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PubMed1985

Complement and polymorphonuclear leukocytes do not determine the vascular permeability induced by intraocular LPS.

The intravitreous injection of an endotoxin of Escherichia coli 055:B5 (LPS; 0.1-0.5 microgram/50 microliters of saline) induces ocular inflammation in rabbits that is maximal 20-24 hours later and disappears by 4 days. The inflammation is characterized by an alteration in ocular vascular permeability (OVP) measured by the ocular extravasation of 125I-albumin and an outpouring of leukocytes, most of which are polymorphonuclear leukocytes (PMNs), as determined by histopathologic study. Nitrogen mustard (mechlorethamine, 1.75 mg/kg) administered 3 days prior to LPS virtually eliminates PMNs in the circulation and those infiltrating ocular tissues 20 hours after intravitreous LPS, and yet the average increase in vascular permeability is not different from that of controls. Cobra venom factor (CVF; 300-400 units) 7 hours before intravitreous LPS produces a greater than 90% decrease in both hemolytic complement activity and zymosan-inducible serum chemotactic activity; yet 20 hours after LPS, the OVP is the same in CVF-treated rabbits and controls. For comparison, an ocular passive Arthus reaction (ovalbumin-anti-ovalbumin) was significantly affected by CVF pretreatment. Chemotactic activity in the aqueous humor is found in both CVF-treated and control rabbits 20 hours after intravitreous LPS. This activity attracts rabbit, but not human, PMNs, is partially heat-sensitive, and is not inhibited when PMNs are preincubated with C5a. These results indicate that neither PMNs nor circulating complement determine the OVP following intravitreous LPS, and that the chemotactic activity present in aqueous humor at the height of the inflammatory response is not primarily C5a.

Animals↗
PubMed1988

[A combination of mycosis fungoides and chronic myeloid leukemia. Apropos of a case].

The coexistence of a T-cell lymphoma with a myelodysplatic syndrome seems to be exceptional. In the case reported here the diagnostic problems raised by the appearance of cutaneous nodules in a patient with chronic myeloid leukaemia (CML) were solved by histo-immunological examinations. A 70-year old male patient had been presenting since 1976 with a psoriasis-like skin disease. He was first seen at the Argenteuil hospital in 1984. Physical examination showed psoriasiform finger-like erythemato-squamous lesions, infiltrated plaques and an ulcerated tumoral swelling of the right elbow. A diagnosis of mycosis fungoides was made on histological and immunological examination results. At histology, this epidermotropic lymphoma was peculiar in that the atypical infiltrate was clearly centred on vessels. Electron microscopy confirmed that the vascular walls were invaded by the mycosis cells. Additional examinations showed hyperleucocytosis and myelaemia which were rapidly attributed to a chronic myelocytic leukaemia since the Philadelphia chromosome was present and the leucocytes had a low alkaline phosphatase score. Bone marrow biopsy disclosed a myeloproliferative syndrome of the CML type. Biopsy of a right axillary lymph node showed myelocytic infiltration associated with dermopathic lymphadenitis. There were no circulating Sezary cells, and a search for extension proved negative. From May, 1984 to June, 1985 the patient's CML was treated with busulfan which produced blood and bone marrow remission. The skin lesions were treated first with mechlorethamine, then with topical corticosteroids. Superficial electron therapy was applied to the tumoral lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1988

Quantitative risk of second cancer in patients in first complete remission from early stages of Hodgkin's disease.

Thirty-three second cancers, excluding basal cell carcinomas of skin and in situ carcinomas of the cervix uteri, were observed among 1,084 patients in first complete remission from Hodgkin's disease treated from 1964 to 1981 by the Lymphoma Group of the European Organization for Research and Treatment of Cancer and the Groupe Pierre et Marie Curie. Five of these second cancers were acute nonlymphocytic leukemias (ANLL), and five were non-Hodgkin's lymphomas (NHL). The 15-year cumulative proportion was 7.6% for second cancers; 0.7% for ANLL; and 1.2% for NHL. For solid tumors (ST) occurring in a previously irradiated area, it was 1.0% after regional radiotherapy (RT); after extended-field RT, it was 8.2% (P = .009). The relative risk (RR) of ANLL after combined chemotherapy with mechlorethamine, vincristine, procarbazine, and prednisone plus RT (relative to the general population incidence rates) was 39 (P less than .001) during the first 4-year period; it was not significantly increased in patients treated by RT without combined chemotherapy. Similar RR was observed for NHL (RR = 31; P less than .001). Moreover, an increased RR of NHL (RR = 53; P less than .001) was observed in patients treated by RT without combined chemotherapy after 10 years. For ST, no significant increased risk was observed regardless of the treatment. There is, however, a slight tendency for the risk of ST related to extended-field RT to increase after 10 years.

Actuarial Analysis↗
PubMed1986

Limitations of urinary mutagen assays for monitoring occupational exposure to antineoplastic drugs.

The sensitivity of the Salmonella reversion test of Ames as a screen for accidental absorption of 17 antineoplastic agents by drug handlers was evaluated. Dilutions of each drug were added to agar inoculated with each of two Salmonella typhimurium strains (TA98 and TA100); control plates contained no test drug. Colonies were counted after incubation at 36 degrees C for 48 hours. The drugs were tested in the presence of a liver preparation to provide metabolic activation of mutagenicity. Urine samples collected from patients after doses of three mutagenic drugs were extracted and tested with the Ames test. For 11 of the 17 drug solutions, no mutagenic activity was seen, but many of these 11 were toxic to the organisms. The most highly mutagenic drugs were doxorubicin and cisplatin, with mechlorethamine, carmustine, dacarbazine, and cyclophosphamide exhibiting less mutagenic activity. Urine from patients treated with doxorubicin or cyclophosphamide showed mutagenicity, but the results suggested that the quantity of these drugs that would have to be absorbed to produce a definite reaction in urine is unlikely to be achieved by drug handlers who use standard precautions. Because of its lack of sensitivity and the potential effects of environmental and dietary factors on the results, this bacterial mutagenicity test should not be used routinely for detection of accidental absorption of antineoplastic drugs.

Antineoplastic Agents↗
PubMed1987

Third-line chemotherapy for resistant Hodgkin's disease with lomustine, etoposide, and methotrexate.

Thirty-two patients with recurrent Hodgkin's disease have been treated with an oral regimen employing lomustine (CCNU, 100 mg/m2 orally on Day 1); etoposide (VP-16, 100 mg/m2 orally on Days 1-3 and 21-23); and methotrexate (30 mg/m2 orally on Days 1, 8, 21, and 28). The regimen was repeated every 6 weeks. Most patients had been treated with MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) and ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine); 20 had had prior irradiation. Lymph node was the predominant site of disease and the majority of patients had B symptoms. Four patients achieved complete response (13%), with a median duration of 33+ months, and 11 achieved partial response (34%), with a median duration of 5 months, for an overall response rate of 47%. The major toxic effect was severe myelosuppression, which occurred in six patients; there were no treatment-related deaths. This oral regimen was easy to administer in heavily pretreated patients with poor venous access and had minimal toxicity.

Administration, Oral↗
PubMed1987

Practical approaches to the management of aggressive lymphomas in the community practice.

Because of the variety of pathologic classifications for non-Hodgkin's lymphomas, it became necessary to develop a new system that incorporated the biologic, immunologic, and morphologic characteristics of these lymphomas. The National Cancer Institute (NCI) developed the Working Formulation that now classifies lymphomas into low, intermediate, and high grade. Physicians should be aware of these changes so that they can communicate with expert pathologists who speak the same language. Staging procedures to evaluate non-Hodgkin's lymphoma are similar to those used to evaluate Hodgkin's disease. The major advance in the treatment of this condition in the past few years has been in diffuse large cell lymphoma. Primary treatment programs using first-generation chemotherapy include CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), which is easy to administer and has a high complete remission (CR) rate of 51% and a 2-year survival of 39%. CHOP is about equal in activity to other first-generation regimens and remains the most frequent regimen to treat diffuse large cell lymphomas. Second-generation regimens were devised to increase the remission rate. COP-BLAM (cyclophosphamide, vincristine, prednisone, bleomycin, doxorubicin, procarbazine), M-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone), and ProMACE-MOPP (prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, mechlorethamine, vincristine, procarbazine, prednisone) have produced CRs in excess of 70% and have demonstrated an increase in survival that has been associated with a concomitant increase in toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

Relationship of glutathione depletion and inhibition of glutathione-S-transferase activity to the antimitotic properties of estramustine.

A depletion of intracellular glutathione (GSH) is accompanied by a subsequent inhibition of GSH-S-transferase activity in a DU145 human prostatic carcinoma cell line treated with cytotoxic concentrations of estramustine. When GSH depletion reached approximately 50% of normal (approximately 2 hours after 10 microM estramustine), the mitotic index of logarithmically dividing cultures began to increase. A linear increase from 3.14% to 22.5% occurred during the period of 2-24 hours following 10 microM estramustine. Morphological studies showed that mitotic figures accumulated in metaphase and had abnormalities consistent with spindle malformation. Nocodazole and cytochalasin B also possess anticytoskeletal properties, but had little effect upon the intracellular levels of GSH or its associated transferase enzymes. The constituent moieties of estramustine, estradiol, and nor-mechlorethamine had effects on thiol metabolism which were dissimilar from estramustine, confirming previous findings that the unmetabolized parent drug is responsible for pharmacological activity. Estramustine had no effect upon GSH reductase activity, suggesting that drug toxicity was not a general thiol phenomenon. Buthionine sulfoximine decreased intracellular GSH in DU145 cells and enhanced the cytotoxic potential of estramustine in this cell line. The anticytoskeletal and antimitotic properties of estramustine may be enhanced by the drug-induced GSH imbalance and subsequent effects on GSH-S-transferase enzymes.

Buthionine Sulfoximine↗
PubMed1986

Isolation and characterization of a Chinese hamster ovary cell line resistant to bifunctional nitrogen mustards.

A drug-resistant derivative of a Chinese hamster ovary cell line has been generated by chronic exposure to progressively higher concentrations of chlorambucil. The cells exhibit greater than 20-fold resistance to the cytotoxic effects of chlorambucil and comparable levels of cross-resistance to mechlorethamine and melphalan. These drugs all belong to a class of bifunctional alkylating agents which generate DNA cross-links by reaction at the N-7 position of guanine. However, no resistance is observed to several other drugs which possess a similar mechanism of action, to cis-platinum diammine dichloride or to bischloroethylnitrosourea and mitomycin C, which cross-link DNA via the O6 position of guanine. Lack of resistance to vincristine, colchicine, or Adriamycin coupled with the failure of the calcium channel blocker verapamil to reverse the phenotype, indicates that the mechanism of resistance is distinct from that characterized by the multidrug-resistant phenotype. Support for this view comes from the finding that no significant alteration in melphalan uptake could be demonstrated. The phenotype is very stable and has been maintained during 12 months of continuous culture without further selection. A slightly elevated basal level of glutathione is present in the resistant cells, but resistance is not overcome by depletion of intracellular glutathione with buthionine sulfoximine. A cytosolic protein with a molecular weight of approximately 25,000 is constitutively overexpressed in the resistant cells. Although these cells have an abnormal karyotype, no conclusive evidence for any cytogenetic indicator of gene amplification could be detected.

Animals↗
PubMed1985

Differential potentiation of alkylating and platinating agent cytotoxicity in human ovarian carcinoma cells by glutathione depletion.

We have determined the effect of glutathione (GSH) depletion on the cytotoxicity of three nitrogen mustards, six platinum complexes, and mitomycin C in a human ovarian carcinoma cell line. GSH levels in COLO 316 cells were depleted by exposure of cell monolayers to 0.5 mM D,L-buthionine-S,R-sulfoximine. GSH depletion significantly potentiated the cytotoxicity of L-phenylalanine mustard, chlorambucil, and mechlorethamine as determined by clonogenic assay on plastic plates. The dose modification factors were 2.6, 2.6, and 1.9, respectively. The same level of GSH depletion had a minimal effect on the cytotoxicity of cis-diamminedichloroplatinum(II) (cis-DDP), carboplatin, dichloro(ethylenediamine)platinum(II), 1,2-diaminocyclohexylplatinum(II) malonate, and iproplatin. The dose modification factors of GSH depletion for these drugs were 1.4 or less. trans-Diamminedichloroplatinum(II) was, however, markedly potentiated by GSH depletion with a dose modification factor of 2.7. Mitomycin C was minimally potentiated by GSH depletion. We have also generated cis-DDP-resistant cells from COLO 316 and 2008 human ovarian carcinoma cells by in vitro selection with cis-DDP. These cis-DDP-resistant cells had identical levels of GSH as the parental cells. GSH depletion sensitized these cells only to the same degree as the parental cells and did not reverse the resistant phenotype. Our results indicate that intracellular GSH levels are not an important determinant of the cytotoxicity of cis-platinum(II) or cis-platinum(IV) complexes in COLO 316 and 2008 cells. In addition, altered GSH metabolism does not appear to be a component of the cis-DDP-resistant phenotype in these cells.

Alkylating Agents↗
PubMedDate not supplied

Double-blind comparison of the antiemetic effects of nabilone and prochlorperazine on chemotherapy-induced emesis.

The antiemetic effect of oral nabilone, a synthetic cannabinoid, given at a dose of 2 mg every 12 hours was compared to oral slow-release capsules of prochlorperazine given at a dose of 10 mg every 12 hours by a double-blind crossover method in 37 patients receiving cancer chemotherapy. Patients received one of the following as the primary emetic stimulus: high-dose cis-dichlorodiammineplatinum(II) (DDP), low-dose DDP, mechlorethamine, streptozotocin, actinomycin D, or DTIC. Although results varied according to strength of emetic stimulus received, both nabilone and prochlorperazine appeared to produce antiemetic effects. Eighteen of the 37 patients achieved a complete or partial elimination of symptoms: seven with nabilone alone, three with prochlorperazine alone, and eight with each drug. Nabilone appeared to be the more effective antiemetic for patients who received chemotherapy agents other than high dose DDP; it was equivalent to prochlorperazine for those who did receive high-dose DDP. Side effects from prochlorperazine were limited to mild drowsiness occurring among 35% of the patients. The side effects from nabilone were drowsiness and dizziness which occurred frequently and were dose-limiting in 25% of patients.

Adult↗
PubMed1977

A new combination chemotherapy for resistant Hodgkin disease.

A new four-drug combination chemotherapeutic regimen (BVDS) was used in the treatment of advanced Hodgkin disease resistant to MOPP (mechlorethamine hydrochloride, vincristine sulfate, procarbazine hydrochloride, and prednisone). The BVDS regimen, consisting of 12 cycles of bleomycin sulfate, vinblastine sulfate, doxorubicin hydrochloride (Adriamycin), and streptozocin (streptozotocin), was administered to ten patients. Responses were seen in five (50%) of these patients. Complete remissions occurred in three (30%). These results suggest that BVDS is an effective alternative regimen to MOPP, and may be of benefit not only to patients resistant to MOPP, but also to newly-diagnosed patients with advanced hodgkin disease when combined sequentially with MOPP.

Adolescent↗
PubMed1984

Neurological complications of antineoplastic therapy.

Increasingly vigorous chemotherapy of cancer including primary and metastatic central nervous system disease has resulted in prolonged good-quality survival. However, there has been an associated increase in neurotoxicity from both radiation therapy and chemotherapy. All classes of chemotherapeutic agents contain drugs that are potentially neurotoxic, often only at high doses. Mechlorethamine, the first nitrogen mustard, is not neurotoxic at conventional dosage, but at high doses, it may produce both an acute and a delayed encephalopathy. Methotrexate administered intrathecally often induces reversible aseptic meningitis, but chronic administration, either intrathecally or high-dose intravenously, may produce fatal leukoencephalopathy. 5-Fluorouracil at high dosage may cause cerebellar ataxia, but may also do so at low dosage when combined with thymidine infusions. Cytosine arabinoside at high dosage may also produce cerebellar ataxia. Vincristine produces a peripheral neuropathy, and less commonly causes both autonomic and cranial neuropathy. The enzyme L-asparaginase can produce a dose-related reversible encephalopathy. BCNU, now the mainstay of glioma chemotherapy, may combine with radiation to produce long-term cerebral atrophy. Both intracarotid and high-dose intravenous BCNU administration may cause encephalopathy. Several other chemotherapeutic agents have also been reported to cause neurotoxicity under certain circumstances.

Adrenal Cortex Hormones↗
PubMed1984

Cyclophosphamide resistance developed in a human melanoma cell line.

The Mer- human melanoma cell line MM253c1 was treated four times with cyclophosphamide activated in situ with rat liver microsomes, the fourth cycle being preceded by treatment with the mutagenic methylating agent N-methyl-N1-nitro-N-nitrosoguanidine. The resulting subline (MM253c1-4CG) showed increased resistance to activated cyclophosphamide; the resistance of seven allogeneic human tumor lines and of a fibroblast strain spanned the two extremes represented by the autologous MM253c1 lines. MM253c1-4CG cells were highly resistant to killing by methylating agents, a property indicative of conversion to the Mer+ phenotype. Compared with the parent line, MM253c1-4CG cells were resistant to DNA cross-linking agents having different structures and transport mechanisms (melphalan, mechlorethamine, and mitomycin) and were slightly more resistant to doxorubicin, gamma rays, and hydroxyurea, but were not resistant to killing by acrolein, cytarabine, hydrogen peroxide, 254 nm UV, [3H]thymidine, or vincristine. No difference in the intracellular concentration of potential alkylation targets (RNA, protein, and SH groups) was found, and neither cell line appeared able to activate cyclophosphamide or detoxify its metabolites. Caffeine and 3-aminobenzamide had no synergistic effect upon cyclophosphamide toxicity in either cell line. 3-Aminobenzamide showed synergism with the methylating agent 5-(3-methyl-1-triazeno)imidazole-4-carboxamide, the effect being greater in MM253c1-4CG than in MM253c1 cells. These results suggest that in vitro activation of cyclophosphamide produces a metabolite similar in stability to phosphoramide mustard, resistance to such toxicity being associated not with conversion to the Mer+ phenotype but with some intracellular change with confers resistance to a variety of DNA cross-linking agents.

Benzamides↗
PubMed1983

Second cancers after radiotherapy and chemotherapy for early stages of Hodgkin's disease.

In a population of 334 patients treated for Hodgkin's disease by the European Organization for Research and Treatment of Cancer between 1964 and 1971, 21 patients with second primary cancers (SC) were observed: 4 patients with acute leukemias, 3 with non-Hodgkin's lymphomas, and 14 with solid tumors. Time to SC ranged from 2 to 16 years after initial treatment. The relative risk (RR) of acute leukemia for the patients with Hodgkin's disease as compared to the general population was 40 (P less than .001). The RR of leukemia in patients treated by polychemotherapy--mechlorethamine, vincristine, procarbazine, and prednisone--for relapse was 300 (P less than .001). However, the RR of leukemia for those patients who did not experience a relapse was 14 (not significant). The RR of other SC in the overall group was 3.76 (P less than .001). For patients whose relapses were treated by polychemotherapy the RR of SC, leukemia excepted, was 26 (P less than .001), whereas for patients not treated by polychemotherapy for relapse the RR was slightly increased (RR = 3.67; P = .027). The cumulative proportions of acute leukemia at 10 years were 0.7% in the "no-relapse" group and 2.7% in the polychemotherapy group. The cumulative proportions of other SC at 10 years was 1.3% in the no-relapse group, 7.2% in the group of patients not treated by polychemotherapy after relapse, and 8.4% in the polychemotherapy group. The first important risk factor for developing an SC was polychemotherapy, and the second was age over 40 years. These data suggest that combination chemotherapy may be responsible for both acute leukemias and other SC.

Adult↗
PubMed1984

[Whole-skin electron therapy: a therapeutic concept for mycosis fungoides and Sézary syndrome. 2: Therapy].

The alterations of mycosis fungoides of a malignant T-cell lymphoma are extremely radiosensitive. In the treatment of the cutaneous manifestation of mycosis fungoides, the whole-skin electron therapy is superior to the superficial application of mechlorethamine (NH2), to photochemotherapy with psoralen and ultraviolet radiation as well as to chemotherapy as monotherapy and combined therapy. Complete remissions are to be expected in 93% of all cases after application of a high total dose of more than 30 Gy. After less than 10 Gy, this rate is 18%. A combination of whole-skin electron therapy (30 Gy) with chemotherapy or with a total lymphoid irradiation with 30 Gy represents a new approach for the treatment of advanced tumor stages.

Adult↗
PubMedDate not supplied

Combination chemotherapy salvage of heavily pretreated patients with Hodgkin's disease: an analysis of prognostic factors in two chemotherapy trials and the literature.

The results of two intensive combination chemotherapy trials for heavily pretreated patients with Hodgkin's disease were markedly different. Only one of 27 patients treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) achieved a complete remission (CR), while a CR was attained by 50% of the patients (nine of 18) treated with ABVD alternating with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP/ABVD). There was a significantly longer survival for patients on MOPP/ABVD. Characteristics of patients in the two trials which might have at least partially explained these differing results were identified. The patients treated with ABVD all had prior histories of multiple relapses or continuous disease activity, while the majority of responding patients treated with MOPP/ABVD had few prior relapses and long disease-free intervals immediately prior to treatment. In the MOPP/ABVD trial, a trend toward a higher CR rate was found for patients with relapses confined to lymph nodes, compared with patients who had extranodal disease, although the difference lacked statistical significance. The characteristics of the patient population undergoing treatment must be considered in the interpretation of the results of chemotherapy salvage regimens for Hodgkin's disease.

Adult↗
PubMed1982

Chemotherapy for advanced Hodgkin's disease: conclusions from the Southeastern Cancer Study Group.

The Southeastern Cancer Study Group has explored a variety of approaches to the management of advanced Hodgkin's disease. These have largely involved the use of nitrosoureas, especially BCNU (carmustine), alone or in combination with other agents. Initial phase II trials of BCNU as a single agent in patients refractory to mechlorethamine demonstrated considerable antitumor activity. Exploratory experiments with BCNU in combination with alkylating agents, vinca alkaloids, and corticosteroids resulted in the development of the combination BVCPP (BCNU, vinblastine, cyclophosphamide, procarbazine, and prednisone). BVCPP, given only once monthly, produces at least a 65% complete response rate with minimal to moderate toxicity, making it an effective alternative to other regimens such as MOPP. Alternating BVCPP with a non-cross-resistant combination (doxorubicin, DTIc [dacarbazine], and bleomycin) offered no advantage in response rate or survival. Continued research with new agents and/or combined modality approaches is necessary in view of continued primary and secondary treatment failure with all regimens used for the management of advanced Hodgkin's disease.

Antineoplastic Agents↗
PubMed1982

Hodgkin's disease with direct extension into pulmonary parenchyma from a mediastinal mass: a presentation requiring special therapeutic considerations.

The significance of limited extranodal Hodgkin's disease involving pulmonary parenchyma by direct extension from a mediastinal mass (E stage) was evaluated in 177 patients with stages IA-IIIB. Disease-free and total survival rates of four groups were compared: 58 patients without and 13 patients with pulmonary E stage treated with radiotherapy followed by six courses of MOPP (mechlorethamine, vincristine, procarbazine, and prednisone), and 86 patients without and 20 patients with E stage treated with radiotherapy alone. The 12-year disease-free and total survival rates projected by life-table analysis were significantly poorer for E stage patients treated with radiotherapy alone. It is concluded that pulmonary E stage requires special therapeutic considerations if end results are to equal those obtained with standard radiotherapy for Hodgkin's disease confined to lymph nodes, and that combined modality therapy is one method by which pulmonary E stage may be treated successfully.

Hodgkin Disease↗