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Investigational New Drugs 1983Diaziquone is an aziridinylbenzoquinone with properties suggestive of an alkylating agent. The drug has shown broad antitumor activity against numerous transplantable... (Review)
Review
Diaziquone is an aziridinylbenzoquinone with properties suggestive of an alkylating agent. The drug has shown broad antitumor activity against numerous transplantable murine tumors including curative activity against several intracerebrally implanted tumors. Parent diaziquone appears to have a t1/2 beta of approximately 30 min. The drug is rapidly and widely distributed to tissues as evidenced by a t1/2 alpha of approximately 1-3 min and a volume of distribution exceeding that of total body water. In addition, it rapidly penetrates the central nervous system, reaching peak concentrations (30-50%) of corresponding plasma levels) in approximately one hour. Diaziquone is rapidly and extensively metabolized by the liver. Diaziquone is a potent marrow suppressive agent inducing significant degrees of leukopenia, granulocytopenia, and thrombocytopenia in humans. Thrombocytopenia is often severe. Although myelosuppression is for the most part dose related, many patients had significant toxicity even at lower doses. Most investigators have attributed this to the extent of prior therapy. Diaziquone demonstrates a very steep dose-response relationship. Myelosuppression was the dose-limiting toxicity in all phase I trials. No nonhematologic dose-limiting toxicity has been identified to date. In phase I and preliminary phase II trials, diaziquone has demonstrated activity against primary brain tumors. Little activity has been seen in other tumor categories. It should be noted, however, that all studies to date have been carried out in heavily pretreated patients. Because of the broad spectrum of antitumor activity in experimental murine tumors, the lack of nonhematologic dose-limiting toxicity, the ability of this drug to attain significant levels in the central nervous system, and the activity of the drug in primary brain tumors, further studies examining its role in the management of patients with cancer are warranted. These studies should be conducted in patients who have had little or no prior therapy in order to better evaluate the efficacy of the drug.
Topics: Animals; Aziridines; Azirines; Benzoquinones; Dogs; Drug Evaluation; Drug Evaluation, Preclinical; Female; Humans; Kinetics; Macaca mulatta; Male; Mice; Neoplasms
PubMed: 6381377
DOI: 10.1007/BF00180194 -
Seminars in Oncology Aug 1993Preparative regimens used prior to bone marrow transplantation (BMT) in patients with malignancies must mediate engraftment and eradicate malignant cells without... (Review)
Review
Preparative regimens used prior to bone marrow transplantation (BMT) in patients with malignancies must mediate engraftment and eradicate malignant cells without producing significant extramedullary toxicities. The first agents to be tested in BMT preparative regimens, total body irradiation (TBI) and cyclophosphamide (Cy), were ineffective as single agents, but resulted in long-term disease-free survival in some leukemic patients when combined. However, Cy/TBI regimens are associated with significant acute and chronic toxicities as well as technical constraints involving the administration of radiation. Accordingly, a nonradiation-based regimen consisting of Cy and busulfan (Bu) was developed. Regimens using either a 4-day course (BuCy4) or a 2-day course (BuCy2) of Cy have been shown to have significant antileukemic effects. In general, however, BuCy regimens do not appear to result in greater antileukemic activity or lower treatment-related toxicity than Cy/TBI regimens. New preparative regimens are currently being developed to lower the incidence of disease recurrence after BMT. One such regimen consists of BuCy plus etoposide. At our institution, we are currently testing the efficacy and toxicity of regimens in which cytarabine or diaziquone are administered in combination with Bu and Cy. It is hoped that these new preparative regimens will enhance the antileukemic effects of BMT without significantly increasing treatment-related toxicity.
Topics: Antineoplastic Combined Chemotherapy Protocols; Aziridines; Benzoquinones; Bone Marrow Transplantation; Busulfan; Cyclophosphamide; Cytarabine; Drug Monitoring; Humans; Premedication; Whole-Body Irradiation
PubMed: 8342077
DOI: No ID Found -
Drug Metabolism Reviews 1988Diaziquone (AZQ) is a quinone-containing alkylating agent undergoing trials as an antitumor drug. The quinone moiety of this compound places it among a group of... (Review)
Review
Diaziquone (AZQ) is a quinone-containing alkylating agent undergoing trials as an antitumor drug. The quinone moiety of this compound places it among a group of compounds whose activity is believed to be modulated by a redox cycle that activates the compounds to their free radicals (e.g., adriamycin). AZQ is unique among these compounds in that it can be reduced to its free radical (AZQH) by a variety of cells in culture, including human and murine cancer cells. Red blood cells (RBC) were also observed to reduce AZQ to its free radical. Using electron spin resonance (ESR), we observed that soon after the AZQ free radical appeared, it decayed and was replaced by a doublet with ESR parameters that suggested the presence of the ascorbyl radical (AH). The identity of AH was confirmed by adding exogenous ascorbic acid to AZQ free radicals generated by a suspension of L1210 murine leukemia cells. The endogenous ascorbic acid was shown to arise mostly from the "buffy coat" of an RBC preparation which contained leukocytes. Leukocytes are second only to the adrenals in level of ascorbic acid in humans. Cyclic voltammetry of ascorbic acid, AZQ, and adriamycin in Hank's Balanced Salt Solution (HBSS pH 7.5), the buffer used for biological measurements, showed that the oxidation peak potential for ascorbic acid (Eap = +0.43 V) is closer to the reduction peak potential for AZQ (Ecp = -0.36 V) than that for adriamycin (Ecp = -0.67 V). This may explain why the ascorbic acid redox system interacts with that of AZQ but not with that of ADR.
Topics: Animals; Ascorbic Acid; Aziridines; Azirines; Benzoquinones; Free Radicals; Humans; Mice; Xenobiotics
PubMed: 3068033
DOI: 10.3109/03602538808994139 -
Blood Jan 1986Diaziquone given as a bolus has not been effective in patients with relapsed or refractory leukemia. Because of in vitro data suggesting enhancement of...
Diaziquone given as a bolus has not been effective in patients with relapsed or refractory leukemia. Because of in vitro data suggesting enhancement of diaziquone-induced cytotoxicity for human and murine leukemia cells with increased duration of drug exposure and the relatively short terminal plasma half-life of diaziquone, 49 patients (34 acute nonlymphocytic leukemia [ANLL], six chronic myelogenous leukemia in blast crisis [CML-B], five acute lymphocytic leukemia [ALL], four 2 degrees ANLL) with leukemia were given diaziquone as a continuous infusion for seven days. The maximum tolerated dose was 28 mg/m2/d for seven days. The dose-limiting toxicity was the duration of bone marrow aplasia (median, 49 days to greater than 500 PMNs in responders; range, 28 to 101 days). Nonhematologic toxicity was minimal. Responses occurred only in patients with relapsed ANLL, of whom 26 were treated at effective doses. There were six complete responses (CR) (23%) and two partial responses (PR) (8%), although five of eight responders never achieved platelet counts greater than 100,000/microL. Thrombocytopenia in these patients was felt to be a manifestation of diaziquone effect, not persistence of leukemia. The median duration of CR was 195 days (range, 88 to 860+). One patient had active CNS leukemia at the start of treatment and has had a durable (28+ month) CR in both sites of disease. Diaziquone produced prolonged aplasia in patients with secondary ANLL and CML-B (five of ten patients died aplastic), whereas patients with ALL all had regrowth of leukemia and two failed to become aplastic. The lack of significant nonhematologic toxicity and the activity in patients with relapsed ANLL render diaziquone of interest as second-line therapy or consolidation therapy in first remission for patients with ANLL.
Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Agents; Aziridines; Azirines; Benzoquinones; Female; Humans; Kinetics; Leukemia; Male; Middle Aged; Platelet Count; Recurrence
PubMed: 3940546
DOI: No ID Found -
Free Radical Biology & Medicine 1989Bioreduction in the activation of diaziquone (2,5-diaziridinyl-3,6-bis (carboethoxyamino)-1,4-benzoquinone) has been investigated by exploring its reduction by whole... (Review)
Review
Bioreduction in the activation of diaziquone (2,5-diaziridinyl-3,6-bis (carboethoxyamino)-1,4-benzoquinone) has been investigated by exploring its reduction by whole cells, rat liver microsomes and purified enzymes. The mechanism of bioreduction was further investigated by exploring the chemical and electrochemical reduction of diaziquone as well as its photochemistry. Reduced diaziquone (by several means) was then tested for activity against parent compound. It appears that reduced diaziquone in most cases is more active than the oxidized form. Diaziquone redox cycles, but it is easily reduced to the hydroquinone which oxidizes to the semiquinone yielding free radicals under aerobiosis. The most probable mechanism of action is that of bioreductive alkylation where the alkylating aziridines are protonated after reduction facilitating the opening of the aziridine rings and thus alkylation.
Topics: Animals; Antineoplastic Agents; Aziridines; Azirines; Benzoquinones; Biotransformation; Free Radicals; Humans; Microsomes, Liver; Oxidation-Reduction
PubMed: 2651223
DOI: 10.1016/0891-5849(89)90087-7 -
Blood Jun 1987The promising antineoplastic agent diaziquone is associated with prolonged aplasia and rare instances of bone marrow necrosis, but only mild extramedullary toxicity. To...
UNLABELLED
The promising antineoplastic agent diaziquone is associated with prolonged aplasia and rare instances of bone marrow necrosis, but only mild extramedullary toxicity. To explore the drug's potential as a myeloablative agent prior to bone marrow transplantation, we compared its effects on hematopoietic versus marrow stromal cells. After short-term (one to six hours) or prolonged (three to seven days) exposure to the drug, marrow was assayed for hematopoietic (CFU-Mix, BFU-E, CFU-GM) and stromal (CFU-F) colony-forming cells and studied in long-term marrow culture (LTMC). One- and three-hour treatments produced little cytotoxicity, even at 5000 ng/mL. After six-hour treatments with this dose, marrow was depleted of CFU-Mix, BFU-E, and CFU-GM, but produced CFU-GM in LTMCs, indicating an ongoing input of CFU-GM from a surviving pre-CFU-Mix population. In contrast, elimination of the latter may be inferred from the absence of CFU-GM in LTMCs exposed for three to seven days to diaziquone at only 150 ng/mL. Under these conditions, CFU-F recovery was 40% and adherent stromal layers in LTMCs were similar to untreated controls regarding rate of development and cellular composition. Our in vitro pre-CFU-Mix-ablative regimen correlates with clinical data that show prolonged but reversible myelosuppression at steady-state diaziquone plasma levels of 101 +/- 10 ng/mL (mean +/- standard error of mean) during 7-day constant infusions.
IN CONCLUSION
hematopoietic cells are more sensitive than marrow stromal cells to the dose- and highly time-dependent cytotoxicity of diaziquone, a direct drug-induced noxious effect on the marrow microenvironment is an unlikely cause of the isolated episodes of marrow necrosis after the use of diaziquone in vivo, and prolonged infusion of diaziquone represents an attractive means for achieving myeloablation in selected clinical situations.
Topics: Aziridines; Azirines; Benzoquinones; Bone Marrow Cells; Bone Marrow Transplantation; Cells, Cultured; Humans; Stem Cells; Time Factors
PubMed: 3555652
DOI: No ID Found -
Cancer Research Nov 1985A model for metastatic skin cancer using intradermal injection of Walker 256 carcinosarcoma has been developed in the rat. Using this model, antitumor activity of...
A model for metastatic skin cancer using intradermal injection of Walker 256 carcinosarcoma has been developed in the rat. Using this model, antitumor activity of topically applied doxorubicin and diaziquone in Vanicream, Plastibase, and dimethyl sulfoxide (DMSO) as vehicles was compared with intraperitoneal injection of the drugs at the same doses beginning 4 days after injection of tumor cells. Doxorubicin applied topically at 0.5 mg/day for 4 days in Vanicream or Plastibase exhibited no antitumor activity, while i.p. administered doxorubicin at 0.5 mg/day for 4 days inhibited tumor growth at day 20 by 66%. Diaziquone applied topically at 0.1 mg/day for 4 days in Vanicream, Plastibase, or DMSO inhibited tumor growth at day 20 by 66, 86, and 43%, respectively, and cured animals of the skin tumor at a dose of 0.5 mg/day. Diaziquone administered i.p. at 0.5 mg/day for 4 days was lethal to rats, and at 0.1 mg/day it produced 93% inhibition of tumor growth at day 20. Diaziquone applied topically at 0.1 mg/day for 4 days in Plastibase cured rats of advanced tumor when treatment was begun 12 days after injection of tumor cells. The area under the plasma radioactivity time curve over 5 h for a single 0.64-mg dose of topically applied [ring-14C]diaziquone in DMSO was 0.01% that of the same dose of [ring-14C]diaziquone administered i.p. in non-tumored rats. The decrease in WBC count following topical application of diaziquone at a dose of 0.1 mg/day for 4 days, compared to the same dose of diaziquone administered i.p., was 62% in Vanicream, 81% in Plastibase and 33% in DMSO. Topical diaziquone was non-toxic to normal skin in the rat and in the domestic pig. It is concluded that topical application of diaziquone offers a therapeutic advantage over systemic treatment for metastatic cancer of the skin.
Topics: Absorption; Administration, Topical; Animals; Antineoplastic Agents; Aziridines; Azirines; Benzoquinones; Carcinoma 256, Walker; Doxorubicin; Female; Rats; Rats, Inbred Strains; Skin; Skin Neoplasms
PubMed: 4053022
DOI: No ID Found -
Seminars in Oncology Oct 1992All cancer chemotherapeutic agents, except altretamine, the nitrosoureas, and dactinomycin, have produced at least an isolated instance of a HSR. Certain drugs, such as... (Review)
Review
All cancer chemotherapeutic agents, except altretamine, the nitrosoureas, and dactinomycin, have produced at least an isolated instance of a HSR. Certain drugs, such as L-asparaginase and mitomycin (administered intravesically), cause HSRs of significant degree in approximately 10% of patients. All four types of HSRs are represented in the reactions produced by antitumor drugs, although Type I is the most common. Some of the Type I reactions are IgE-mediated, and others are probably mediated by nonspecific release of vasoactive substances from targets such as mast cells. It is possible to continue therapy with some drugs, despite a prior HSR, if the prophylactic measures outlined in Table 2 are taken. An example of this is provided by taxol in which the lengthening of the infusion time and the administration of preventive medication allowed some patients to continue taxol therapy. The mechanisms of the HSRs have been carefully assessed in only a minority of patients who sustained such toxicity. Such evaluation would increase our understanding of this form of drug toxicity and perhaps lead to means of effectively reducing the risk and severity.
Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Asparaginase; Aziridines; Benzoquinones; Bleomycin; Chlorambucil; Cisplatin; Cyclophosphamide; Cytarabine; Dacarbazine; Drug Hypersensitivity; Etoposide; Fluorouracil; Humans; Ifosfamide; Melphalan; Methotrexate; Mitomycins; Neoplasms; Paclitaxel; Pentostatin; Procarbazine; Teniposide
PubMed: 1384149
DOI: No ID Found -
Clinical Pharmacology and Therapeutics May 1982Plasma and cerebrospinal fluid (CSF) kinetics of diaziquone, 2,5-diaziridinyl-3,6-biscarboethoxyamino-1,4-benzoquinone (AZQ), were evaluated after intravenous injection...
Plasma and cerebrospinal fluid (CSF) kinetics of diaziquone, 2,5-diaziridinyl-3,6-biscarboethoxyamino-1,4-benzoquinone (AZQ), were evaluated after intravenous injection in patients with implanted Ommaya reservoirs. After a 30-min infusion plasma disappearance was very rapid, with a disposition half-life of 2 to 6 min and on elimination half-life of 25 to 35 min. Area under the concentration-time curve for CSF was 22% to 42% of the corresponding plasma area. Based upon total plasma AZQ concentration, volume of distribution for AZQ was 2.0 to 10.0 l/m2. Plasma binding of AZQ was 79% in one normal subject. When the effect of plasma binding is considered, distribution volumes are more plausible and it appears that free plasma AZQ is completely available to the CSF.
Topics: Adult; Antineoplastic Agents; Aziridines; Azirines; Benzoquinones; Female; Humans; Kinetics; Male; Protein Binding
PubMed: 7075113
DOI: 10.1038/clpt.1982.90 -
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