-
Investigational New Drugs May 1991Based upon the activity observed in this trial, there does not appear to be a significant role for AZQ as a salvage agent for leiomyosarcoma of the uterus at the dose... (Clinical Trial)
Clinical Trial
Based upon the activity observed in this trial, there does not appear to be a significant role for AZQ as a salvage agent for leiomyosarcoma of the uterus at the dose and schedule tested.
Topics: Adult; Aged; Antineoplastic Agents; Aziridines; Benzoquinones; Drug Evaluation; Female; Humans; Leiomyosarcoma; Middle Aged; Neoplasm Recurrence, Local; Uterine Neoplasms
PubMed: 1874603
DOI: 10.1007/BF00175091 -
Oncology (Williston Park, N.Y.) May 1991The meninges are a unique site of recurrence for certain malignancies because of the limited penetration of systemically administered cytotoxic drugs across the...
The meninges are a unique site of recurrence for certain malignancies because of the limited penetration of systemically administered cytotoxic drugs across the blood-brain barrier. While this phenomenon was first recognized in children with acute lymphoblastic leukemia, a similar pattern is also occurring in breast cancer, ovarian cancer, and small cell lung cancer. Recognition of the limitations of standard systemic antileukemic therapy for the treatment of meningeal disease led to the development of new therapeutic strategies targeted directly at the CNS. These include intralumbar therapy using methotrexate or cytarabine, intraventricular chemotherapy, and high-dose systemic drug administration. New agents showing promise are intrathecal diaziquone, 6-mercaptopurine, and mafosfamide.
Topics: Adolescent; Adult; Antineoplastic Agents; Aziridines; Benzoquinones; Blood-Brain Barrier; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Humans; Infant; Infant, Newborn; Leukemia; Meningeal Neoplasms; Mercaptopurine; Methotrexate; Thiotepa
PubMed: 1831994
DOI: No ID Found -
Investigational New Drugs Feb 1991AZQ was given intravenously to 23 patients with mixed mesodermal sarcoma of the uterus refractory to conventional treatment at a dose of 22.5-30 mg/m2 q three weeks.... (Clinical Trial)
Clinical Trial
AZQ was given intravenously to 23 patients with mixed mesodermal sarcoma of the uterus refractory to conventional treatment at a dose of 22.5-30 mg/m2 q three weeks. There was one partial response lasting seven weeks and one drug-related death. Based upon the activity observed in this trial, there does not appear to be a significant role for AZQ as a salvage agent for mixed mesodermal sarcomas of the uterus at the dose and schedule tested.
Topics: Adult; Aged; Antineoplastic Agents; Aziridines; Benzoquinones; Drug Evaluation; Female; Humans; Middle Aged; Sarcoma; Uterine Neoplasms
PubMed: 2026490
DOI: 10.1007/BF00194555 -
Free Radical Biology & Medicine 1991The participation of DT-diaphorase or NAD(P)H:(quinone acceptor) oxidoreductase (E.C. 1.6.99.2) in metabolism or in events leading to toxicity is often implied on the... (Review)
Review
The participation of DT-diaphorase or NAD(P)H:(quinone acceptor) oxidoreductase (E.C. 1.6.99.2) in metabolism or in events leading to toxicity is often implied on the basis of the inhibitory effects of dicoumarol. DT-diaphorase functions via a ping pong bi-bi kinetic mechanism involving oxidized and reduced flavin forms of the free enzyme. Dicoumarol, a potent (Ki = 10 nM) inhibitor, binds to the oxidized form of the enzyme, competitively versus reduced pyridine nucleotide. Inhibition is effectively complete at 1 microM dicoumarol in typical studies using DCPIP, one of the best known substrates for the enzyme, as electron acceptor. The antitumor quinone Diaziquone (AZQ) is a poor substrate for DT-diaphorase relative to DCPIP, but effective inhibition of its reduction requires ten-fold higher concentrations of dicoumarol than for inhibition of DCPIP reduction under otherwise similar conditions. The variable inhibition of DT-diaphorase by dicoumarol dependent on the efficiency of the electron acceptor can be explained on the basis of the complete rate equation describing its ping pong type kinetic mechanism. Thus, the concentration of dicoumarol used to inhibit DT-diaphorase must be chosen carefully and consideration should be given to the efficiency of the electron acceptor. The absence of an inhibitory effect using low doses of dicoumarol cannot rule out a reaction mediated by DT-diaphorase. Although higher doses of dicoumarol may be required to inhibit DT-diaphorase mediated metabolism of less efficient electron acceptors, the use of such doses in cells may also affect biochemical processes other than DT-diaphorase and should be approached with caution.
Topics: Animals; Dicumarol; Free Radicals; Humans; NAD(P)H Dehydrogenase (Quinone); Substrate Specificity
PubMed: 1718826
DOI: 10.1016/0891-5849(91)90191-5 -
Free Radical Biology & Medicine 1991One-electron reduction of diaziquone (AZQ) by purified rat liver NADPH cytochrome c reductase was associated with formation of AZQ semiquinone, superoxide anions,...
Free radical formation and DNA strand breakage during metabolism of diaziquone by NAD(P)H quinone-acceptor oxidoreductase (DT-diaphorase) and NADPH cytochrome c reductase.
One-electron reduction of diaziquone (AZQ) by purified rat liver NADPH cytochrome c reductase was associated with formation of AZQ semiquinone, superoxide anions, hydrogen peroxide, and hydroxyl radicals as indicated by ESR spin-trapping studies. Reactive oxygen formation correlated with AZQ-dependent production of single and double PM2 plasmid DNA strand breaks mediated by this system as detected by gel electrophoresis. Direct two-electron reduction of AZQ by purified rat liver NAD(P)H (quinone acceptor) oxidoreductase (QAO) was also associated with formation of AZQ semiquinone, superoxide anions, hydrogen peroxide, and hydroxyl radicals as detected by ESR spin trapping. Furthermore, PM2 plasmid DNA strand breaks were detected in the presence of this system. Plasmid DNA strand breakage was inhibited by dicumarol (49 +/- 5%), catalase (57 +/- 2.3%), SOD (42.2 +/- 3.6%) and ethanol (41.1 +/- 3.9%) showing QAO and reactive oxygen formation was involved in the PM2 plasmid DNA strand breaks observed. These results show that both one- and two-electron enzymatic reduction of AZQ give rise to formation of reactive oxygen species and DNA strand breaks. Autoxidation of the AZQ semiquinone and hydroquinone in the presence of molecular oxygen appears to be responsible for these processes. QAO appears to be involved in the metabolic activation of AZQ to free radical species. The cellular levels and distribution of this enzyme may play an important role in the response of tumor and normal cells to this antitumor agent.
Topics: Animals; Aziridines; Benzoquinones; DNA Damage; Electron Spin Resonance Spectroscopy; Free Radicals; Liver; NAD(P)H Dehydrogenase (Quinone); NADH Dehydrogenase; Oxidation-Reduction; Plasmids; Rats
PubMed: 1663902
DOI: 10.1016/0891-5849(91)90141-o -
Free Radical Biology & Medicine 1991The S9 fraction of MCF-7 human breast carcinoma cells has NAD(P)H (quinone-acceptor) oxidoreductase activity as measured by the reduction of dichlorophenol-indophenol...
The reductive metabolism of diaziquone (AZQ) in the S9 fraction of MCF-7 cells: free radical formation and NAD(P)H: quinone-acceptor oxidoreductase (DT-diaphorase) activity.
The S9 fraction of MCF-7 human breast carcinoma cells has NAD(P)H (quinone-acceptor) oxidoreductase activity as measured by the reduction of dichlorophenol-indophenol (DCPIP). This reduction is dependent on the activators Tween-20 and bovine serum albumin and it is inhibitable by dicumarol. The S9 fraction also has cytochrome c reductase activity which is approximately 29 times less than the two-electron reduction activity of NAD(P)H (quinone-acceptor) oxidoreductase. Diaziquone (AZQ) is a substrate for this NAD(P)H oxidoreductase active S9 fraction as judged by its enzymatic reduction detected spectrophotometrically and by electron spin resonance spectroscopy. Two-electron mediated enzymatic reduction of AZQ was evidenced by the formation of the colorless dihydroquinone (AZQH2) which could be followed at 340 nm. The production of the dihydroquinone was inhibitable by dicumarol implicating NAD(P)H oxidoreductase in its formation. Under aerobic conditions, electron spin resonance spectroscopy showed evidence for the production of AZQ semiquinone (AZQH) and oxygen radicals. Under anaerobic conditions no oxygen radicals were observed, but the semiquinone was stable for hours. These results are also inhibitable by dicumarol and suggest a two-step one-electron oxidation process of the dihydroquinone. The production of semiquinone and oxygen radicals as detected by electron spin resonance spectroscopy was more sensitive to dicumarol when NADPH was used as cofactor (68% inhibition of OH and 65% inhibition of AZQH) than when NADH was used (28% inhibition of OH and 5% inhibition of AZQH). This suggests that NADH flavin reductases play a more important role in the one-electron reduction pathway of AZQ in MCF-7 S9 fraction than NADPH reductases. The reduction of AZQ by NAD(P)H (quinone-acceptor) oxidoreductase may play an important role in the bioreductive alkylating properties of AZQ.
Topics: Antineoplastic Agents; Aziridines; Benzoquinones; Breast Neoplasms; Cell-Free System; Electron Spin Resonance Spectroscopy; Free Radicals; Humans; NAD(P)H Dehydrogenase (Quinone); Oxidation-Reduction; Oxygen Consumption; Quinone Reductases; Substrate Specificity; Tumor Cells, Cultured
PubMed: 1654286
DOI: 10.1016/0891-5849(91)90044-4 -
Cancer Research Nov 1990Reduction of 2,5-diaziridinyl-3,6-bis(carboethoxyamino)-1,4-benzoquinone (diaziquone; AZQ) by purified rat hepatic DT-diaphorase was NADH and enzyme dependent and was...
Metabolism of diaziquone by NAD(P)H:(quinone acceptor) oxidoreductase (DT-diaphorase): role in diaziquone-induced DNA damage and cytotoxicity in human colon carcinoma cells.
Reduction of 2,5-diaziridinyl-3,6-bis(carboethoxyamino)-1,4-benzoquinone (diaziquone; AZQ) by purified rat hepatic DT-diaphorase was NADH and enzyme dependent and was inhibited by prior boiling of the enzyme or by dicumarol. Under aerobic conditions some of the hydroquinone (AZQH2) formed by reduction oxidized to regenerate AZQ and an approximate 1:1 stoichiometry was observed between AZQH2 reoxidized and oxygen consumed. The steady state kinetics of AZQ reduction were consistent with a ping-pong mechanism and a high Km for AZQ. There was no evidence for saturation in the range of 25-200 microM AZQ at 200 microM NADH. AZQ (0-20 microM) induced dicumarol-inhibitable DNA interstrand cross-linking and cytotoxicity in HT-29 human colon carcinoma cells which have high DT-diaphorase activity but not in BE cells which have low DT-diaphorase activity. Extensive metabolism (greater than 90%) of AZQ (100 microM) in HT-29 cytosol occurred, which was either NADH or NADPH dependent and could be inhibited by dicumarol. Little metabolism of AZQ could be detected in BE cell cytosols. DT-diaphorase was purified from HT-29 cells and metabolism of AZQ by this enzyme was confirmed. These data show that AZQ can be metabolized by purified rat hepatic and human HT-29 DT-diaphorase and suggest that in HT-29 cells, DT-diaphorase catalyzed reduction of AZQ represents a bioactivation process leading to the production of genotoxic and cytotoxic metabolites.
Topics: Animals; Antineoplastic Agents; Aziridines; Benzoquinones; Carcinoma; Cell Division; Chromatography, High Pressure Liquid; Colonic Neoplasms; Glutathione; Humans; In Vitro Techniques; Kinetics; Liver; NAD(P)H Dehydrogenase (Quinone); Oxidation-Reduction; Quinone Reductases; Rats; Spectrum Analysis; Tumor Cells, Cultured
PubMed: 2121335
DOI: No ID Found -
Neurology Nov 1990The Brain Tumor Study Group has shown procarbazine (PCB) to be as effective an adjuvant treatment as 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). We treated 35 patients...
The Brain Tumor Study Group has shown procarbazine (PCB) to be as effective an adjuvant treatment as 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). We treated 35 patients with recurrent malignant astrocytomas after radiation and nitrosourea failure with successive courses of PCB 150 mg/m2/d for 28 days every 8 weeks. After 2 courses, 2 patients had complete responses, 7 had partial responses, 11 had stable disease, and 15 had progression. Significantly more patients receiving PCB had complete or partial responses or stable disease than a similar group of patients in a previous trial who received intra-arterial (IA) cisplatin (DDP). There is a significant advantage in time to disease progression for those receiving PCB compared with those receiving IA diaziquone (AZQ). Our results suggest that PCB is a more effective 2nd agent than IA DDP or AZQ following radiation and nitrosourea failure.
Topics: Adult; Aged; Astrocytoma; Brain Neoplasms; Combined Modality Therapy; Cranial Irradiation; Drug Evaluation; Female; Glioblastoma; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Nitrosourea Compounds; Procarbazine; Remission Induction
PubMed: 2172864
DOI: 10.1212/wnl.40.11.1743 -
Investigational New Drugs Nov 1990To assess the response rates and toxicity of AZQ in children with recurrent brain and other malignant solid tumors, a phase II study was implemented by the Pediatric... (Clinical Trial)
Clinical Trial
To assess the response rates and toxicity of AZQ in children with recurrent brain and other malignant solid tumors, a phase II study was implemented by the Pediatric Oncology Group. Eligible patients received AZQ 18 mg/M2/week i.v. for 4 doses followed by a 2 week rest period. Each dose was given over four hours (1/3 over the initial 20 minutes). After the first year, the dosage was reduced to 13 mg/M2 due to myelotoxicity resulting in treatment delays. No objective responses were observed in 73 evaluable children with various non-central nervous system tumors. Of the 91 patients with brain tumors, there were 4 CR's and 2 PR's in patients with astrocytoma, ependymoma, glioblastoma multiforme, oligodendroglioma, brain stem glioma and intracranial yolk sac tumor (median duration, 10 months; range, 2-20+ months). Three of 4 CR's were achieved with a dosage of 18 mg/M2/week. An additional 13 children with brain tumors experienced stable or improved disease (duration, 2-36 + months; median 7.5 months). The principal toxicity was myelosuppression which was cumulative but there were also 3 allergic reactions to AZQ. We conclude that for selected brain tumors, the rates of objective response and stable disease plus the duration of responses support further assessment of AZQ in combination with other agents. Furthermore, the 18 mg/M2 dosage may provide better responses.
Topics: Adolescent; Adult; Antineoplastic Agents; Aziridines; Benzoquinones; Brain Neoplasms; Child; Child, Preschool; Drug Administration Schedule; Drug Evaluation; Drugs, Investigational; Humans; Neoplasm Recurrence, Local; Neoplasms
PubMed: 2084075
DOI: 10.1007/BF00198601 -
American Journal of Hematology Oct 1990Twenty-one patients with relapsed or refractory acute myeloid leukemia (AML) were treated with mitoxantrone (12 mg/m2/day, days 1-3) and diaziquone (continuous infusion...
Twenty-one patients with relapsed or refractory acute myeloid leukemia (AML) were treated with mitoxantrone (12 mg/m2/day, days 1-3) and diaziquone (continuous infusion days 1-5). The dosage of diaziquone was increased for sequential cohorts of seven patients from 20 mg/m2/day to 24 mg/m2/day, and finally to 28 mg/m2/day to determine the maximum tolerated dose for this chemotherapy combination. Myelosuppression was the dose-limiting toxicity. The median time to recovery of blood counts was greater at the highest dose of diaziquone (48 days) than at the lower two doses (31 and 28 days). Other toxic effects were minimal. Overall, 9/21 (43%, 95% confidence interval, 0.22 to 0.66) patients achieved complete remission. We conclude that this combination of drugs shows sufficient antileukemic activity with acceptable toxicity to warrant further trials.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Aziridines; Benzoquinones; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Mitoxantrone; Neoplasm Recurrence, Local; Remission Induction; Survival Analysis; Time Factors
PubMed: 2399909
DOI: 10.1002/ajh.2830350203