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Cancer Treatment Reports May 1986
Topics: Aged; Antineoplastic Agents; Aziridines; Azirines; Benzoquinones; Carcinoma, Squamous Cell; Drug Evaluation; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Risk
PubMed: 3708616
DOI: No ID Found -
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 -
Journal of Clinical Oncology : Official... Aug 1991Diaziquone (AZQ), a synthetic quinone with demonstrated activity against acute nonlymphocytic leukemia (ANLL), primary CNS tumors, and non-Hodgkin's lymphoma (NHL), is... (Clinical Trial)
Clinical Trial
Diaziquone (AZQ), a synthetic quinone with demonstrated activity against acute nonlymphocytic leukemia (ANLL), primary CNS tumors, and non-Hodgkin's lymphoma (NHL), is virtually devoid of nonhematopoietic toxicity at conventional doses. As a prelude to its inclusion into bone marrow transplant (BMT) preparative regimens, a phase I study of high-dose AZQ with autologous BMT (ABMT) was performed. Patients with refractory solid tumors and lymphomas were treated with a single 24-hour infusion of AZQ at 50 to 355 mg/m2 in dose escalations of 20%. Fifty-six patients received 69 courses. Those receiving greater than 60 mg/m2 had nadir granulocyte and platelet counts less than 500/microL and 20,000/microL, respectively. Nausea, vomiting, stomatitis, and diarrhea were mild, transient, and not dose-related. Transient minimal elevations of liver function tests were seen in five patients and were also not dose-related. The maximally tolerated dose (MTD) of high-dose AZQ was found to be 245 mg/m2, with nephrotoxicity being dose-limiting. Significant azotemia was seen in four of 12 patients treated at 295 and 355 mg/m2, including fatal anuric renal failure in three of these patients. Reversible proteinuria also occurred in 24 of 26 courses above 150 mg/m2, including nephrotic range proteinuria in eight courses, all at doses of 205 to 355 mg/m2. The proteinuria was also associated with multiple proximal tubular defects including generalized aminoaciduria and proximal renal tubular acidosis. There were six early deaths including two of early renal failure (295 and 355 mg/m2), two of sepsis (205 and 245 mg/m2), one of a pulmonary embolus (85 mg/m2), and one of progressive disease (60 mg/m2). Of 50 patients who were assessable for response, there were seven responses including two of 10 with primary CNS tumors, one of 12 with malignant melanoma, one of five with non-small-cell lung carcinoma, two of two with breast carcinoma, and one of one with ovarian carcinoma. Because of its activity in ANLL and NHL and its unique toxicity spectrum, high-dose AZQ may improve the efficacy of current BMT preparative regimens without significantly increasing their nonhematopoietic toxicity.
Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Aziridines; Benzoquinones; Bone Marrow Transplantation; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Evaluation; Female; Humans; Infusions, Intravenous; Kidney Diseases; Leukocyte Count; Male; Middle Aged; Neoplasms; Platelet Count
PubMed: 2072148
DOI: 10.1200/JCO.1991.9.8.1487 -
Cancer Treatment Reports Mar 1985
Clinical Trial
Topics: Adult; Aged; Aziridines; Azirines; Benzoquinones; Clinical Trials as Topic; Female; Humans; Male; Middle Aged; Multiple Myeloma; Pilot Projects; Thrombocytopenia
PubMed: 3884154
DOI: No ID Found -
Xenobiotica; the Fate of Foreign... May 19881. The influence of the free radical of diaziquone on inhibition of cell growth in vitro was studied using P388 murine leukaemia cells and a mixture of AZQH2 + AZQ. This...
1. The influence of the free radical of diaziquone on inhibition of cell growth in vitro was studied using P388 murine leukaemia cells and a mixture of AZQH2 + AZQ. This mixture generates the AZQ free radical by the disproportionation-comproportionation reaction AZQH2 + AZQ in equilibrium with 2AZQH. 2. Reduced AZQ (AZQH2) was produced electrochemically under anaerobic conditions. This colourless solution was added anaerobically to a solution of AZQ at a 9:1 ratio of AZQH2 to AZQ. The free radical (AZQH) generated was detected by electron spin resonance (ESR) and amounted to about 7% of the concn of AZQH2 + AZQ. The AZQ free radical was stable enough to treat cells in culture. 3. Aerobic suspensions of P388 murine leukaemia cells treated with AZQH experienced a surge of free radicals lasting approx. 30 min at concn near 10 times that of the AZQ free radicals generated by P388 cells. 4. Cell growth inhibition indicates that the concentration of AZQ required to arrest the growth of P388 cells by 50% (IC50) is twice that of the AZQ free radical generating mixture. The mechanism of action of AZQ probably does not exclusively involve AZQ free radicals, but they appear to play an important role.
Topics: Animals; Antineoplastic Agents; Aziridines; Azirines; Benzoquinones; Electron Spin Resonance Spectroscopy; Free Radicals; Growth Inhibitors; Mice; Oxidation-Reduction; Tumor Cells, Cultured
PubMed: 2840783
DOI: 10.3109/00498258809041696 -
Mutation Research May 1987A mouse peripheral blood lymphocyte (PBL) micronucleus (MN) test was developed using a modification of the technique for assessing MN in human PBLs described by Fenech...
A mouse peripheral blood lymphocyte (PBL) micronucleus (MN) test was developed using a modification of the technique for assessing MN in human PBLs described by Fenech and Morley (1985). Male C57Bl/6 mice (5/dose) were injected i.p. with either 0, 2.5, 5.0, 7.5, or 10.0 mg diaziquone (AZQ)/kg. After 24 h the mice were bled by cardiac puncture, PBLs were isolated on a Ficoll-density gradient and then cultured in RPMI 1640 medium using 8 micrograms phytohemagglutinin/ml. In some cultures cytochalasin B (CYB) was added at 21 h during the medium change to block cytokinesis. In other cultures, CYB was omitted to compare the sensitivity of analyzing MN in binucleate versus unblocked mononucleate cells. All doses of AZQ yielded significant increases in MN-containing binucleated PBLs. The use of CYB in the mouse PBL MN test increased the sensitivity approximately 3-fold. The MN test in mouse PBLs should be useful in comparative cytogenetic studies of mice and humans.
Topics: Animals; Aziridines; Azirines; Benzoquinones; Cell Cycle; Cell Nucleus; Chromosome Aberrations; Cytochalasin B; Dose-Response Relationship, Drug; Leukocyte Count; Lymphocytes; Male; Mice; Mutagenicity Tests
PubMed: 3574322
DOI: 10.1016/0027-5107(87)90093-5 -
Frontiers in Bioscience : a Journal and... Nov 2000Aziridinyl quinones can be activated by cellular reductases eg. DT-diaphorase and cytochrome P450 reductase to form highly reactive DNA alkylating agents. The mechanisms... (Review)
Review
Aziridinyl quinones can be activated by cellular reductases eg. DT-diaphorase and cytochrome P450 reductase to form highly reactive DNA alkylating agents. The mechanisms by which this activation and alkylation take place are many and varied. Using clinically relevant and experimental agents this review will describe many of these mechanisms. The agents discussed are Mitomycin C, EO9 and analogues, diaziridinylbenzoquinones and the pyrrolo[1, 2-alpha]benzimidazolequinones.
Topics: Alkylation; Antineoplastic Agents, Alkylating; Aziridines; Benzimidazoles; Benzoquinones; Carbazilquinone; DNA; Doxorubicin; Humans; Indolequinones; Indoles; Mitomycin; Molecular Structure; Oxidation-Reduction; Quinones; Structure-Activity Relationship
PubMed: 11056081
DOI: 10.2741/hargreav -
Biochemical Pharmacology Oct 1992The alkylating activity of reduced diaziquone was studied by the nitrobenzylpyridine (NBP) assay and was compared to those of the parent compound and... (Comparative Study)
Comparative Study
Reductive metabolism of diaziquone (AZQ) in the S9 fraction of MCF-7 cells. II. Enhancement of the alkylating activity of AZQ by NAD(P)H: quinone-acceptor oxidoreductase (DT-diaphorase).
The alkylating activity of reduced diaziquone was studied by the nitrobenzylpyridine (NBP) assay and was compared to those of the parent compound and aziridine-containing N,N',N"-triethylenethiophosphoramide (Thio-TEPA). Diaziquone (AZQ) was reduced enzymatically by 2e- using S9 cell fraction from MCF-7 cells which is rich in NAA(P)H:quinone-acceptor oxidoreductase (DT-diaphorase) (QAO) activity. One electron enzymatic reduction was performed with NADPH-cytochrome c reductase. The alkylating activity of AZQ increased 3-fold when reduced by 2e-. This increase was inhibited by dicumarol, an inhibitor of QAO. In contrast, the alkylating activity of AZQ did not increase beyond that of the parent compound when reduced by 1e- using purified NADPH-cytochrome c reductase. Similar results were obtained when AZQ was reduced chemically with borohydride (2e-) and with NADPH (1e-). Anaerobic incubations of AZQ with the S9 fraction of MCF-7 cells (2e- reduction) resulted in an increase in NBP alkylation over its aerobic counterpart (1.8-fold) while maintaining the near 3-fold increase in alkylation over untreated AZQ. In contrast, AZQ incubations with NADPH-cytochrome c reductase (1e- reduction) under the same conditions did not result in an NBP alkylation increase over untreated AZQ. These results indicate that AZQ hydroquinone is most likely the responsible species for the observed alkylation of this antitumor agent to DNA and other nucleophiles. The results also suggest that NAD(P)H:quinone-acceptor oxidoreductase is a very important enzyme in the bioactivation of AZQ.
Topics: Alkylation; Animals; Aziridines; Benzoquinones; Biotransformation; Cell Line; Cyclic N-Oxides; Humans; Liver; NADH Dehydrogenase; NADP; Oxidation-Reduction; Tumor Cells, Cultured
PubMed: 1301071
DOI: 10.1016/0006-2952(92)90481-w -
Investigational New Drugs 1995Diaziquone (AZQ) is a lipid soluble alkylating agent which was designed for increased CNS penetration. Its principle toxicity is myelosuppression. We conducted a phase I... (Clinical Trial)
Clinical Trial
Diaziquone (AZQ) is a lipid soluble alkylating agent which was designed for increased CNS penetration. Its principle toxicity is myelosuppression. We conducted a phase I trial using AZQ in combination with GM-CSF to determine if the maximal tolerate dose (MTD) of AZQ could be escalated. Using GM-CSF on a standard schedule, we were unable to escalate the previously determined MTD of diaziquone with the use of this colony stimulating factor.
Topics: Antineoplastic Agents; Aziridines; Benzoquinones; Blood Platelets; Bone Marrow; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Therapy, Combination; Drugs, Investigational; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Infusions, Intravenous; Injections, Subcutaneous; Melanoma; Neutrophils
PubMed: 8617583
DOI: 10.1007/BF00872869 -
Chemical Research in Toxicology Apr 1998The biologic functions attributed to the nucleophosphoprotein p53 have been increasing in recent years. Some studies suggested that wild type p53 is responsible for cell... (Comparative Study)
Comparative Study
The biologic functions attributed to the nucleophosphoprotein p53 have been increasing in recent years. Some studies suggested that wild type p53 is responsible for cell cycle arrest brought about as a response to exposure of mammalian cells to DNA-damaging agents. This cell cycle arrest occurs in order for cells to repair the damaged macromolecules. Extensively damaged cells are also thought to undergo apoptosis via the p53-dependent or -independent signal transduction pathways. In this study, we investigated the ability of diaziridinylbenzoquinones to increase p53 levels in the human breast cancer cell line MCF-7. Diaziquone (AZQ), an anticancer agent, and its derivatives, diaziridinequinone (DZQ) and methyldiaziridinequinone (MeDZQ), induced p53 in a dose- and time-dependent manner as measured by the electrophoretic mobility shift assay. Wild type p53 induction by AZQ was suppressed when DT-diaphorase activity was inhibited by pretreating the cells with dicumarol. Aside from their potent alkylating activity, these agents also undergo redox cycling as evidenced by oxygen consumption and the production of reactive oxygen species (ROS). Inhibition of ROS production by the antioxidant enzyme catalase reduced AZQ- and DZQ-mediated p53 induction by about 45%. Thiotepa, a non-quinone aziridine-containing agent, and 1,4-benzoquinone (p-BQ), a redox cycling quinone, increased p53 levels. The nonalkylator oxygen-radical-generating agent menadione (MD) caused p53 induction only when MCF-7 cells were allowed to recover in drug-free media. On the basis of these data, we propose that the bioreductive activation of AZQ is a prerequisite for p53 induction. Moreover, the induction of p53 by AZQ requires both the quinone and the aziridine moieties of the AZQ molecule. Although AZQ and its analogues increased p53 levels in MCF-7 cells, p53 induction in these cells may not be responsible for the apoptosis seen upon treatment of MCF-7 cells with these agents. The uncoupling of p53 induction and apoptosis is evidenced by the generation of nucleosomal DNA laddering in aziridinequinone-treated T47D cells, a breast cancer cell line bearing a p53 mutation.
Topics: Adenocarcinoma; Antineoplastic Agents; Aziridines; Benzoquinones; Breast Neoplasms; Humans; Tumor Cells, Cultured; Tumor Suppressor Protein p53
PubMed: 9548807
DOI: 10.1021/tx9701945