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Leukemia Feb 1998A phase II trial was conducted to determine which of the three possible two-drug combinations of diaziquone, etoposide and mitoxantrone was associated with the highest... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
An evaluation of combinations of diaziquone, etoposide and mitoxantrone in the treatment of adults with relapsed or refractory acute myeloid leukemia: results of 8722, a randomized phase II study conducted by Cancer and Leukemia Group B.
A phase II trial was conducted to determine which of the three possible two-drug combinations of diaziquone, etoposide and mitoxantrone was associated with the highest response rate in patients with relapsed or refractory acute myeloid leukemia (AML). Of the 167 patients (median age 55) with AML who entered the trial, 123 were in first relapse, 22 were in second relapse and 22 had failed to achieve complete remission (CR). CR rates were 30% for diaziquone and mitoxantrone, and 23% for the other two combinations (mitoxantrone/etoposide and diaziquone/etoposide), NS. Patients in first relapse had higher CR rates (40%) than other patients. Of the 166 patients who actually received treatment, 43 died before having either a CR or persistent leukemia. Non-hematologic toxicity was primarily mucosal with 24% of patients experiencing grade 3 or greater stomatitis on the two diaziquone arms, and 43% on the mitoxantrone/etoposide arm. The combination of diaziquone and mitoxantrone was selected for further testing in patients with AML.
Topics: Acute Disease; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Aziridines; Benzoquinones; Etoposide; Female; Humans; Leukemia, Myeloid; Male; Middle Aged; Mitoxantrone
PubMed: 9519774
DOI: 10.1038/sj.leu.2400905 -
Cancer Research Jun 1984We used diaziquone (NSC 182986) alone and in combination with other antineoplastic drugs to treat six human glioma and one human medulloblastoma tumor lines growing s.c....
We used diaziquone (NSC 182986) alone and in combination with other antineoplastic drugs to treat six human glioma and one human medulloblastoma tumor lines growing s.c. in athymic mice. Pharmacokinetic studies of diaziquone in the plasma of athymic mice indicated rapid clearance with a half-life of approximately 11.5 min. Diaziquone produced significant growth delays in at least one experiment using each of seven different tumor lines, and it produced consistent and significant delays in five of the seven. There was no obvious difference between a single dose and a dose administered once daily for 5 days, and tumor regressions to a volume smaller than that at treatment were uncommon in any of the single-drug experiments. Using our most extensively characterized human glioma line, D-54 MG, we found striking enhancement of the therapeutic effect by using nontoxic combinations of either diaziquone and carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea, NSC 409962) or diaziquone and procarbazine (NSC 77213). These combinations produced significant increases in the median growth delay, significant increases in the number of tumor regressions, and some instances in which no palpable tumors were present 100 days after treatment. In contrast, in experiments using diaziquone -based chemotherapy combinations with either cyclophosphamide, cis-platinum, or vincristine, there was only slight enhancement of the therapeutic effect. These results, using human glioma and medulloblastoma tumor lines in athymic mice, suggest a broad range of activity of diaziquone against primary nervous system tumors and enhancement of its therapeutic effect with either 1,3-bis(2-chloroethyl)-1-nitrosourea or procarbazine. If Phase II and Phase III clinical trials corroborate these findings, the value of the nude mouse system for the evaluation of new therapeutic approaches to brain neoplasms would be further confirmed.
Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Aziridines; Azirines; Benzoquinones; Brain Neoplasms; Cell Division; Cell Line; Drug Evaluation, Preclinical; Glioma; Humans; Medulloblastoma; Mice; Mice, Nude; Neoplasm Transplantation; Transplantation, Heterologous
PubMed: 6722774
DOI: No ID Found -
Journal of Clinical Oncology : Official... Mar 1987We treated 103 patients with histologically confirmed anaplastic supratentorial astrocytic neoplasms with either diaziquone (AZQ) and carmustine (BCNU) or AZQ and...
We treated 103 patients with histologically confirmed anaplastic supratentorial astrocytic neoplasms with either diaziquone (AZQ) and carmustine (BCNU) or AZQ and procarbazine. There were 74 patients with glioblastoma multiforme (GBM) and 29 patients with anaplastic astrocytoma (AA). AZQ plus BCNU produced partial (PR) or unequivocal responses in seven of 32 (21.9%) patients with GBMs and three of ten (30%) patients with AAs. Two patients with GBMs (6.3%) and five patients with AAs (50%) showed stable disease (SD). AZQ plus procarbazine produced PRs or unequivocal responses in five of 42 (11.9%) patients with GBMs and nine of 19 (47.4%) patients with AAs. Eight patients with GBMs (19%) and one patient with an AA (5.2%) showed SD. In addition to histologic diagnosis, only the Karnofsky performance-status (KPS) rating independently influenced response and survival. Differences in response rates between the two regimens were not significant, although estimated median survival after adjusting for performance status was slightly better with AZQ plus BCNU than with AZQ plus procarbazine (P = .031). Neither age nor prior chemotherapy were significant independent risk factors. Toxicity was mild and primarily hematologic. We conclude that these AZQ-based regimens have activity in patients with recurrent anaplastic gliomas, but that they are not clearly superior to other agents in current use. The histologic diagnosis of GBM is associated with a significantly worse prognosis than AA, and we believe that this important distinction must be recognized in phase II as well as phase III trials.
Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Astrocytoma; Aziridines; Benzoquinones; Carmustine; Cerebellar Neoplasms; Child; Dacarbazine; Drug Evaluation; Glioblastoma; Humans; Middle Aged; Neoplasm Recurrence, Local; Statistics as Topic
PubMed: 3029339
DOI: 10.1200/JCO.1987.5.3.464 -
Journal of Clinical Oncology : Official... Jan 1993We conducted a phase III trial comparing intravenous (IV) diaziquone (AZQ) and carmustine (BCNU) as single agents in patients with cerebral anaplastic gliomas who had... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
PURPOSE
We conducted a phase III trial comparing intravenous (IV) diaziquone (AZQ) and carmustine (BCNU) as single agents in patients with cerebral anaplastic gliomas who had received surgery and radiotherapy. Its purpose was to compare the efficacy of AZQ with that of BCNU, the standard agent for brain tumor chemotherapy.
PATIENTS AND METHODS
Randomization between the two regimens occurred 8 weeks after completion of radiotherapy. A total of 251 patients were randomized to receive either AZQ or BCNU, and there were no significant differences between the two treatment arms in any of the known prognostic variables, including age, histologic grade, and Karnofsky performance status (KPS).
RESULTS
There was no significant difference in either time to tumor progression or survival between the two treatment arms. Age and histology were strong predictors of outcome, whereas KPS had relatively less effect. Three groups of patients with distinctly different outcomes could be identified: (1) older age (45+) and glioblastoma/gliosarcoma (GBM/GS) patients had a median survival of 37 weeks after randomization; (2) patients with either older age or GBM/GS had a median survival of 61 weeks; and (3) younger age (< 45) and non-GBM/GS (usually anaplastic astrocytoma) patients had a median survival of 147 weeks. Toxicity was primarily hematologic, although acute gastrointestinal toxicity and chronic pulmonary toxicity were more common with BCNU. Patients randomized to AZQ who had significant hematologic toxicity that required dose reduction after the first treatment cycle had significantly longer time to tumor progression and survival than those who did not require dose reduction (P = .011 and .016, respectively).
CONCLUSION
There was no significant difference in efficacy between AZQ and BCNU in patients with anaplastic gliomas as tested in this study, although AZQ was somewhat better tolerated.
Topics: Adult; Analysis of Variance; Antineoplastic Agents; Aziridines; Benzoquinones; Brain Neoplasms; Carmustine; Combined Modality Therapy; Female; Glioma; Humans; Male; Middle Aged; Proportional Hazards Models; Survival Analysis
PubMed: 8418246
DOI: 10.1200/JCO.1993.11.1.77 -
Cancer Research Oct 19892,5-Diaziridinyl-3,6-bis(carboethoxyamine)-1,4-benzoquinone (AZQ) is a lipid-soluble antitumor agent. The following evidence using isolated rat hepatocytes as a model...
2,5-Diaziridinyl-3,6-bis(carboethoxyamine)-1,4-benzoquinone (AZQ) is a lipid-soluble antitumor agent. The following evidence using isolated rat hepatocytes as a model for cytotoxicity studies suggests that, under aerobic conditions, AZQ participates in futile oxidation-reduction cycling and oxygen activation. The H2O2 formed can mediate oxidative stress cytotoxicity in compromised cells. (a) Addition of AZQ to hepatocytes causes the stoichiometric oxidation of glutathione (GSH) to oxidized glutathione. No subsequent reduction back to GSH occurred. This was found to be the result of reversible inactivation of glutathione reductase by AZQ. The extent of GSH oxidation increased with AZQ concentration. (b) Cytotoxicity occurred when AZQ concentrations were sufficient to completely deplete GSH. (c) Addition of AZQ to hepatocytes enhanced cyanide-resistant respiration. (d) If the hepatocytes were compromised with azide or cyanamide to inhibit catalase, cytotoxicity was increased 10-fold or 100-fold if ascorbate was also present. (e) AZQ readily induced Ca2+ release by energized mitochondria. Ascorbate markedly enhanced the effectiveness of AZQ, and catalase delayed Ca2+ release. H2O2 formed by aerobic oxidation-reduction cycling of AZQ may therefore cause mitochondrial Ca2+ release.
Topics: Animals; Antineoplastic Agents; Aziridines; Benzoquinones; Calcium; Catalase; Cell Survival; Glutathione; Glutathione Reductase; Homeostasis; In Vitro Techniques; Liver; Mitochondria, Liver; Rats; Rats, Inbred Strains
PubMed: 2790779
DOI: No ID Found -
Chemical Research in Toxicology 1995The antitumor agent diaziquone (AZQ) reacts with reduced glutathione (GSH) in aqueous solutions and under aerobic conditions to give rise to the glutathionyl and...
The antitumor agent diaziquone (AZQ) reacts with reduced glutathione (GSH) in aqueous solutions and under aerobic conditions to give rise to the glutathionyl and hydroxyl free radicals, as well as the AZQ semiquinone. Under anaerobic conditions, the only radical observed was the glutathionyl radical. These radicals are quickly abrogated when superoxide dismutase and catalase are coincubated. Separately, superoxide dismutase favors the formation of thiyl radicals while catalase favors the formation of hydroxyl radicals and AZQ semiquinone. The metal chelator diethylenetriaminepentaacetic acid favors the production of hydroxyl radicals and AZQ semiquinone. The reaction of AZQ with GSH at pH 7.2 and 5.5 results in a variety of conjugates. These conjugates include addition of glutathione to both aziridines, displacement of the aziridines by GSH, and a combination of both. The majority of the conjugates are formed by nucleophilic attack of GSH to the AZQ aziridines or by 1,4-Michael addition to the AZQ quinone or a combination of both. There may be a small free radical component in conjugate formation, but the majority of the free radicals observed are from redox reactions that involve the oxidation of glutathione and the reduction and autoxidation of AZQ to produce oxygen radicals and hydrogen peroxide, a process that is enhanced by trace metal ions.
Topics: Antineoplastic Agents; Antioxidants; Aziridines; Benzoquinones; Catalase; Drug Interactions; Electron Spin Resonance Spectroscopy; Free Radicals; Glutathione; Oxygen Consumption; Superoxide Dismutase
PubMed: 7578933
DOI: 10.1021/tx00045a018 -
Pharmacology & Therapeutics 1985
Review
Topics: Absorption; Acetaminophen; Adrenergic beta-Antagonists; Analgesics, Opioid; Animals; Anti-Bacterial Agents; Anticoagulants; Anticonvulsants; Aspirin; Aziridines; Benzodiazepines; Benzoquinones; Cimetidine; Drug Interactions; Humans; Ibuprofen; Imipramine; Kinetics; Lidocaine; Liver Circulation; Pituitary Gland; Procaine; Xanthines
PubMed: 2864708
DOI: 10.1016/0163-7258(85)90075-0 -
Cancer Dec 1989The authors treated 30 patients ages 1 to 19 with relapsed or refractory acute non-lymphoblastic leukemia (ANLL) with the combination of diaziquone (AZQ) and...
The authors treated 30 patients ages 1 to 19 with relapsed or refractory acute non-lymphoblastic leukemia (ANLL) with the combination of diaziquone (AZQ) and 2,2'-anhydro-arabinosyl-5-fluorocytosine (AAFC) intravenously in two dose schedules. The first 12 patients were treated with 19 courses of AZQ 30 mg/m2 X 3 days and AAFC 600 mg/m2/dose every 12 hours X 10 doses. An additional patient was treated with three courses at 80% of the above doses. Hepatic toxicity was National Cancer Institute Grade III in eight of 22 and Grade IV in one of 22 courses. Infectious complications were severe in all patients, including responders. One patient achieved a complete remission and one a partial remission; the latter died with marrow aplasia after a second course. Altogether three patients developed profound aplasia and died before marrow recovery. The authors treated a second group of 17 patients with AZQ 22.5 mg/m2/day X 3 days and AAFC 450 mg/m2/dose every 12 hours X 10 doses. Three patients achieved a complete remission and one patient a partial remission for 3, 4, 9, and 9 months, respectively. The remainder had progressive disease or no response. All patients developed profound myelosuppression but no toxic deaths occurred. Hepatic toxicity was reduced. Therapy induced cytoreduction of bone marrow was determined by flow cytometry in ten patients; none of these patients responded during the interval studied. Although AZQ and AAFC are active in childhood ANLL with acceptable toxicity, the combination does not appear more active than AZQ used alone. Future studies should define the role of AZQ in combination with other agents.
Topics: Adolescent; Ancitabine; Antineoplastic Agents; Aziridines; Benzoquinones; Bone Marrow; Cell Survival; Child; Child, Preschool; Cytarabine; Drug Administration Schedule; Drug Evaluation; Female; Humans; Infant; Leukemia, Myeloid, Acute; Male
PubMed: 2479459
DOI: 10.1002/1097-0142(19891215)64:12<2416::aid-cncr2820641203>3.0.co;2-y -
Journal of Neuro-oncology 1985Diaziquone, 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...
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.
Topics: Adult; Aged; Aziridines; Azirines; Benzoquinones; Blood-Brain Barrier; Brain Neoplasms; Combined Modality Therapy; Drug Evaluation; Female; Glioma; Humans; Male; Middle Aged
PubMed: 4056853
DOI: 10.1007/BF00165185 -
Frontiers in Bioscience : a Journal and... Nov 2000Quinone-containing alkylating agents are a class of chemical agents that have received considerable interest as anticancer drugs. These agents contain a quinone moiety... (Review)
Review
Quinone-containing alkylating agents are a class of chemical agents that have received considerable interest as anticancer drugs. These agents contain a quinone moiety that can be reduced and an alkylating group that can form covalent bonds with a variety of cellular components. The oxidation state of the quinone element can modulate the activity of the alkylating element, and reduction of the quinone is required for activation of the alkylating activity of many of these agents. The quinone element may also contribute to the cytotoxic activity of quinone-containing alkylating agents through the formation of reactive oxygen species during redox cycling. The natural product, mitomycin C, has been the most widely used quinone-containing alkylating agent in the clinic, but other quinone-containing alkylating agents like porfiromycin, diaziquone, carbazilquinone, triaziquone and EO9 have also been used in the clinic for the treatment of cancer. In addition, many other quinone-containing alkylating agents have been tested in preclinical studies and the development of new agents is being actively pursued. This chapter describes the current and past clinical uses of these agents in the treatment of cancer and discusses new agents that are currently in clinical trials.
Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Aziridines; Benzoquinones; Clinical Trials as Topic; Drug Evaluation, Preclinical; History, 20th Century; Humans; Indolequinones; Indoles; Mitomycin; Neoplasms; Quinones; Structure-Activity Relationship
PubMed: 11056078
DOI: 10.2741/begleit