential treatments of cells with 43 degrees C hyperthermia and X-rays (or reverse order) modify both the immediate survival after treatments as well as the subsequent recovery kinetics. Very similar results are found after BLM and hyperthermia treatments, suggesting strongly that after exposure to that drug a real repair system is operative. However, although recovery after X-irradiation is similar in vitro and in vivo, after BLM the site of treatment and of recovery strongly influences the magnitude and kinetics of recovery.

Bleomycin↗
PubMed1982

Treatment of advanced Hodgkin's disease: 10-year experience in the Eastern Cooperative Oncology group.

Between 1972 and 1981, the Eastern Cooperative Oncology Group completed two major studies of advanced Hodgkin's disease. The first trial EST 2472, demonstrated that the five-drug combination of carmustine (BCNU), cyclophosphamide, vinblastine, procarbazine, and prednisone (BCVPP) is an effective alternative to mechlorethamine, vincristine, prednisone, and procarbazine (MOPP) chemotherapy. Although the complete remission (CR) rate for BCVPP (77%) was similar to that for MOPP (73%) in this randomized trial, the choice of induction chemotherapy significantly influenced CR duration. Patients achieving CR with BCVPP had a significantly greater disease-free survival than those who achieved CR with MOPP (65% vs 50%, respectively, at 5 years, P = 0.02). Overall survival is not different at this time between patients who received BCVPP and those who received MOPP. BCVPP produced significantly less gastrointestinal toxicity and neurotoxicity than MOPP. There was no influence on CR duration or survival with maintenance chemotherapy or BCG immunotherapy when compared to no further treatment. In the second trial, EST 1476, there was only a 58% CR rate with six cycles of low-dose bleomycin-MOPP induction chemotherapy. Complete responders and continuing partial responders were then randomized to receive either non-cross-resistant chemotherapy with doxorubicin, bleomycin, vinblastine, and DTIC (dacarbazine) (ABVD) or low-dose radiotherapy to all sites of pretreatment involvement except bone marrow. Fifty percent of the partial responses were converted to CR with either ABVD or radiotherapy consolidation. The overall CR rate at the end of consolidation was 68%. At the present time, there is no significant difference in disease-free or overall survival between ABVD and radiotherapy.

Adult↗