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Journal of Neuro-oncology Aug 1990Seventy-five children with recurrent, progressive or metastatic primary brain tumors were treated with aziridinylbenzoquinone (AZQ; Diaziquone) at 9 mg/m2/day by...
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.
Topics: Adolescent; Adult; Antineoplastic Agents; Aziridines; Benzoquinones; Brain Neoplasms; Child; Child, Preschool; Drug Evaluation; Female; Humans; Infant; Male
PubMed: 2213117
DOI: 10.1007/BF00167071 -
Anti-cancer Drug Design Aug 1990The interaction between glutathione and potential anti-tumour 3,6-disubstituted 2,5-bis(1-aziridinyl)-1,4-benzoquinone (BABQ) derivatives has been studied using u.v....
The interaction between glutathione and potential anti-tumour 3,6-disubstituted 2,5-bis(1-aziridinyl)-1,4-benzoquinone (BABQ) derivatives has been studied using u.v. spectrophotometry and h.p.l.c. The formation of BABQ-glutathione adducts was demonstrated in vitro for the BABQ parent compound (TW13), triaziquone (2,3,5-tris(1-aziridinyl)-1,4-benzoquinone) and for BABQ derivatives containing halogen substituents. The clinically-used BABQ derivative diaziquone (AZQ; 2,5-bis(1-aziridinyl)-3,6-bis(ethoxycarbonylamino)-1,4-benzoquinon e) did not react with glutathione. TW13 and triaziquone markedly inactivated bacteriophage M13-DNA in the presence of glutathione. This inactivation is probably produced by reductive activation of the BABQ derivative to a DNA-alkylating semiquinone radical. However, formation of bulky glutathione adducts decreases reactivity to DNA. Halogen-substituted BABQ derivatives react rapidly with glutathione to form adducts. This appeared to prevent DNA alkylation by these compounds. Comparison of these results with in vivo and in vitro activity against tumour models (L1210) suggests that in vivo halogen-substituted BABQ derivatives are efficiently inactivated by glutathione conjugation. The differences between the halogen-substituted BABQ derivatives on the one hand and TW13 and triaziquone on the other hand are probably caused by a difference in reaction mechanism with glutathione. From the viewpoint of drug design, halogen-substituted BABQ derivatives are expected to be inactive anti-tumour agents, in spite of high reactivity and activity in tumour models in vitro.
Topics: Animals; Antineoplastic Agents; Aziridines; Chromatography, High Pressure Liquid; DNA Damage; DNA, Bacterial; Drug Interactions; Escherichia coli; Glutathione; Leukemia L1210; Mice; Quinones; Structure-Activity Relationship; Triaziquone
PubMed: 2205226
DOI: No ID Found -
Biomedical & Environmental Mass... Jun 1990A packed-column supercritical-fluid chromatograph was interfaced with a mass spectrometer via a modification of a thermospray probe. This modification allowed a...
A packed-column supercritical-fluid chromatograph was interfaced with a mass spectrometer via a modification of a thermospray probe. This modification allowed a capillary restrictor for the supercritical fluid (CO2) and reagent gas for chemical ionization to be introduced directly into a thermospray source. Chemical ionization conditions were observed when either the filament or discharge electrode was used and the source pressure was above 0.5 torr. The discharge electrode produced more efficient ionization, resulting in approximately a tenfold larger signal than that observed in the filament mode. The usefulness of this instrumentation was demonstrated on several anticancer drugs. Methanol positive ion chemical ionization (PICI) spectra were recorded for cyclophosphamide, diaziquone, mitomycin C and thiotepa. Methane PICI spectra of thiotepa were obtained in the absence of methanol as a mobile-phase modifier. A 50 ng on-column injection of diaziquone produced approximately a 6:1 signal to noise ratio in the scanning mode.
Topics: Antineoplastic Agents; Aziridines; Benzoquinones; Chromatography; Cyclophosphamide; Mass Spectrometry; Mitomycin; Mitomycins; Thiotepa
PubMed: 2113408
DOI: 10.1002/bms.1200190604 -
Investigational New Drugs May 1990We conducted a phase I clinical study of aziridinylbenzoquinone (Diaziquone, AZQ) given as a 4 hour infusion weekly X 4. Forty-five children with recurrent acute...
We conducted a phase I clinical study of aziridinylbenzoquinone (Diaziquone, AZQ) given as a 4 hour infusion weekly X 4. Forty-five children with recurrent acute leukemia and 33 children with various advanced solid tumors participated. Severe myelosuppression was the dose limiting toxic effect, occurring in all patients at the upper dose levels. Gastrointestinal and hepatic toxicities were infrequent and not severe. No allergic reactions occurred. Objective tumor regression was noted in 3 of 25 patients with a CNS tumor and in 6 of 45 patients with acute leukemia. For phase II trials the recommended dosage of Diaziquone given by this schedule is 18 mg/M2/week X 4 for patients with a solid tumor, and is 30 mg/M2/week X 4 for children with acute leukemia.
Topics: Adolescent; Adult; Antineoplastic Agents; Aziridines; Benzoquinones; Brain Neoplasms; Child; Child, Preschool; Drug Evaluation; Female; Humans; Infant; Infusions, Intravenous; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Male; Pediatrics; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 2384303
DOI: 10.1007/BF00177252 -
Investigative Ophthalmology & Visual... May 1990The benefits of chemotherapy in the management of early or bilateral retinoblastoma are doubtful and are difficult to study. A xenograft model has been developed in...
The benefits of chemotherapy in the management of early or bilateral retinoblastoma are doubtful and are difficult to study. A xenograft model has been developed in which the therapeutic response of retinoblastoma heterotransplanted to the anterior chambers of nude mouse eyes can be evaluated. Cyclophosphamide has been shown to be the most effective of the conventional agents. The new drug diaziquone was tested in the model against five patient-derived xenografted cell lines, using both systemic (intraperitoneal) and local (eye drops) methods of administration. A total of 359 xenograft tumors in 229 experimental animals were monitored after treatment with intraperitoneal cyclophosphamide, intraperitoneal diaziquone, or local diaziquone. Responses to all three regimens were demonstrated in each of the five xenograft lines. Diaziquone compared favorably with cyclophosphamide as systemically administered chemotherapy. Local diaziquone was as effective as intraperitoneal injection in producing tumor responses. It is suggested that methods for local administration of diaziquone may be adapted to the clinical setting, and that a role for this modality may be found in a combination of nonoperative approaches to the management of small, intraocular tumors.
Topics: Animals; Antineoplastic Agents; Aziridines; Benzoquinones; Cyclophosphamide; Disease Models, Animal; Eye Neoplasms; Injections, Intraperitoneal; Mice; Mice, Nude; Ophthalmic Solutions; Retinoblastoma; Transplantation, Heterologous; Tumor Cells, Cultured
PubMed: 2335447
DOI: No ID Found -
Cancer Research Apr 1990Eight analogues of 2,5-bis(carboethoxyamino)-3,6-diaziridinyl-1,4-benzoquinone have been synthesized and tested for cytotoxicity against four different leukemic and...
Eight analogues of 2,5-bis(carboethoxyamino)-3,6-diaziridinyl-1,4-benzoquinone have been synthesized and tested for cytotoxicity against four different leukemic and lymphomic cell lines. For K562 and BSM cells, the toxicity could be correlated with the ease of reduction of the compounds as determined by the one-electron reduction potentials and the electron spin resonance detection of the reduced compounds produced by the cells. The cell toxicity could also be correlated with the efficiency of the compounds to form cross-links in DNA. However, no such correlations could be observed for the L1210 and Raji cells, although the activity of the NADPH dependent reducing enzymes in these cells was similar to that in the others. It is believed that for the L1210 and Raji cells, the influx/efflux of the different compounds may be more important to the cytotoxicity than their reduction or alkylation.
Topics: Animals; Antineoplastic Agents; Aziridines; Benzoquinones; Cells, Cultured; Chemical Phenomena; Chemistry; Dose-Response Relationship, Drug; Electron Spin Resonance Spectroscopy; Free Radicals; Humans; In Vitro Techniques; Mice; Oxidation-Reduction; Structure-Activity Relationship
PubMed: 2156610
DOI: No ID Found -
Continuous infusion diaziquone and etoposide: a phase I study in adult patients with acute leukemia.Leukemia Mar 1990Diaziquone (AZQ) and etoposide (VP-16) were administered as simultaneous 5-day continuous infusions to 27 patients with acute leukemia (22 with acute myeloid leukemia...
Diaziquone (AZQ) and etoposide (VP-16) were administered as simultaneous 5-day continuous infusions to 27 patients with acute leukemia (22 with acute myeloid leukemia (AML), three with chronic myeloid leukemia in blast crisis (CML-B), and two with acute lymphocytic leukemia) at four different doses in a phase I trial. Gastrointestinal toxicity, primarily stomatitis, was dose limiting, occurring in six of 10 patients at the highest dose level. Diarrhea was the only other grade 3 toxicity noted (three of 10 at the highest dose level). The duration of bone marrow aplasia was excessive at the highest dose (median 48 days to granulocytes greater than 500/mm3, range 33-67) but acceptable (31 days) at the maximum tolerated dose: AZQ 28 mg/m2/day x 5 days, VP-16 150 mg/m2/day x 5 days. Complete remissions were seen in seven patients (six AML, one CML-B) and a partial remission in one patient with AML. The median duration of unmaintained complete remission was 3 months (range 1.5-26+).
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Aziridines; Benzoquinones; Blast Crisis; Bone Marrow; Drug Evaluation; Etoposide; Female; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 2314118
DOI: No ID Found -
Cancer Research Mar 1990Diaziquone [AZQ, 2,5-bis(carboethoxyamino)-3,6-diaziridinyl-1,4-benzoquinone] has been investigated for its toxicity toward Chinese hamster ovary cells AA8-4 under both... (Comparative Study)
Comparative Study
Diaziquone [AZQ, 2,5-bis(carboethoxyamino)-3,6-diaziridinyl-1,4-benzoquinone] has been investigated for its toxicity toward Chinese hamster ovary cells AA8-4 under both aerobic and hypoxic conditions. Under acute (1-5 h) exposures to 2.5-10 microM AZQ in alpha-medium plus 10% fetal calf serum, AZQ showed an approximately linear concentration x time dependency for cell killing which was 3-4 times less under hypoxic compared to aerobic conditions. This selective toxicity toward hypoxic cells was prevented by low levels of oxygen. Under aerobic exposure conditions the toxicity of 2.5 microM AZQ was greatly increased by addition of 1-2 mM ascorbate. This ascorbate mediated toxicity of AZQ, presumably extracellular, could be prevented by the simultaneous addition of catalase. Under hypoxic exposure conditions there was no enhancement of AZQ toxicity by ascorbate or protection by catalase. The present results are consistent with two mechanisms for AZQ toxicity proposed earlier by others: toxicity due to (a) redox cycling and increased levels of oxidative stress and (b) reduction of the quinone leading to enhanced reactivity of the aziridines. The relative potency of AZQ as a hypoxic or aerobic cell selective toxin is determined by the balance between these two mechanisms.
Topics: Aerobiosis; Animals; Antineoplastic Agents; Aziridines; Benzoquinones; Cell Hypoxia; Cell Survival; Cross-Linking Reagents; Time Factors
PubMed: 2302714
DOI: No ID Found -
European Journal of Cancer (Oxford,... Feb 1990Plasma levels of 2,5-diaziridinyl-3,6-bis(2-hydroxyethylamino)-1,4-benzoquinone (BZQ, NSC 224070) were measured in nine patients after i.v. administration of the drug...
Plasma levels of 2,5-diaziridinyl-3,6-bis(2-hydroxyethylamino)-1,4-benzoquinone (BZQ, NSC 224070) were measured in nine patients after i.v. administration of the drug during a Phase I trial. Our own isocratic high performance liquid chromatographic (HPLC) method with a sensitivity of 3 ng/ml was used to quantify BZQ. Patients receiving 18-60 mg BZQ i.v. showed alpha and beta plasma decays with half-lives of 6.2 +/- 1.5 (mean +/- S.D.) and 24 +/- 4 min respectively. The apparent volume of the central compartment was 12.2 +/- 4.6 l, and the total volume of distribution was 33.6 +/- 11.3 l. The calculated plasma AUCs were linearly related to dose. A marked similarity in kinetic parameters was found for BZQ and diaziquone (AZQ, NSC 182986), another diaziridinylbenzoquinone that has recently completed phase II clinical trials.
Topics: Aged; Antineoplastic Agents; Aziridines; Benzoquinones; Chromatography, High Pressure Liquid; Drug Evaluation; Female; Humans; Male; Middle Aged
PubMed: 2138904
DOI: 10.1016/0277-5379(90)90291-z -
Role of the glutathione-glutathione peroxidase cycle in the cytotoxicity of the anticancer quinones.Pharmacology & Therapeutics 1990Recent studies have suggested that the selenoenzyme glutathione peroxidase, in the presence of reducing equivalents from the tripeptide glutathione, is responsible for... (Review)
Review
Recent studies have suggested that the selenoenzyme glutathione peroxidase, in the presence of reducing equivalents from the tripeptide glutathione, is responsible for detoxifying hydrogen peroxide and lipid hydroperoxides generated as a consequence of the cyclic reduction and oxidation of quinone-containing anticancer agents including doxorubicin, daunorubicin, mitomycin C, diaziquone, and menadione. Alterations in the intracellular levels of glutathione peroxidase or glutathione can significantly affect the activity of these drugs against human tumor cells and the expression of their normal tissue toxicity, especially with respect to the heart. Furthermore, augmentation of the glutathione peroxidase pathway appears to render certain human tumor cells relatively resistant to the anticancer quinones; therefore, the glutathione peroxidase system may, at least in part, modulate certain forms of acquired drug resistance in man. Thus, the glutathione peroxidase cycle appears to play a central role in maintaining intracellular peroxide homeostasis during quinone-induced oxidative stress.
Topics: Animals; Antineoplastic Agents; Glutathione; Glutathione Peroxidase; Humans; Quinones
PubMed: 2290853
DOI: 10.1016/0163-7258(90)90062-7