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Annals of Neurology Apr 1988Eight consecutive patients with recurrent malignant oligodendroglioma were treated with systemic chemotherapy. Six patients received a combination of procarbazine,...
Eight consecutive patients with recurrent malignant oligodendroglioma were treated with systemic chemotherapy. Six patients received a combination of procarbazine, lomustine (CCNU), and vincristine; 1 received carmustine (BCNU), and 1 diaziquone. All responded by clinical and computed tomographic scan criteria. One patient had a complete response for 78 weeks, and 7 patients had unequivocal partial responses lasting 30+ to 68+ weeks. Two partial responders had complete control of systemic metastases. Malignant oligodendroglioma is a uniquely chemosensitive glial tumor.
Topics: Adult; Antineoplastic Agents; Aziridines; Benzoquinones; Brain Neoplasms; Carmustine; Female; Humans; Lomustine; Male; Middle Aged; Oligodendroglioma; Procarbazine; Vincristine
PubMed: 3382171
DOI: 10.1002/ana.410230408 -
Free Radical Biology & Medicine Sep 2000Quantifying oxygen radicals that arise during the redox cycling of quinone-containing anticancer agents such as diaziquone (AZQ) has been difficult, as has been their...
Quantifying oxygen radicals that arise during the redox cycling of quinone-containing anticancer agents such as diaziquone (AZQ) has been difficult, as has been their detection at low drug concentrations. This is due to the fact that EPR spin trapping, the method most often used for *OH detection, requires the use of high drug concentrations. Using a new highly sensitive technique that employs a fluorescamine-derivatized nitroxide, we show that low levels of NADPH-cytochrome P450 reductase (4.25 microg/ml) catalyze the production of hydroxyl radicals at very low, clinically relevant AZQ concentrations. Thus, at this enzyme concentration, we were able to detect a rate of 0.10 nM s(-1) hydroxyl radical production by 5 microM AZQ, a clinically relevant concentration. The Michaelis-Menten constants for AZQ-mediated hydroxyl radical production are: K(M) = 10.7 +/- 1.4 microM, and V(max) = 5.2 +/- 0.9 x 10(-8) M s(-1) (mg protein)(-1). Experiments employing catalase, superoxide dismutase, and NADPH-cytochrome P450 reductase, confirm the previously deduced conclusions from high drug concentrations, that is, that at low concentrations, AZQ acts to shuttle reducing equivalents from the enzyme to oxygen, thus generating the redox cycle. The data presented here suggest that the levels and locations of redox active metal ions may be the principal controlling factor in the pathway of AZQ activity that involves oxidative stress.
Topics: Animals; Antineoplastic Agents; Aziridines; Benzoquinones; Chromatography, High Pressure Liquid; Dimethyl Sulfoxide; Electron Spin Resonance Spectroscopy; Free Radicals; Hydroxyl Radical; Iron; Kinetics; Liver; Molecular Structure; NADPH-Ferrihemoprotein Reductase; Oxidation-Reduction; Oxygen; Rats; Superoxide Dismutase
PubMed: 11025198
DOI: 10.1016/s0891-5849(00)00402-0 -
Cancer Research Nov 1986Exposure of leukemia L1210 cells in culture to the drug diaziquone resulted in inhibition of incorporation of labeled thymidine into nucleic acid and loss of cell...
Exposure of leukemia L1210 cells in culture to the drug diaziquone resulted in inhibition of incorporation of labeled thymidine into nucleic acid and loss of cell viability. These effects were markedly potentiated by irradiation of cells previously exposed to diaziquone in culture. This result shows that diaziquone can catalyze phototoxicity; the action spectrum of the drug may limit clinical applications of this phenomenon.
Topics: Animals; Aziridines; Azirines; Benzoquinones; Cell Cycle; Cell Survival; Cell-Free System; Dose-Response Relationship, Radiation; Leukemia L1210; Mice; Phototherapy; Spectrum Analysis
PubMed: 3756904
DOI: No ID Found -
Chemico-biological Interactions 1987Sodium borohydride reduced diaziquone (AZQ) can cause cross-links between DNA molecules, between DNA and proteins and cause single- and double-strand DNA breaks. In...
Sodium borohydride reduced diaziquone (AZQ) can cause cross-links between DNA molecules, between DNA and proteins and cause single- and double-strand DNA breaks. In order to understand these effects better, we investigated the reduction of diaziquone by borohydride, and looked at reaction products. We found that a major product was formed during the oxidation of the colorless 2-electron reduced AZQ, and that this product was a monoaziridinyl quinone. We interpret this result to mean that both the leaving aziridine as well as the remaining one can alkylate. This mode of alkylation does not explain cross-links which may occur by a different mechanism requiring simultaneous opening of the aziridine rings. Most of the antitumor activity of borohydride reduced AZQ is probably exerted during the oxidation of the 2-electron reduced AZQ (AZQH2).
Topics: Antineoplastic Agents; Aziridines; Azirines; Benzoquinones; Borohydrides; Chromatography, High Pressure Liquid; Electron Spin Resonance Spectroscopy; Free Radicals; Oxidation-Reduction; Spectrophotometry
PubMed: 2826025
DOI: 10.1016/0009-2797(87)90058-5 -
Investigational New Drugs May 1990We conducted a phase I clinical study of aziridinylbenzoquinone (Diaziquone, AZQ) given as a 4 hour infusion weekly X 4. Forty-five children with recurrent acute...
We conducted a phase I clinical study of aziridinylbenzoquinone (Diaziquone, AZQ) given as a 4 hour infusion weekly X 4. Forty-five children with recurrent acute leukemia and 33 children with various advanced solid tumors participated. Severe myelosuppression was the dose limiting toxic effect, occurring in all patients at the upper dose levels. Gastrointestinal and hepatic toxicities were infrequent and not severe. No allergic reactions occurred. Objective tumor regression was noted in 3 of 25 patients with a CNS tumor and in 6 of 45 patients with acute leukemia. For phase II trials the recommended dosage of Diaziquone given by this schedule is 18 mg/M2/week X 4 for patients with a solid tumor, and is 30 mg/M2/week X 4 for children with acute leukemia.
Topics: Adolescent; Adult; Antineoplastic Agents; Aziridines; Benzoquinones; Brain Neoplasms; Child; Child, Preschool; Drug Evaluation; Female; Humans; Infant; Infusions, Intravenous; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Male; Pediatrics; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 2384303
DOI: 10.1007/BF00177252 -
American Journal of Clinical Oncology Feb 1989Twenty-nine patients with a diagnosis of advanced adenocarcinoma of the stomach with gross unresectable or measurable residual disease and no prior therapy were entered...
Twenty-nine patients with a diagnosis of advanced adenocarcinoma of the stomach with gross unresectable or measurable residual disease and no prior therapy were entered into a study utilizing diaziquone (AZQ) in an intermittent 3-week schedule of 40 mg/m2. Of 28 eligible patients, 1 (4%) experienced a partial response, 7 (25%) had stable disease of no response, and 18 (64%) developed increasing disease. Two (7%) were unevaluable. Median survival was 3.8 months. Major toxicities were myelosuppression and gastrointestinal, 11 of which were considered to be life-threatening. AZQ used as a single intermittent agent appears to have no significant activity to warrant use in untreated advanced gastric carcinoma. However, recognizing the short plasma half-life of AZQ, significant responses by other schedules of administration are not precluded.
Topics: Adenocarcinoma; Aged; Aziridines; Azirines; Benzoquinones; Drug Administration Schedule; Drug Evaluation; Female; Humans; Male; Middle Aged; Stomach Neoplasms
PubMed: 2912017
DOI: 10.1097/00000421-198902000-00003 -
Cancer Research Mar 1990Diaziquone [AZQ, 2,5-bis(carboethoxyamino)-3,6-diaziridinyl-1,4-benzoquinone] has been investigated for its toxicity toward Chinese hamster ovary cells AA8-4 under both... (Comparative Study)
Comparative Study
Diaziquone [AZQ, 2,5-bis(carboethoxyamino)-3,6-diaziridinyl-1,4-benzoquinone] has been investigated for its toxicity toward Chinese hamster ovary cells AA8-4 under both aerobic and hypoxic conditions. Under acute (1-5 h) exposures to 2.5-10 microM AZQ in alpha-medium plus 10% fetal calf serum, AZQ showed an approximately linear concentration x time dependency for cell killing which was 3-4 times less under hypoxic compared to aerobic conditions. This selective toxicity toward hypoxic cells was prevented by low levels of oxygen. Under aerobic exposure conditions the toxicity of 2.5 microM AZQ was greatly increased by addition of 1-2 mM ascorbate. This ascorbate mediated toxicity of AZQ, presumably extracellular, could be prevented by the simultaneous addition of catalase. Under hypoxic exposure conditions there was no enhancement of AZQ toxicity by ascorbate or protection by catalase. The present results are consistent with two mechanisms for AZQ toxicity proposed earlier by others: toxicity due to (a) redox cycling and increased levels of oxidative stress and (b) reduction of the quinone leading to enhanced reactivity of the aziridines. The relative potency of AZQ as a hypoxic or aerobic cell selective toxin is determined by the balance between these two mechanisms.
Topics: Aerobiosis; Animals; Antineoplastic Agents; Aziridines; Benzoquinones; Cell Hypoxia; Cell Survival; Cross-Linking Reagents; Time Factors
PubMed: 2302714
DOI: No ID Found -
Investigational New Drugs 1983The anticancer agent 1,4-cyclohexadiene-1,4-dicarbonic acid, 2,5-bis(aziridinyl)-3,6-dioxo-, diethyl ester (AZQ) (NSC 182986) was studied in vitro to determine survival,...
The anticancer agent 1,4-cyclohexadiene-1,4-dicarbonic acid, 2,5-bis(aziridinyl)-3,6-dioxo-, diethyl ester (AZQ) (NSC 182986) was studied in vitro to determine survival, cell cycle stage sensitivity, and cell cycle kinetics effects. One hour treatments with AZQ doses ranging from 1 micrograms/ml to 25 micrograms/ml revealed that human stomach tumor clones were most sensitive of three cell types studied to to the killing effects of AZQ; this sensitivity was followed in order by human astrocytomas and Chinese hamster ovary (CHO) cells. Depending on the AZQ dose, nondividing CHO cells were 10 to 180 times more sensitive than dividing CHO cells. Synchronized CHO cells were most sensitive to AZQ's killing effects when treated at the late S/G2 phase boundary, with the overall order of sensitivity being late S/G2, G2, mid-S, and G1 phase. Mitotic cells were neither killed by doses used in these studies, nor were they inhibited in their progression from mitosis into the G1 phase. Synchronized CHO cells treated in all other phases of the cell cycle were either blocked completely or delayed for up to 2 hours in their progression through the cell cycle. Flow microfluorometry (FMF) studies on exponentially growing CHO cells demonstrated that even at noncytotoxic doses (1 microgram/ml), AZQ caused very large, but reversible enrichments of cells in the S and G2 phases of the cell cycle. Since AZQ has already been shown to be effective against a variety of animal and human tumors (especially brain tumors) the data reported here may be useful in designing more effective treatment schedules and drug combination regimens.
Topics: Adenocarcinoma; Animals; Astrocytoma; Aziridines; Azirines; Benzoquinones; Cell Division; Cell Line; Cell Survival; Cricetinae; Cricetulus; Female; Humans; Kinetics; Ovary; Stomach Neoplasms
PubMed: 6678853
DOI: 10.1007/BF00180187 -
Cancer Research Feb 1989Meningeal carcinomatosis in humans is refractory to most attempts at therapy and has a grave prognosis. As part of a search for new agents to treat meningeal...
Toxicity of intrathecally administered cytotoxic drugs and their antitumor activity against an intrathecal Walker 256 carcinosarcoma model for meningeal carcinomatosis in the rat.
Meningeal carcinomatosis in humans is refractory to most attempts at therapy and has a grave prognosis. As part of a search for new agents to treat meningeal carcinomatosis, the toxicity of a series of antitumor agents administered through an implanted catheter directly into the cerebrospinal fluid (CSF) of the lumbar spinal cord of 200-g rats has been examined. The highest non-toxic dose (HNTD) of the agents producing no signs of histological damage, motor dysfunction, or neurobehavioral changes was bleomycin (80 micrograms), cytarabine (640 micrograms), dacarbazine (1 microgram), doxorubicin (20 micrograms), 5-fluorouracil (150 micrograms), methotrexate (1000 micrograms), mitomycin C (10 micrograms), and triethylene phosphoramide (800 micrograms). No toxicity was observed at the highest dose that could be administered because of limited solubility of 1,3-bis(2-chloroethyl)-1-nitrosourea (100 micrograms), or diaziquone (70 micrograms). The rat model gave reasonable prediction of the toxicity of antitumor agents that have been administered intra-CSF to humans but with a tendency to underpredict toxicity. The antitumor activity of the agents administered intra-CSF at the HNTD against a Walker 256 carcinosarcoma model for meningeal carcinomatosis in the rat was examined. Diaziquone, doxorubicin, methotrexate, and mitomycin C gave a 25% or greater increase in lifespan and diaziquone and mitomycin C gave some long-term survivors. BCNU, bleomycin and 5-fluorouracil gave less than a 25% increase in lifespan. When mitomycin C was administered intra-CSF at the HNTD and diaziquone at the limit of solubility daily for 4 days there was no toxicity and an increase in survival of Walker 256 carcinosarcoma tumored animals compared to animals administered a single daily dose. Intrathecal diaziquone was more active against meningeal Walker 256 carcinosarcoma than i.v. diaziquone. Intravenous methotrexate had no activity against meningeal Walker 256 carcinosarcoma. We conclude that intra-CSF administration of some anticancer agents such as diaziquone and mitomycin C at doses that do not produce toxicity can significantly increase the survival of rats with experimental meningeal carcinomatosis.
Topics: Animals; Antineoplastic Agents; Carcinoma 256, Walker; Humans; Injections, Spinal; Male; Meningeal Neoplasms; Rats; Rats, Inbred Strains
PubMed: 2912564
DOI: No ID Found -
Cancer Treatment Reviews Sep 1989Glioblastomas and previously irradiated recurrent gliomas remain incurable. Chemotherapy is able to palliate patients by shrinking tumors, thereby improving neurological... (Review)
Review
Glioblastomas and previously irradiated recurrent gliomas remain incurable. Chemotherapy is able to palliate patients by shrinking tumors, thereby improving neurological status and quality of life. Chemotherapy may also be capable of prolonging survival in some instances. The effectiveness of chemotherapy against gliomas is comparable to the efficacy of chemotherapy against many other solid tumors. When given in an adjuvant setting along with radiation postoperatively, studies suggest that the nitrosoureas, dibromodulcitol, dianhydrogalactitol, procarbazine, teniposide, dacarbazine, and cisplatin may possibly be useful, although results for many of these drugs are inconclusive. Some chemotherapy combinations also appear to be useful in an adjuvant setting, particularly BCNU plus ifosfamide, BCNU plus cisplatin, CCNU plus dibromodulcitol, and CCNU plus lonidamine. However, there is not yet conclusive evidence that combination chemotherapy is superior to single agent adjuvant chemotherapy in the treatment of gliomas. While the use of chemotherapy prior to postoperative cranial radiation is worthy of further study, it has not to date proven to be more effective than chemotherapy combined with radiation. In patients whose tumors have recurred following radiation, palliation may be achieved with the nitrosoureas, procarbazine, teniposide, and diaziquone. Cisplatin, high dose methotrexate, the interferons, and a variety of other medications also may be of use. As in the case of adjuvant chemotherapy, chemotherapy combinations for recurrent tumor have not been conclusively demonstrated to be superior to single agent treatment, although some CCNU-based combinations are of interest. Many different chemotherapy drugs have been administered by intracarotid infusion. There is a moderately high risk of serious local retinal and neurological toxicity using this approach, and efficacy has not been proven to be improved by this approach. However, further studies of intraarterial administration of chemotherapy are warranted in light of theoretical considerations, pharmacological observations of enhanced local drug concentrations, and the observation that patients who have failed the same drugs intravenously may respond when lower doses of the drug are administered intraarterially. In addition, some patients have had tumor shrinkage in the area infused while tumor has grown in other areas. Thus, while intracarotid chemotherapy must be regarded as still investigational and potentially quite toxic, further studies are indicated. High dose chemotherapy has been administered in combination with autologous bone marrow rescue. High response rates and prolonged survival durations have been reported in some instances, justifying further study despite substantial toxicity.(ABSTRACT TRUNCATED AT 400 WORDS)
Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Glioma; Humans
PubMed: 2695239
DOI: 10.1016/0305-7372(89)90007-8