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PubMed1980

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↗
PubMed1994

AF64A-induced brain damage and its relation to dementia.

Several data obtained in the AF64A-model are of particular relevance for our understanding of the pathogenesis and progression of Alzheimer's disease. The AF64A-induced withdrawal of cholinergic function in the rat hippocampus was associated with reversible functional changes in other neurotransmitters, including noradrenaline, serotonin, somatostatin and glutamate, thereby mimicking changes in Alzheimer's disease. Identical changes in markers for synaptic vesicles were found in Alzheimer's disease and AF64A-model. A study on the role of gender revealed a higher susceptibility to the neurotoxic action of AF64A in female rats. The cholinergic deficit was also responsible for a disinhibition of the negative feedback regulation of glucocorticoids. Increased exposure to glucocorticoids, however, enhanced the vulnerability of hippocampal cholinergic neurons to AF64A. These data indicate that the AF64A-induced cholinergic deficit in the rat brain represents a reliable tool to study several mechanisms possibly involved in Alzheimer's disease.

Acetylcholine↗
PubMed1993

Determination of the Ca2+ and Mg2+ affinity constants of troponin C from eel skeletal muscle and positioning of the single tryptophan in the primary structure.

The complete amino acid sequence of troponin C (ETnC) from the white muscle of the European eel has been determined by Edman degradation procedures. Its single tryptophan residue is situated in helix H at amino acid position 152 of the aligned sequence; the tryptophan is the first residue on the C-terminal side of Ca2+ binding loop IV. The increase of tryptophan fluorescence emission intensity occurring upon titration of ETnC with Ca2+ has been used to determine the affinity constants of ETnC for Ca2+. The calculated affinity of ETnC for Ca2+ results in a K(Ca) of 1.3 10(7) M-1, typical of the Ca(2+)-Mg2+ sites of the second domain of fast skeletal muscle TnCs. Moreover, a direct competition between Ca2+ and Mg2+ was also observed. The calculated affinity of ETnC for Mg2+ is K(Mg) = 1.2 10(3) M-1. In order to probe the affinity constants of the Ca2+ binding sites of the regulatory domain, ETnC was labelled with dansylaziridine (Danz). The Danz fluorescent signal was used to estimate the affinity constants of ETnC-Danz for Ca2+ and also for Mg2+ (assuming a competitive behaviour between these two metal ions). The calculated affinity constants are K(Ca) = 9.4 10(5) M-1 and K(Mg) = 2.0 10(2) M-1, respectively. These values are typical of the Ca(2+)-specific sites of the regulatory domain of fast skeletal muscle TnCs.

Amino Acid Sequence↗
PubMed1987

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↗
PubMed1983

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↗
PubMed1984

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↗
PubMed1985

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↗
PubMed1985

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↗
PubMed1992

Reversal by 3,3',5-triido-L-thyronine of the working memory deficit, and the decrease in acetylcholine, glutamate and gamma-aminobutyric acid induced by ethylcholine aziridinium ion in mice.

The effect of 3,3',5-triiodo-L-thyronine (T3) on working memory in ethylcholine aziridinium ion (AF64A)-treated mice was studied in a delayed non-matching to sample task using a T-maze. After behavioural testing was completed, mice were killed by microwave irradiation and regional brain levels of acetylcholine, aspartate, glutamate, glutamine, glycine, taurine, and gamma-aminobutyric acid (GABA) were measured by high-performance liquid chromatography with electrochemical detection. Treatment with AF64A (7 nmol, i.c.v.) produced a deficit in working memory performance in the non-matching to sample task at 30 s delay, and decreased acetylcholine, glutamate, and GABA levels in the hippocampus, but not in the septum and cerebral cortex. Administration of T3 (0.3 mg/kg, p.o., once daily for 6 days) to AF64A-treated animals improved the deficit in working memory performance and reversed the decrease in acetylcholine, glutamate, and GABA levels in the hippocampus. These results indicate that the deficit in performance induced by AF64A can be improved by T3 administration.

Acetylcholine↗
PubMed1986

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↗
PubMed1983

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↗
PubMed1990

A phase II study of diaziquone in children with recurrent or progressive primary brain tumors: a report from the Childrens Cancer Study Group.

Seventy-five children with recurrent, progressive or metastatic primary brain tumors were treated with aziridinylbenzoquinone (AZQ; Diaziquone) at 9 mg/m2/day by 30-minute intravenous infusion for five days every three weeks. Sixty-six patients were evaluable for response by imaging studies. There were five partial responses and one complete response for a combined response rate of 9%. A complete response lasting for 35+ months occurred in one of twelve patients with metastatic or locally recurrent ependymoma. Objective responses were also seen in patients with primitive neuroectodermal tumors (PNET) (1/8), low-grade glioma (1/6), and primary central nervous system lymphoma (1/1). Stable disease of greater than six months duration was seen in patients with ependymoma, PNET and medulloblastoma. Profound and prolonged myelo-suppression was the significant toxicity observed. As administered in this study, AZQ has marginal activity and severe toxicity.

Adolescent↗
PubMed1991

Cholinergic deficit induced by ethylcholine aziridinium (AF64A) in rat hippocampus: effect on glutamatergic systems.

The reaction of the glutamatergic systems in the rat hippocampus to the withdrawal of cholinergic function after cholinergic degeneration induced by ethylcholine aziridinium (AF64A) was investigated. Furthermore, the question whether blockade of N-methyl-D-aspartate (NMDA) receptors by MK-801 has an impact on the extent of the cholinergic lesion was addressed. After bilateral intracerebroventricular injection of AF64A (2 nmol/ventricle) the activity of choline acetyltransferase (ChAT) started to decline in the hippocampus within 24 h. The reduction of ChAT activity reached its maximum within 4 days (65%) and persisted during the observation period of 65 days. The loss of ChAT activity was accompanied by a transient decline in the level of glutamate, which was most pronounced 1 to 2 days after AF64A (25% reduction). Within 65 days the glutamate level returned to normal. A detailed subdissection of the hippocampus revealed that the cholinergic system was most affected in the ventral part of the hippocampus and the CA3 subfield. On the other hand, the transient reduction in glutamate was restricted to the CA1 and CA3 area. In the dentate gyrus the marked loss of cholinergic function was not accompanied by any reduction in glutamate level. Treatment of the AF64A-injected rats with the muscarinic agonist pilocarpine prevented the decline in glutamate levels. The transient nature of the decline in glutamate as well as its reversal by treatment with pilocarpine are suggestive of an increased release of glutamate in response to the withdrawal of cholinergic function.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

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↗
PubMed1992

Intracerebral chemotherapy in the 9L rat brain tumor model.

We have used the 9L rat brain tumor model to search for effective chemotherapeutic approaches to the management of brain tumors. Several antineoplastic agents which have been proposed or are currently being used for human brain tumors, including 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU), bleomycin, aziridinylbenzoquinone (AZQ), cis-Platinum, and acivicin, were administered intravenously (iv), intraperitoneally (ip), or intracerebrally (ic) to rats burdened with the intracranial 9L gliosarcoma. The results confirm that BCNU is the most effective systemic agent among the chemotherapeutic agents tested as indicated by its ability to significantly increase the median survival time (MST) and life span of the tumor-burdened animals. Bleomycin is an effective agent against the intracranial 9L tumor when administered ic. While neither systemic single iv dose AZQ (0.5-2.5 mg/kg) nor multiple ip treatments (0.5-1.0 mg/kg x 5, q 6 h) were effective in prolonging the survival, single ic dose AZQ (5-50 micrograms/rat) treatment significantly increased the MST of the treated animals (P < 0.05). Systemic AZQ treatments using higher doses produced a hematological toxicity, resulting in a decrease in MST of the treated animals. Cis-Platinum, either administered ip or ic, produced only a marginal effect on survival, although acute neurologic toxicity limited the dose of cis-Platinum that could be administered ic. Acivicin, either administered ip or ic, produced no effect on the survival of treated animals. Our results suggest that local treatment with certain antineoplastic agents may be an efficient therapy in the management of brain tumors.

Animals↗
PubMed1989

Intravenous BCNU and AZQ in patients with recurrent malignant gliomas.

Twenty-four patients with recurrent malignant glioma were treated with intravenous BCNU (80 mg/m2/day X 3 days) alternating with AZQ (8 mg/m2/day X 5 days) every 6-8 weeks. Twenty patients received two or more courses of chemotherapy, ten anaplastic astrocytomas (AA), eight glioblastomas (GBM), and two malignant oligodendrogliomas (Oligo). All had prior surgery and irradiation; one had prior chemotherapy. Median age was 37.5 years. The median Zubrod performance status (PS) was 1. Three patients (15%) achieved response status, and 7 (35%) had stable disease with median times to tumor progression (MTP) of 56 wks and 35 wks. MTP for patients with progression was 11 weeks. No GBM was responsive to chemotherapy and none of the ten patients with stable or responsive disease were older than fifty years. Dose limiting toxicity was consisted of thrombocytopenia and leukopenia. Young patients with recurrent AA and good PS appear more likely to respond to alternating BCNU/AZQ chemotherapy. The overall response rate (response plus stable) of 50% was comparable to that of BCNU alone and the hematologic toxicity was cumulative.

Adolescent↗