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

Abstract

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.

A Model for NAD(P)H: Quinoneoxidoreductase 1 (NQO1) Targeted Individualized Cancer Chemotherapy

“…These drugs are potent antitumor agents, but produce a variety of side effects including lung,7,18 hearing, muscle and renal toxicity 10,12. However, marrow toxicity is often the dose limiting toxicity for these agents 7,9,10,19. Bioreductive agents can be activated by two electron reducing enzymes like NAD(P)H:quinoneoxidoreductase 1 (NQO1; DT-diaphorase)1,20 or one electron reducing enzymes like NADPH cytochrome P450 reductase (P450 Red) 5,21…”

“…The clinical potential 3,4 and mode of action 5,6 of these agents have been actively studied, and the use of the prototype drug mitomycin C (MMC) in the clinic has been reviewed. 7 Other agents like porfi romycin, diaziquone (AZQ), 3-hydroxymethyl-5-aziridinyl-1-methyl-2-(1H-indole-4,7-dione)prop-β-en-α-ol (EO9), tirapazamine (TPZ) and 2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone (RH1) have been tested clinically, [7][8][9][10][11][12][13][14][15] and there is also ongoing work to develop new agents. 16,17 These drugs are potent antitumor agents, but produce a variety of side effects including lung, 7,18 hearing, muscle and renal toxicity.…”

A Model for NAD(P)H:Quinoneoxidoreductase 1 (NQO1) Targeted Individualized Cancer Chemotherapy

“…The clinical potential 3,4 and mode of action 5,6 of these agents have been actively studied, and the use of the prototype drug mitomycin C (MMC) in the clinic has been reviewed. 7 Other agents like porfi romycin, diaziquone (AZQ), 3-hydroxymethyl-5-aziridinyl-1-methyl-2-(1H-indole-4,7-dione)prop-β-en-α-ol (EO9), tirapazamine (TPZ) and 2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone (RH1) have been tested clinically, [7][8][9][10][11][12][13][14][15] and there is also ongoing work to develop new agents. 16,17 These drugs are potent antitumor agents, but produce a variety of side effects including lung, 7,18 hearing, muscle and renal toxicity.…”

“…10,12 However, marrow toxicity is often the dose limiting toxicity for these agents. 7,9,10,19 Bioreductive agents can be activated by two electron reducing enzymes like NAD(P)H:quinoneoxidoreductase 1 (NQO1; DT-diaphorase) 1,20 or one electron reducing enzymes like NADPH cytochrome P450 reductase (P450 Red). 5,21 NQO1 is a fl avoprotein that catalyzes 2-electron reduction of quinones and N-oxides.…”

Covalent binding studies on the 14C-labeled antitumour compound 2,5-bis(1-aziridinyl)-1,4-benzoquinone. Involvement of semiquinone radical in binding to DNA, and binding to proteins and bacterial macromolecules in situ

“…From this series, Diaziquone (AZQ) was one of the most promising compounds. This compound has been used in many clinical phase I and II trials and appears to be active against brain tumours in man [4,5] and several other tumours. The BABQ compounds are (bio)reductively activated drugs, a term introduced by Lin et al [6], like other antitumour agents containing a quinone moiety, such as adriamycin and mitomycin C (for a review, see Powis [7]).…”