2,5-Diaziridinyl-3,6-bis(carboethoxyamino)-1,4-benzoquinone I: Kinetics in Aqueous Solutions by High-Performance Liquid Chromatography

Poochikianx, G.K.; Cradock, James C.

doi:10.1002/jps.2600700211

Cited by 25 publications

(9 citation statements)

References 8 publications

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“…The output signals were recorded with a strip-chart recorder. This was similar to the method described by Poochikian et al (8,9). The location of unchanged AZQ was ascertained by running unlabelled AZQ through the column.…”

Section: Chromatographymentioning

confidence: 99%

Intracerebral penetration and tissue distribution of 2,5-diaziridinyl 3,6-bis(carboethoxyamino) 1,4-benzoquinone (AZQ, NSC-182986)

Savaraj

Feun

et al. 1983

J Neuro-Oncol

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[14C]AZQ (2-4 mg/m2, 100-200 mCi) was administered at varying times to five patients undergoing surgical resection of intracerebral tumors. Plasma, cerebrospinal fluid (CSF), edematous brain, and tumor specimens were obtained during surgery and the concentration of AZQ was determined radiochemically and chromatographically. Total [14C]AZQ equivalent concentration in tumor for two patients was determined to be 47.5% and 85% of concurrent plasma concentration which was similar to that found in normal brain (60.4% and 75.5% respectively). Only 18-45% of the total radioactivity in tumor tissue and 30-56% in plasma were accounted for by unchanged AZQ. These findings suggest that AZQ may be metabolized to a certain extent. Tissue samples from various organs were obtained during autopsy in a patient who expired ten days after AZQ administration. The highest AZQ concentration was found in the liver, followed by the kidney. Comparable amounts were found in normal brain and brain tumor (22 ng/g vs. 31 ng/g respectively). These results indicate that AZQ penetrates readily into the normal brain and brain tumor with a tendency to persist.

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Section: Chromatographymentioning

confidence: 99%

Intracerebral penetration and tissue distribution of 2,5-diaziridinyl 3,6-bis(carboethoxyamino) 1,4-benzoquinone (AZQ, NSC-182986)

Savaraj

Feun

et al. 1983

J Neuro-Oncol

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“…Slight deviations from simple first order degradation kinetics were obviously sometimes occurring but were not further investigated. BZQ was found to be very much more labile than AZQ in acid solution (14), suggesting that the 2-hydroxyethyl groups on the benzoquinone ring of BZQ made formation of a protonated aziridinyl nitrogen easier, thus rendering this group more susceptible to nucleophilic attack. The difference in stability is far less pronounced at pH 8, and it may be that in more alkaline solutions, the stability of the two drugs would be found to be very similar.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…The stability of the drug in vitro has also been investigated and was observed to be greatest at pH 6.3 (14). In lactated Ringer's solution (pH 6.4) at ambient temperature, 5% of the drug degraded in approximately 29 h (14). This work on the synthesis of aziridinylbenzoquinones showed that 2,5-diaziridinyl-3,6-bis(2-hydroxyethylamino)-l,4-benzoquinone (BZQ; NSC 224070) also possessed antitumour activity (3).…”

Section: Introductionmentioning

confidence: 99%

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

Bosanquet¹,

McLoughlin²

1985

Invest New Drugs

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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.

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“…Under these conditions, AZQ would be expected to be stable with a T90 of 40 hrs and, therefore, a loss of less than 3% due to biodegradation [28]. Before treatment was started, a neurologic exam was performed and blood chemistries and blood counts were obtained; blood counts were repeated every other week or more frequently if indicated.…”

Section: Methodsmentioning

confidence: 99%

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

Chamberlain¹,

Prados²,

Silver³

et al. 1988

J Neuro-Oncol

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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.

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2,5-Diaziridinyl-3,6-bis(carboethoxyamino)-1,4-benzoquinone I: Kinetics in Aqueous Solutions by High-Performance Liquid Chromatography

Cited by 25 publications

References 8 publications

Intracerebral penetration and tissue distribution of 2,5-diaziridinyl 3,6-bis(carboethoxyamino) 1,4-benzoquinone (AZQ, NSC-182986)

Intracerebral penetration and tissue distribution of 2,5-diaziridinyl 3,6-bis(carboethoxyamino) 1,4-benzoquinone (AZQ, NSC-182986)

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

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

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