2,5-Diaziridinyl-3,6-bis(carboethoxyamino)-1,4-benzoquinone Ii: Isolation and Characterization of Degradation Products

Poochikianx, G.K.; Kelley, James A.

doi:10.1002/jps.2600700212

Cited by 25 publications

(6 citation statements)

References 10 publications

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“…diaziquone) techniques (8)(9)(10)(11). Concer/tration of diaziquone in CNS tumors was 30 to 80% (median 50%) of concurrent plasma concentration, with a tendency to persist.…”

Section: Chmentioning

confidence: 99%

Phase II evaluation of diaziquone (CI-904, AZQ) in the treatment of human malignant glioma

Maral

Poisson

et al. 1985

J Neuro-Oncol

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Diaziquone, a new alkylating agent which crosses the blood brain barrier, has shown a 20% response rate in phase II studies in heavily pretreated patients. We have treated 23 patients at our institution as part of a multicentric phase II European trial of diaziquone. All had histologically proven malignant glioma unequivocally progressing on CT scan. Prior therapy had consisted of surgical excision (13 patients), cobalt radiotherapy to CNS (13 patients), and chemotherapy with nitrosourea derivatives (11 patients). Six patients had no prior therapy. Median age was 42 years (range 22-69) and performance status was 3+ or better. They were treated with monthly courses of diaziquone 5.5 mg/m2 I.V. (10 min.) X 5 days. Dosage adjustments were made according to leucocyte and platelet nadirs. Thrombocytopenia was the dose limiting toxicity. Very mild gastrointestinal toxicity was observed. One patient developed hemolytic anemia. One complete response (clinical and CT scan), 7 partial clinical responses (3: greater than 50%, 4: 25-50%), and 1 disease stabilization (less than 25%) were documented. The longest response has now lasted over 26 months. These preliminary results show that chemotherapy with diaziquone can achieve a response rate as high as 35% in malignant glioma even in patients previously treated with a chemotherapy regimen including a nitrosourea (four of the seven objective responses were seen in such patients). Diaziquone is well tolerated and deserves further study in the management of malignant glioma.

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“…diaziquone) techniques (8)(9)(10)(11). Concer/tration of diaziquone in CNS tumors was 30 to 80% (median 50%) of concurrent plasma concentration, with a tendency to persist.…”

Section: Chmentioning

confidence: 99%

Phase II evaluation of diaziquone (CI-904, AZQ) in the treatment of human malignant glioma

Maral

Poisson

et al. 1985

J Neuro-Oncol

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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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“…These could include drug adsorption to containers (18), complexing with metals (e.g. of needles), autocatalysis by BZQ's own degradation products, co-precipitation of BZQ with its degradation products, and reaction with atmospheric oxygen, although this latter problem was not observed with AZQ (17).…”

Section: Discussionmentioning

confidence: 97%

“…Keeping the drug protected from light reduced its degradation. This was a surprising result to find since solutions of AZQ were not so affected (17). Experiments where the values of k were < 0.02 were performed over two or more days, and an overall rate was calculated using equation [2].…”

Section: Discussionmentioning

confidence: 99%

“…2. In line with the degradation of AZQ at acid pH(17), the two degradation products are possibly 2-aziridinyl-3,5,6-tris(2-hydroxyethylami- no)-l,4-benzoquinone (BZQ(OH)) and 2,3,5,6-tetrakis(2-hydroxyethylamino)-1,4-benzoquinone (BZQ(OH)2). The limit of detection of BZQ was about 500 pg: this gave a peak height of about 6 mm on the maximum sensitivity of 0.002 A.U.F.S.…”

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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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2,5-Diaziridinyl-3,6-bis(carboethoxyamino)-1,4-benzoquinone Ii: Isolation and Characterization of Degradation Products

Cited by 25 publications

References 10 publications

Phase II evaluation of diaziquone (CI-904, AZQ) in the treatment of human malignant glioma

Phase II evaluation of diaziquone (CI-904, AZQ) in the treatment of human malignant glioma

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

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