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PubMed1989

A phase II clinical trial of diaziquone (AZQ) in the treatment of patients with recurrent adenocarcinoma and adenosquamous carcinoma of the cervix. A Gynecologic Oncology Group study.

Twenty-six patients with recurrent adenocarcinoma and adenosquamous carcinoma of the uterine cervix were treated with diaziquone (AZQ) 22.5 mg/m2 diluted in 150 ml normal saline every three weeks. In the absence of adverse effects the second dose and all subsequent doses were escalated to 30 mg/m2. All patients had measurable disease and only 11 had received prior chemotherapy. Two partial responses were noted among 15 patients with no prior chemotherapy, while no responses were observed among 11 previously treated patients. The major toxicity was leukopenia and thrombocytopenia. Median progression-free interval was 1.5 months and median survival was 4 months. AZQ displays minimal activity against recurrent nonsquamous carcinoma of the cervix at the dose and schedule used.

Adenocarcinoma↗
PubMed1985

Stability of 2,5-diaziridinyl-3,6-bis(2-hydroxyethylamino)-1,4-benzoquinone (BZQ; NSC 224070) in aqueous solutions by high-performance liquid chromatography.

The stability of the potential antitumour agent 2,5-diaziridinyl-3,6-bis(2 -hydroxyethylamino)-1,4-benzoquinone (BZQ; NSC 224070) has been investigated by high-performance liquid chromatography. At 22 degrees C in 0.05M buffer, BZQ was most stable at pH 9 with an apparent first-order rate constant (k) of about 0.014 h-1. There was reduced stability at pH values above and below 9.0. At a pH of 3 and 12 the values of k were 38 and 0.3 h-1, respectively. Stability of BZQ was adversely affected by increased temperatures (above 0 degrees C), increased buffer concentration and light. Solutions of BZQ could not be frozen for any length of time, as the drug precipitated out in a form that would not redissolve (possibly a polymer). For parenteral administration to patients, it is suggested that BZQ would be most stable in 1.26% sodium bicarbonate solution when at room temperature, under normal laboratory lighting, 5% of the drug degraded (t0.95) in 5.5 h. Increased stability is obtainable in this medium by refrigeration and vigorous exclusion of light. Long term (24 h) infusions of BZQ could be considered in hypotonic sodium bicarbonate (30 mM) with careful exclusion of light as long as the volume of the infusion was small, e.g. 1 ml/h. Under these conditions t0.95 was 42 h at 21.5 degrees C.

Antineoplastic Agents↗
PubMed1990

Phase I evaluation of diaziquone in childhood cancer. A Pediatric Oncology Group study.

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.

Adolescent↗
PubMed1988

A phase I/II study of 24 hour intravenous AZQ in recurrent primary brain tumors.

This study was undertaken to determine the maximum tolerated dose of aziridinylbenzoquinone (AZQ) given as a 24-hour intravenous infusion every 21-28 days. Thirty-four patients with recurrent or progressive gliomas received AZQ at a dose of 25, 30, 35, 40, or 45 mg/m2. At a dose of 45 mg/m2, leukopenia and thrombocytopenia of grade 3 or greater was observed in 42% and 25% of patients respectively; no patient required transfusion or antibiotics for fever. For administration of AZQ at a 24-hour intravenous infusion, we recommend a starting dose of 40 mg/m2 for patients without previous exposure to cytotoxic agents, and 35 mg/m2 for patients treated with such agents. In 14 patients with glioblastoma, tumor regression was observed in 1 patient (14%) and stabilization of disease was demonstrated in 7 patients (50%). In 17 patients with anaplastic astrocytomas there were no responses, but 8 patients (47%) stabilized. Of two patients with an oligodendroglioma, one continues without progression at 34 weeks after initial response. One patient with malignant ependymoma stabilized and had not progressed at 39 weeks. The median time to tumor progression in patients who stabilized and responded was 18 weeks for those with glioblastoma multiforme and 16 weeks in those with anaplastic astrocytomas.

Antineoplastic Agents↗
PubMed1983

Survival and cell cycle kinetics responses of Chinese hamster ovary cells, and clones of human adenocarcinoma of the stomach and astrocytoma to diaziquone (AZQ) in vitro.

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.

Adenocarcinoma↗
PubMed1983

Diaziquone (AZQ).

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.

Animals↗
PubMed1993

Prebiotic syntheses of vitamin coenzymes: I. Cysteamine and 2-mercaptoethanesulfonic acid (coenzyme M).

The reaction of NH3 and SO3(2-) with ethylene sulfide is shown to be a prebiotic synthesis of cysteamine and 2-mercaptoethanesulfonic acid (coenzyme M). A similar reaction with ethylene imine would give cysteamine and taurine. Ethylene oxide would react with NH3 and N(CH3)3 to give the phospholipid components ethanolamine and choline. The prebiotic sources of ethylene sulfide, ethylene imine and ethylene oxide are discussed. Cysteamine itself is not a suitable thioester for metabolic processes because of acyl transfer to the amino group, but this can be prevented by using an amide of cysteamine. The use of cysteamine in coenzyme A may have been due to its prebiotic abundance. The facile prebiotic synthesis of both cysteamine and coenzyme M suggests that they were involved in very early metabolic pathways.

Aziridines↗
PubMed1991

A phase II trial of diaziquone (AZQ) in mixed mesodermal sarcomas of the uterus. A Gynecologic Oncology Group study.

AZQ was given intravenously to 23 patients with mixed mesodermal sarcoma of the uterus refractory to conventional treatment at a dose of 22.5-30 mg/m2 q three weeks. There was one partial response lasting seven weeks and one drug-related death. Based upon the activity observed in this trial, there does not appear to be a significant role for AZQ as a salvage agent for mixed mesodermal sarcomas of the uterus at the dose and schedule tested.

Adult↗
PubMed1990

Aziridinylbenzoquinone (AZQ) in the treatment of recurrent pediatric brain and other malignant solid tumors. A Pediatric Oncology Group phase II study.

To assess the response rates and toxicity of AZQ in children with recurrent brain and other malignant solid tumors, a phase II study was implemented by the Pediatric Oncology Group. Eligible patients received AZQ 18 mg/M2/week i.v. for 4 doses followed by a 2 week rest period. Each dose was given over four hours (1/3 over the initial 20 minutes). After the first year, the dosage was reduced to 13 mg/M2 due to myelotoxicity resulting in treatment delays. No objective responses were observed in 73 evaluable children with various non-central nervous system tumors. Of the 91 patients with brain tumors, there were 4 CR's and 2 PR's in patients with astrocytoma, ependymoma, glioblastoma multiforme, oligodendroglioma, brain stem glioma and intracranial yolk sac tumor (median duration, 10 months; range, 2-20+ months). Three of 4 CR's were achieved with a dosage of 18 mg/M2/week. An additional 13 children with brain tumors experienced stable or improved disease (duration, 2-36 + months; median 7.5 months). The principal toxicity was myelosuppression which was cumulative but there were also 3 allergic reactions to AZQ. We conclude that for selected brain tumors, the rates of objective response and stable disease plus the duration of responses support further assessment of AZQ in combination with other agents. Furthermore, the 18 mg/M2 dosage may provide better responses.

Adolescent↗
PubMed1996

Purity determinations in the bulk drug of the novel indoloquinone antitumor agent EO9.

The pharmaceutical development of the investigational cytotoxic drug EO9 included the structural characterization of the bulk drug by nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS) and infrared (IR) spectroscopy, and analytical characterization by high-performance liquid chromatography and ultraviolet/visible spectrophotometry. The presence of impurities in the bulk drug was investigated. The intermediates in the synthesis of EO9 were structurally characterized by NMR spectroscopy and MS, and analytically characterized by HPLC analysis with photodiode array (PDA) detection. All of the intermediates were below their limits of detection in EO9 bulk drug. The amounts of residual organic solvents were determined by gas chromatography. Methanol and ethanol were detected, but the amounts present did not exceed the limits as set in the United States Pharmacopeia XXII.

Antineoplastic Agents↗
PubMed1988

Effect of AF64A on the cholinergic systems of the retina and optic tectum of goldfish.

AF64A, a presumed selective cholinergic neurotoxin has been used to study the effect on cholinergic systems of the goldfish retina and optic tectum. Toxin injection in the vitreum and in the optic tectum caused a selective decrease of choline acetyltransferase activity in both areas, while no significant decrease of glutamate decarboxylase and D-3H aspartate uptake were observed at different times after the injections. The effect was particularly dramatic in the retina of long term-injected animals, where choline acetyltransferase dropped to practically zero level. The ultrastructural analysis showed selective degeneration of some neurons in the amacrine and ganglion cell layer of the retina as well as of synaptic terminals and neuronal cell bodies in the optic tectum. The results favour a selective cholinotoxicity of AF64A in fish nerve tissue at doses substantially higher than those found to have additional unselective effects in mammals.

Animals↗
PubMed1987

A phase II trial of diaziquone in patients with head and neck cancer.

Diaziquone (AZQ) is a lipophilic alkylating agent which crosses the blood-brain barrier and has marked antitumor activity in a broad spectrum of murine tumor systems. Myelosuppression has been the dose-limiting toxicity in phase I trials. In this study 36 patients with head and neck cancer received diaziquone. Thirty-one of these patients (28 male, 3 female) were evaluable for efficacy. The initial starting dose was 7 mg/m2/day X 5 days i.v. repeated every 28 days. Because of the severe myelosuppression encountered in the first four patients, the starting dose was decreased by 20% to 5.5 mg/m2/day X 5 days repeated every 28 days. The majority of patients were considered to be good-risk patients as evidenced by performance status (80% 0-1 Zubrod) and prior therapy. Even with this dosage reduction, myelosuppression (especially thrombocytopenia) was again the dose-limiting toxicity with 25% of patients experiencing granulocyte and platelet nadirs below 1000/mm3 and 50,000/mm3 respectively. Thirty-five percent of patients required a subsequent dosage reduction of 20% prior to receiving a second course of therapy. There was one complete (CR), four partial (PR) and three minor (MR) responses. All but the CR were of relatively short duration (mean of 30 days). The patient with a CR has remained disease-free for nearly 3 years. In this group of patients the activity of diaziquone as a single agent at this dose and schedule (CR + PR + MR = 26%; CR + PR = 16%) is less than that of methotrexate, bleomycin, and cis-platinum but is encouraging. Further trials utilizing combinations are warranted.

Adult↗
PubMed1986

CB 1954 revisited. II. Toxicity and antitumour activity.

We have assessed the antitumour activity of the nitrophenylaziridine CB 1954 in vitro and in vivo. For EMT6 mouse mammary tumour multicellular spheroids under hypoxic conditions in vitro, a 6-h exposure to 40 micrograms/ml reduced the surviving fraction to as low as 10(-3) and the growth delay was 5.4 days. Oxic cells were twofold less sensitive. Phenyl AIC protected oxic and hypoxic cells equally. Under oxic conditions minimal cell killing was seen with HT29 cells, either in multicellular spheroids or in monolayer; a 6-h exposure to 40 micrograms/ml gave a spheroid growth delay of 1.5-1.7 days. No growth delay was seen with single maximum tolerated doses of CB 1954 against HT29 grown as a xenograft in immunosuppressed mice. Only minimal growth delays of 1-2 days were seen with similar doses against the EMT6 tumour and the RIF-1 and KHT sarcomas in mice. Little activity was seen with maximum tolerated doses given once a day for 5 days against EMT6 and RIF-1. No chemosensitization was measurable with CCNU, cyclophosphamide or melphalan in the KHT tumour.

Animals↗
PubMed1980

Phase I study of ethylbis(2,2-dimethyl-1-aziridinyl) phosphinate (AB-163).

Ethylbis(2,2-dimethyl-1-aziridinyl)phosphinate (AB-163) was used to treat 27 patients in a phase I trial. The limiting toxicity on a weekly schedule of IV administration involved nausea and vomiting associated with a variety of cholinergic side effects, including possible seizures. A starting dose of 300--400 mg/M2/week is suggested for a Phase II trial. One partial response in a patient with squamous-cell carcinoma of the cervix metastatic to the lungs was seen.

Adult↗
PubMed1989

Evaluation of response to chemotherapy in retinoblastoma heterotransplanted to the eyes of nude mice.

The role of chemotherapy in the treatment of retinoblastoma (RB) is unsatisfactory and clinical research is severely limited. A xenograft model for testing chemotherapeutic and other agents has been developed by the heterotransplantation of human RB cells into the anterior chamber of the nude mouse eye. A grading system for visually monitored tumor growth was designed to allow serial observations and documentation of the response to therapy in the model. This method of monitoring compared favorably with histopathologic, photographic, or other criteria in the reproducible, sequential evaluation of tumor status. Six chemotherapeutic agents [vincristine (VCR), doxorubicin (DOX), actinomycin D (ACT-D), dimethyltriazeno-imidazole carboxamide (DTIC), cyclophosphamide (CPM), and diaziquone (AZQ)] were then tested in the model against a patient-derived xenograft line. Results were expressed as the delay in tumor progression judged by serial grading. CPM produced a consistent response in all treated tumors, as did DTIC to a lesser, more variable extent. In 3 of 10 tumors treated with CPM and in 1 of 18 treated with DTIC, complete responses were maintained for at least 20 weeks. VCR, DOX, and ACT-D were ineffective, producing patterns of tumor progression no different from those in the control group. AZQ was most effective, producing responses far exceeding those of conventional agents. The model allows quantitative documentation of the response to therapy in heterotransplanted human RB. Further testing of new agents and combinations is warranted. AZQ may be active against RB.

Animals↗
PubMed1993

Morphological assessment of ethyl choline mustard aziridinium-induced neurotoxicity in rat brain reaggregate cultures.

Foetal rat brain reaggregate cultures have been employed to investigate the morphological changes associated with the neurotoxic action of ethylcholine mustard aziridinium (ECMA). In a companion study we provided evidence for apparent selective cholinergic neurotoxicity. Exposure of 9-day-old cultures to 12.5 microM ECMA for 3 days produced dilatation of selected axon preterminals and terminals in the outer core tissue layer. Axoplasm in these dilated terminals was electron lucent and contained a flocculent, plasma-like material with remnants of the smooth endoplasmic reticulum. Their synaptic vesicle content was much reduced or, absent. Microglial cells were engaged in phagocytosis of these effete structures and a few necrotic neurons were enveloped by glial processes. Exposure to 50 microM ECMA produced widespread necrosis with some surviving neurons, surrounded by the still-persisting capsular layer. Treatment with 100 microM ECMA generated a greater extent of tissue necrosis, with only a few surviving neurons and glial cells being contained within the necrotic tissue mass. Reaggregates frequently disintegrated following capsule loss. Our results indicate that the initial morphological manifestation of ECMA-induced toxicity is dilatation of axon terminals, that are probably of cholinergic origin and are targeted due to their possession of the high-affinity choline transport system which is unique to these neurons.

Animals↗