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Cancer Treatment Reports Mar 1985Diaziquone (AZQ), a new lipid-soluble antitumor agent, was given by 15-30-minute infusion on a daily X 5 schedule to 47 children with refractory solid tumors and...
Diaziquone (AZQ), a new lipid-soluble antitumor agent, was given by 15-30-minute infusion on a daily X 5 schedule to 47 children with refractory solid tumors and leukemia. The starting daily dose of 6 mg/m2 was escalated to 10 and 35 mg/m2 in patients with solid tumors and leukemia, respectively. In patients with solid tumors, myelosuppression was dose-limiting at a daily dose of 10 mg/m2. In patients with leukemia, prolonged pancytopenia and bone marrow hypoplasia were observed at daily doses greater than or equal to 25 mg/m2. At these higher doses, significant hyperbilirubinemia associated with sepsis was also seen. Corresponding increases of transaminases or alkaline phosphatase and significant hemolysis were not noted. The maximum tolerated dose for this daily dose schedule was 9 mg/m2 in children with solid tumors and 25 mg/m2 in children with relapsed leukemia. Responses to AZQ included stabilization of disease in osteosarcoma, neurofibrosarcoma, pinealoma, and ependymoma. A patient with juvenile chronic myelocytic leukemia in blast crisis converted back to the chronic phase. A patient with acute lymphoblastic leukemia had a substantial decrease in cerebrospinal fluid blast count. Bone marrow aplasia was achieved in children with acute lymphoblastic leukemia and acute nonlymphoblastic leukemia; however, remissions were not achieved. A phase II study of AZQ in children with refractory malignancies is now being performed by the Childrens Cancer Study Group.
Topics: Adolescent; Age Factors; Aziridines; Azirines; Benzoquinones; Bone Marrow; Child; Child, Preschool; Drug Evaluation; Female; Hemoglobins; Humans; Infant; Leukemia, Lymphoid; Leukemia, Myeloid; Leukocyte Count; Liver; Male; Neoplasms; Platelet Count
PubMed: 3856480
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 Communications 1989P388 leukemia sublines were isolated from leukemia-cell-bearing CD2F1 mice that had been treated in vivo with increasing amounts of diaziquone (AZQ). The sublines...
P388 leukemia sublines were isolated from leukemia-cell-bearing CD2F1 mice that had been treated in vivo with increasing amounts of diaziquone (AZQ). The sublines isolated for in vitro studies were AZQ19 and AZQ30 which corresponded to the 19th and 30th in vivo passages, respectively. The AZQ19 subline displayed a very low degree of resistance to AZQ (1.5-fold), whereas the AZQ30 subline was sensitive. Both sublines, however, had much higher degrees of resistance to Adriamycin than to AZQ (24-fold for AZQ30 cells and 10-fold for AZQ19 cells). Both cell lines were also more resistant to actinomycin D, colchicine, and vincristine than to AZQ. The AZQ19 line was resistant to the alkylator thio-TEPA to the same degree that it was to AZQ, but the AZQ30 line was sensitive to thio-TEPA. On the other hand, AZQ30 cells were resistant to hydrogen peroxide with a very low degree of resistance (1.27-fold, P less than 0.05), whereas the AZQ19 line was sensitive. Drug accumulation experiments indicated that AZQ-resistant cells differed from the parental line in that they did not accumulate Adriamycin or vinblastine. In the case of AZQ, however, resistant and parental lines accumulated the same amounts of exchangeable AZQ. Using the immunoblotting technique, no P-glycoprotein was found in resistant cells. The resistant lines consumed oxygen at greater rates than the parental line. Oxygen consumption (Mean +/- SD) in sensitive cells was 2.0 +/- 0.4% O2 consumed/min, whereas in resistant cells it was nearly 3.1 +/- 0.6% O2 consumed/min. The increase in oxygen consumption with drug resistance was statistically significant (P less than 0.01). The kinetics of production of hydroxyl free radicals and of AZQ free radicals were faster in the resistant lines reflecting, in essence, their increased oxygen consumption. It appears that the two sublines analyzed here show resistance mechanisms that may have been elicited by the two distinct chemical constituents of AZQ. Therefore, in the AZQ19-resistant line, the alkylating aspect of AZQ was emphasized, whereas in the AZQ30 line, the quinone and, thus, free radical aspect was emphasized. This is consistent with AZQ30 cells being sensitive to the alkylator thio-TEPA and resistant to hydrogen peroxide, and the AZQ19 line being resistant to thio-TEPA and sensitive to hydrogen peroxide. In addition, the AZQ30 cell line was relatively more resistant than the AZQ19 line to Adriamycin.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antineoplastic Agents; Aziridines; Benzoquinones; Biological Transport; Doxorubicin; Drug Resistance; Free Radicals; Genetic Variation; Kinetics; Leukemia P388; Membrane Glycoproteins; Mice; Neoplasm Proteins; Tumor Cells, Cultured; Vinblastine
PubMed: 2576972
DOI: No ID Found -
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 -
Cancer Treatment Reports Mar 1986Diaziquone (AZQ) is a lypophilic alkylating agent that crosses the blood-brain barrier and has shown broad activity in animal tumor models. Five of 12 patients with...
Diaziquone (AZQ) is a lypophilic alkylating agent that crosses the blood-brain barrier and has shown broad activity in animal tumor models. Five of 12 patients with malignant astrocytoma treated with iv AZQ had clinical and/or radiographic improvement (Schold, Neurology 34:615, 1984). Intra-arterial administration of AZQ to patients with brain tumors should produce higher peak levels of drug in the tumor and should reduce systemic toxicity. Twenty-one patients with astrocytoma (grade II, four; grade III, 11; and grade IV, six), in all of whom irradiation and intra-arterial carmustine chemotherapy failed, received intra-arterial AZQ as a single dose every 28 days. Two of 20 evaluable patients experienced partial responses of 5 and 8+ months, respectively. Four patients had disease stabilization of 3, 4, 5, and 8 months' duration, respectively, and one of these patients had tumor shrinkage (partial response) after seven courses of AZQ. The initial dose in the first three patients was 10 mg/m2, and doses in subsequent groups of three patients were begun at increases of 5 mg/m2. The within-group dose escalation was 5 mg/m2 per course if there was no hematologic toxicity. Dose-limiting toxicity was myelosuppression, which occurred at doses greater than 15 mg/m2. The maximum tolerated dose was 25 mg/m2. Intra-arterial AZQ appears to be of marginal effectiveness in patients refractory to carmustine and offers no advantage over iv AZQ in efficacy or toxicity.
Topics: Adult; Aged; Antineoplastic Agents; Astrocytoma; Aziridines; Azirines; Benzoquinones; Bone Marrow; Brain Neoplasms; Carmustine; Drug Evaluation; Eye; Female; Glioblastoma; Humans; Infusions, Intra-Arterial; Male; Middle Aged; Neoplasm Recurrence, Local
PubMed: 3006913
DOI: No ID Found -
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 -
Ophthalmic Paediatrics and Genetics Jun 1989The benefits and optimal applications of chemotherapy in the management of retinoblastoma remain to be defined. There are major obstacles to its further study in the... (Comparative Study)
Comparative Study
The benefits and optimal applications of chemotherapy in the management of retinoblastoma remain to be defined. There are major obstacles to its further study in the clinical setting. A xenograft model of human retinoblastoma heterotransplanted directly into the anterior chamber of the nude mouse eye has been adapted for evaluation of therapeutic efficacy. Cyclophosphamide, the most effective conventional drug, and diaziquone, an experimental agent, both produced documented and comparable responses in each of four xenograft cell lines. There was no evidence of rapidly emerging drug resistance or cross-resistance between two agents when sequential chemotherapy courses were given. Diaziquone is an effective chemotherapeutic agent for retinoblastoma in the xenograft model, and may have applications in clinical management.
Topics: Animals; Anterior Chamber; Aziridines; Azirines; Benzoquinones; Cyclophosphamide; Disease Models, Animal; Eye Neoplasms; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Retinoblastoma; Transplantation, Heterologous
PubMed: 2779985
DOI: 10.3109/13816818909088349 -
Cancer Research Mar 1985We investigated the in vitro interaction with and antitumor effect on several murine and human leukemic cell lines of diaziquone (AZQ). L1210 cells accumulated AZQ from...
We investigated the in vitro interaction with and antitumor effect on several murine and human leukemic cell lines of diaziquone (AZQ). L1210 cells accumulated AZQ from Roswell Park Memorial Institute Medium 1640 with or without newborn calf serum by a temperature-dependent and sodium azide-resistant process. AZQ inhibited, in a dose-dependent fashion, [3H]thymidine incorporation into L1210 cells, but this inhibition was slow to develop, requiring approximately 6 hr to become apparent. The minimal inhibitory concentration of AZQ for this process was 0.05 to 0.25 nmol/ml. AZQ was a much less effective inhibitor of L1210 cell [3H]uridine and [14C]valine incorporation. In suspension cultures, AZQ inhibited growth of L1210 and HL-60 cells at minimal inhibitory concentrations of 0.5 to 1 nmol/ml. In soft agar cultures, AZQ inhibited HL-60 cell cloning at minimal inhibitory concentrations of 0.1 to 0.3 nmol/ml. AZQ provoked a dose-dependent increase in oxygen consumption when added to intact L1210, HL-60, and K562 cells and was converted to an AZQ anion free radical by these cells. When the aziridine rings of AZQ were opened by acid treatment, the resulting molecule was not accumulated by L1210 cells, did not provoke O2 consumption, did not form free radicals when added to L1210 cells, and was a much less effective inhibitor of [3H]thymidine incorporation by L1210 cells than was AZQ.
Topics: Animals; Antineoplastic Agents; Aziridines; Azirines; Benzoquinones; Carbon Radioisotopes; Cell Division; Cell Line; Free Radicals; Humans; Leukemia; Mice; Oxygen Consumption; Thymidine; Uridine
PubMed: 3971389
DOI: No ID Found -
Cancer Treatment Reports Sep 1985
Clinical Trial Randomized Controlled Trial
Topics: Aclarubicin; Aged; Anaphylaxis; Anthraquinones; Antineoplastic Combined Chemotherapy Protocols; Aziridines; Benzoquinones; Drug Evaluation; Female; Hematologic Diseases; Humans; Infusions, Parenteral; Lung Neoplasms; Male; Middle Aged; Mitoxantrone; Naphthacenes
PubMed: 3861248
DOI: No ID Found -
Molecular Pharmacology Nov 1984The one-electron electrochemical reduction of diaziquone was analyzed using electron spin resonance and compared to its enzymatic reduction. Two analogues were used to... (Comparative Study)
Comparative Study
Free radicals in quinone-containing antitumor agents. Electrochemical reduction of diaziquone (2,5-diaziridine-3,6-bis(carboethoxyamino)-1,4 -benzoquinone) and two analogues.
The one-electron electrochemical reduction of diaziquone was analyzed using electron spin resonance and compared to its enzymatic reduction. Two analogues were used to help the analysis. The analogues contained chlorine atoms which substituted either the carboethoxyamino groups or the aziridine groups of the parent compound. The diaziquone free radical produced electrochemically in dimethyl sulfoxide exhibited an 11-line electron spin resonance spectrum. The hyperfine couplings responsible for this spectrum were due to the aziridine nitrogens (aNAz), and the imide hydrogens (aHNHR) and nitrogens (aNNHR) of the carboethoxyamino groups. The couplings had the following order of strength: (aNAz) greater than (aHNHR) greater than (aNNHR). The nuclei responsible for the (aNAz) and (aHNHR) coupling were found to be magnetically inequivalent. Adding water to the dimethyl sulfoxide solution of electrochemically reduced diaziquone changed its 11-line ESR spectrum to a 5-line spectrum identical to the one observed for enzymatically reduced diaziquone. Hence, the identity of this latter free radical was resolved. Electrochemically reduced free radicals of antitumor agents can be used to understand biologically reduced ones and thus explore drug activity-free radical structure relationships.
Topics: Animals; Antineoplastic Agents; Aziridines; Azirines; Benzoquinones; Dimethyl Sulfoxide; Electrochemistry; Electron Spin Resonance Spectroscopy; Free Radicals; Microsomes, Liver; NADPH-Ferrihemoprotein Reductase; Oxidation-Reduction; Quinones; Structure-Activity Relationship
PubMed: 6092903
DOI: No ID Found