The effect of the cholinergic neurotoxin ECMA on neural function in brain reaggregate cultures.
Explore the source record for details and available documents.
Animals↗
SEARCH · Search PubMed
Results for “Azirines”
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Therapeutic effects of BM 12,531 (Prop. INN azimexon).
The antitumor effect of BM 12,531, 2-[2-cyanaziridinyl-(1)]-2[carbamoylaziridinyl-(1)]-propane (Prop. INN azimexon), on L1210 leukemia in mice is described. The immunostimulating compound BM 12,531 can also reduce the acute toxicity of X-irradiation in mice. The most effective doses in these experiments are 1 or 5 mg/kg twice a week, whereas 50 and 500 mg/kg twice a week decrease the therapeutic effect. The mortality of Candida-infected and irradiated mice is also reduced by oral administration of BM 12,531. BM 12,531 has synergistic effects with subtherapeutic doses of chloramphenicol in an experimental E. coli infection in mice.
Adjuvants, Immunologic↗
In vivo immunomodulating properties of two synthetic agents: azimexon and tuftsin.
Mice were submitted to various immunologic tests at different times after a single intravenous (IV) injection of azimexon or tuftsin in order to determine the mode of action of these chemically defined immunomodulators. Azimexon, (BM 12,531) an aziridine derivative, potentiated antibody responses to both thymus-dependent (TNP-KLH) and thymus-independent (TNP-LPS) antigens and DTH reaction to oxazolone when injected at least 1 day before the antigen. It activated macrophages, rendering them cytostatic for tumor cells, but depressed ADCC activity of spleen cells directed against antibody-coated CRBC. Tuftsin, a basic tetrapeptide, potentiated antibody response to TNP-KLH when injected at least 3 days before the antigen. The response to TNP-LPS was stimulated on days 1 and 3, but was slightly depressed on day 7. It rendered macrophages highly cytostatic for tumor cells but, as observed with azimexon, the activation process required 7 days to develop. ADCC was enhanced throughout the period of observation.
Adjuvants, Immunologic↗
Effects of BM 12,531 (azimexon) on in vitro lymphocyte and macrophage proliferation.
BM 12,531 (azimexon) is an experimental immunomodulating agent which augments cellular immune responses in vivo. This study indicates that BM 12,531, while not directly mitogenic for human peripheral blood lymphocytes nor guinea pig peritoneal macrophages, potentiates the proliferative effects of phytohemagglutinin and a lymphokine, respectively. The optimal effects (0.001--0.01 microgram/ml) are somewhat greater in magnitude than those of levamisole. Unlike levamisole, BM 12,531 has no effect on cyclic 3',5' GMP levels or on guanylate cyclase activity of lymphocytes. The data suggest that both the thymus-derived lymphocyte and the monocyte-derived macrophage are cell targets of BM 12,531 action at concentrations achievable in vivo.
Adjuvants, Immunologic↗
Immunorestoration of anergic cancer patients by azimexon.
Azimexon, a new synthetic immunoadjuvant, can act on delayed-type hypersensitivity (DTH) reactions. Seven of 11 anergic cancer patients have been immunorestored by a relatively low dosage of azimexon. The effect on the lymphocyte responsiveness, and particularly of a new T-lymphocyte mitogen (TPA), are described. The possible mechanisms of the anergy of the cancer patients and of the mode of action of azimexon are discussed.
Adjuvants, Immunologic↗
Three new agents for immunotherapy trials: azimexon, bestatin, and tuftsin.
Explore the source record for details and available documents.
Adjuvants, Immunologic↗
Thiono compounds. 4. In vitro mutagenic and antineoplastic activity of TEPA and thio-TEPA.
Tris (1-aziridinyl) phosphine oxide (TEPA) and tris (1-aziridinyl) phosphine sulfide (thio-TEPA) induced base pair mutations in the Ames mutagenic assay. Thio-TEPA required metabolic activation while TEPA was active without metabolic activation. Growth of a human vaginal carcinoma (A431), a human breast carcinoma (MDA-MB-231), and a human cervical carcinoma (HeLa) were inhibited in soft agar in vitro at concentrations which induced mutagenesis in the Ames Assay. A fourth line, JEG choriocarcinoma, was sensitive to the antigrowth properties of both drugs at concentrations below that which induced mutagenesis. These data suggest that as more antineoplastic agents become available, and as mean survival times increase, knowledge of the relative in vitro sensitivity of a patient's neoplasm to a specific antineoplastic drug (i.e., dose required for growth inhibition) as a function of its mutagenic index might be useful for prediction of clinical remission, as well as the risk of secondary neoplasm induction.
Antineoplastic Agents↗
Comprehensive phase II evaluation of aziridinylbenzoquinone (AZQ, diaziquone) in recurrent human primary brain tumors.
Ninety-three patients with primary intracranial brain tumors recurrent after cerebral irradiation were treated with aziridinylbenzoquinone (AZQ; Diaziquone). Twenty-four (26%) had tumor regression lasting a median of 9.2 months. Prior chemotherapy was not significantly associated with tumor regression but was associated with survival (median 7.3 months no prior chemotherapy versus 4.7 months with prior chemotherapy; logrank p = 0.03). AZQ demonstrated anti-tumor activity in a wide variety of primary intracranial neoplasms recurrent after radiation therapy and deserves study in patients at the time of diagnosis. We believe alternating or combining AZQ and BCNU should be rewarding. The principal toxicity of AZQ is myelosuppression.
Adolescent↗
Intracerebral penetration and tissue distribution of 2,5-diaziridinyl 3,6-bis(carboethoxyamino) 1,4-benzoquinone (AZQ, NSC-182986).
[14C]AZQ (2-4 mg/m2, 100-200 mCi) was administered at varying times to five patients undergoing surgical resection of intracerebral tumors. Plasma, cerebrospinal fluid (CSF), edematous brain, and tumor specimens were obtained during surgery and the concentration of AZQ was determined radiochemically and chromatographically. Total [14C]AZQ equivalent concentration in tumor for two patients was determined to be 47.5% and 85% of concurrent plasma concentration which was similar to that found in normal brain (60.4% and 75.5% respectively). Only 18-45% of the total radioactivity in tumor tissue and 30-56% in plasma were accounted for by unchanged AZQ. These findings suggest that AZQ may be metabolized to a certain extent. Tissue samples from various organs were obtained during autopsy in a patient who expired ten days after AZQ administration. The highest AZQ concentration was found in the liver, followed by the kidney. Comparable amounts were found in normal brain and brain tumor (22 ng/g vs. 31 ng/g respectively). These results indicate that AZQ penetrates readily into the normal brain and brain tumor with a tendency to persist.
Adult↗
A phase II trial of 2,5,-diaziridinyl 3,6-bis (carboethoxy amino) 1,4-benzoquinone (AZQ, NSC 182986) in recurrent primary brain tumors.
Forty-one patients with recurrent primary malignant brain tumors were treated with 2,5-diaziridinyl 3,6-bis (carboethoxyamino), 1,4-benzoquinone (AZQ) at an initial dose of 6-8 mg/m2/day X 5 days. Courses were repeated monthly upon recovery of myelosuppression. Six of 25 evaluable patients (24%) showed definite tumor regression, and 7 (28%) showed disease stability as determined by monthly CT scans and neurologic examination. For all patients receiving one course of AZQ, the response rate was 16% (6 of 37 patients) and the stable disease rate 19%. The estimated median time to tumor progression with AZQ was 54 weeks for the responding patients and 36 weeks for the stable patients. Toxicity consisted of myelosuppression, primarily thrombocytopenia, which was delayed and cumulative. Other toxicities were uncommon. Further clinical trials in patients with malignant primary brain tumors, including combination studies with other drugs, are indicated.
Adolescent↗
Phase II study of aziridinylbenzoquinone (AZQ: NSC-182986) in the treatment of malignant gliomas recurrent after radiation. Preliminary report.
Seventeen patients with malignant gliomas recurrent after chemotherapy and/or radiation failure were treated with aziridinylbenzoquinone (AZQ) at a dose of 20-15 mg/M2 weekly for four weeks followed by a two week rest. Regression of disease was observed in four patients, 4/17 (24%) for 35, 15+, 40+, and 10 weeks. Toxicity was limited to moderate reversible myelosuppression. AZQ in this dose and schedule has limited but definite activity in patients with malignant gliomas progressive after primary radiation therapy failure.
Adolescent↗
Phase II evaluation of diaziquone (CI-904, AZQ) in the treatment of human malignant glioma.
Diaziquone, a new alkylating agent which crosses the blood brain barrier, has shown a 20% response rate in phase II studies in heavily pretreated patients. We have treated 23 patients at our institution as part of a multicentric phase II European trial of diaziquone. All had histologically proven malignant glioma unequivocally progressing on CT scan. Prior therapy had consisted of surgical excision (13 patients), cobalt radiotherapy to CNS (13 patients), and chemotherapy with nitrosourea derivatives (11 patients). Six patients had no prior therapy. Median age was 42 years (range 22-69) and performance status was 3+ or better. They were treated with monthly courses of diaziquone 5.5 mg/m2 I.V. (10 min.) X 5 days. Dosage adjustments were made according to leucocyte and platelet nadirs. Thrombocytopenia was the dose limiting toxicity. Very mild gastrointestinal toxicity was observed. One patient developed hemolytic anemia. One complete response (clinical and CT scan), 7 partial clinical responses (3: greater than 50%, 4: 25-50%), and 1 disease stabilization (less than 25%) were documented. The longest response has now lasted over 26 months. These preliminary results show that chemotherapy with diaziquone can achieve a response rate as high as 35% in malignant glioma even in patients previously treated with a chemotherapy regimen including a nitrosourea (four of the seven objective responses were seen in such patients). Diaziquone is well tolerated and deserves further study in the management of malignant glioma.
Adult↗
Effect of combined AZQ and radiation on the tolerance of the rat spinal cord.
The effect of combined AZQ (aziridinylbenzoquinone) and ionizing radiation on the rat spinal cord has been investigated. The highest dose of AZQ (3 mg/kg) tolerated by rats weighing 250 g was injected intravenously 15 min before a single dose of radiation or the first of 2 fractional doses. The development of paralysis due to white-matter necrosis in rats of each dose group was scored and dose-response curves were constructed. It has been found that a combination of AZQ with radiation did not lead to a significant shift of the dose-response curve as compared to that of radiation alone. Thus, AZQ administered according to the schedule used in the present study did not seem to reduce the radiation tolerance of the central nervous system.
Animals↗
The pharmacologic fate of 2,5-diaziridinyl-3,6-bis(carboethoxyamino) 1,4-benzoquinone (AZQ NSC-182986) by intracarotid or intravenous administration in beagles.
Beagle dogs received either intravenous (I.V.) or intracarotid (I.C.) 14C ring labelled 2,5-diaziridinyl-3,6-bis-(carboethoxyamino) 1,4-benzoquinone (AZQ) at a dose of 2 mg/kg. Blood, urine and cerebrospinal fluid (CSF) samples were collected at intervals. At varying times, dogs from each group were sacrificed and histologic examination and drug determinations were performed on the major organs. By both routes of administration, the elimination of AZQ from plasma was biphasic with an initial half-life of 18 min and a terminal half-life of 26 hr. The apparent volume of distribution was 7.9 l/kg and the total clearance was 3.5 ml/kg/h. The 96 hr cumulative urinary excretion of total 14C was 41% of the administered dose, including 4% as the unchanged drug. At 1, 48, and 96 hr after I.C. AZQ, drug concentrations in the brain tissue were twice those by the I.V. route. High drug concentrations in the CSF were produced by both routes, although the CSF to plasma ratio was higher by I.C. than I.V. In extracranial organs, tissue concentrations of AZQ were at least twice as high by I.V. than by I.C. administration. No significant clinical or neurologic toxicity were noted when AZQ was given I.C. In the dog I.C. administration of AZQ seems to accelerate drug entry into the brain tissue.
Animals↗
High dose AZQ in renal cancer. A Southwest Oncology Group phase II study.
Fifty-seven patients with renal cancer were treated with AZQ, utilizing one of three IV push schedules. Only one partial response was seen in 55 evaluable patients, and considerable myelosuppression was encountered. Gastrointestinal toxicity was more severe in those patients who had received prior treatment. At these higher doses AZQ is deemed an inactive agent in patients with renal cell carcinoma, at least when the drug is administered as a push schedule.
Antineoplastic Agents↗
A phase I/II study of 24 hour intravenous AZQ in recurrent primary brain tumors.
This study was undertaken to determine the maximum tolerated dose of aziridinylbenzoquinone (AZQ) given as a 24-hour intravenous infusion every 21-28 days. Thirty-four patients with recurrent or progressive gliomas received AZQ at a dose of 25, 30, 35, 40, or 45 mg/m2. At a dose of 45 mg/m2, leukopenia and thrombocytopenia of grade 3 or greater was observed in 42% and 25% of patients respectively; no patient required transfusion or antibiotics for fever. For administration of AZQ at a 24-hour intravenous infusion, we recommend a starting dose of 40 mg/m2 for patients without previous exposure to cytotoxic agents, and 35 mg/m2 for patients treated with such agents. In 14 patients with glioblastoma, tumor regression was observed in 1 patient (14%) and stabilization of disease was demonstrated in 7 patients (50%). In 17 patients with anaplastic astrocytomas there were no responses, but 8 patients (47%) stabilized. Of two patients with an oligodendroglioma, one continues without progression at 34 weeks after initial response. One patient with malignant ependymoma stabilized and had not progressed at 39 weeks. The median time to tumor progression in patients who stabilized and responded was 18 weeks for those with glioblastoma multiforme and 16 weeks in those with anaplastic astrocytomas.
Antineoplastic Agents↗
Survival and cell cycle kinetics responses of Chinese hamster ovary cells, and clones of human adenocarcinoma of the stomach and astrocytoma to diaziquone (AZQ) in vitro.
The anticancer agent 1,4-cyclohexadiene-1,4-dicarbonic acid, 2,5-bis(aziridinyl)-3,6-dioxo-, diethyl ester (AZQ) (NSC 182986) was studied in vitro to determine survival, cell cycle stage sensitivity, and cell cycle kinetics effects. One hour treatments with AZQ doses ranging from 1 micrograms/ml to 25 micrograms/ml revealed that human stomach tumor clones were most sensitive of three cell types studied to to the killing effects of AZQ; this sensitivity was followed in order by human astrocytomas and Chinese hamster ovary (CHO) cells. Depending on the AZQ dose, nondividing CHO cells were 10 to 180 times more sensitive than dividing CHO cells. Synchronized CHO cells were most sensitive to AZQ's killing effects when treated at the late S/G2 phase boundary, with the overall order of sensitivity being late S/G2, G2, mid-S, and G1 phase. Mitotic cells were neither killed by doses used in these studies, nor were they inhibited in their progression from mitosis into the G1 phase. Synchronized CHO cells treated in all other phases of the cell cycle were either blocked completely or delayed for up to 2 hours in their progression through the cell cycle. Flow microfluorometry (FMF) studies on exponentially growing CHO cells demonstrated that even at noncytotoxic doses (1 microgram/ml), AZQ caused very large, but reversible enrichments of cells in the S and G2 phases of the cell cycle. Since AZQ has already been shown to be effective against a variety of animal and human tumors (especially brain tumors) the data reported here may be useful in designing more effective treatment schedules and drug combination regimens.
Adenocarcinoma↗
Diaziquone (AZQ).
Diaziquone is an aziridinylbenzoquinone with properties suggestive of an alkylating agent. The drug has shown broad antitumor activity against numerous transplantable murine tumors including curative activity against several intracerebrally implanted tumors. Parent diaziquone appears to have a t1/2 beta of approximately 30 min. The drug is rapidly and widely distributed to tissues as evidenced by a t1/2 alpha of approximately 1-3 min and a volume of distribution exceeding that of total body water. In addition, it rapidly penetrates the central nervous system, reaching peak concentrations (30-50%) of corresponding plasma levels) in approximately one hour. Diaziquone is rapidly and extensively metabolized by the liver. Diaziquone is a potent marrow suppressive agent inducing significant degrees of leukopenia, granulocytopenia, and thrombocytopenia in humans. Thrombocytopenia is often severe. Although myelosuppression is for the most part dose related, many patients had significant toxicity even at lower doses. Most investigators have attributed this to the extent of prior therapy. Diaziquone demonstrates a very steep dose-response relationship. Myelosuppression was the dose-limiting toxicity in all phase I trials. No nonhematologic dose-limiting toxicity has been identified to date. In phase I and preliminary phase II trials, diaziquone has demonstrated activity against primary brain tumors. Little activity has been seen in other tumor categories. It should be noted, however, that all studies to date have been carried out in heavily pretreated patients. Because of the broad spectrum of antitumor activity in experimental murine tumors, the lack of nonhematologic dose-limiting toxicity, the ability of this drug to attain significant levels in the central nervous system, and the activity of the drug in primary brain tumors, further studies examining its role in the management of patients with cancer are warranted. These studies should be conducted in patients who have had little or no prior therapy in order to better evaluate the efficacy of the drug.
Animals↗