Disease relevance of CI 904

• The promising antineoplastic agent diaziquone is associated with prolonged aplasia and rare instances of bone marrow necrosis, but only mild extramedullary toxicity [1].
• Diaziquone produced prolonged aplasia in patients with secondary ANLL and CML-B (five of ten patients died aplastic), whereas patients with ALL all had regrowth of leukemia and two failed to become aplastic [2].
• This study evaluated the effect of filgrastim (granulocyte colony-stimulating factor [G-CSF]) on the duration of granulocytopenia and thrombocytopenia after intensive consolidation therapy with diaziquone (AZO) and mitroxantrone for patients less than 60 years of age with acute myeloid leukemia (AML) in complete remission [3].
• Thrombocytopenia in these patients was felt to be a manifestation of diaziquone effect, not persistence of leukemia [2].
• Phase II and pharmacokinetic study of aziridinylbenzoquinone [2,5-diaziridinyl-3,6-bis(carboethoxyamino)-1,4-benzoquinone, diaziquone, NSC 182986] in high-grade gliomas [4].

High impact information on CI 904

• The 60 patients underwent 72 autologous transplants after three high-dose chemotherapy regimens: 30 received high-dose carmustine in combination, five received high-dose busulfan and cyclophosphamide, and 37 received high-dose aziridinylbenzoquinone [5].
• The lack of significant nonhematologic toxicity and the activity in patients with relapsed ANLL render diaziquone of interest as second-line therapy or consolidation therapy in first remission for patients with ANLL [2].
• Intensification included one cycle of high-dose cytarabine (HDAC) followed by etoposide/cyclophosphamide and mitoxantrone/diaziquone (group I), three HDAC cycles (group II), four intermediate-dose cytarabine (IDAC) or HDAC cycles (group III), or one HDAC/etoposide cycle and autologous stem-cell transplantation (ASCT; group IV) [6].
• The order was the same for human E. coli DTD with one exception; diaziquone was reduced slightly faster than mitomycin A [7].
• High-density growth-arrested wild-type BALB/c 3T3 cells exhibited a greater sensitivity to growth inhibition by the antitumor quinone diaziquone [1,4-cyclohexadiene-1,4- dicarbamic acid, 2,5-bis(1-aziridinyl)-3,6-dioxo-, diethyl ether], which is metabolically activated by DT-diaphorase, than do low-cell-density, growth-arrested cells [8].

Chemical compound and disease context of CI 904

• Using our most extensively characterized human glioma line, D-54 MG, we found striking enhancement of the therapeutic effect by using nontoxic combinations of either diaziquone and carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea, NSC 409962) or diaziquone and procarbazine (NSC 77213) [9].
• 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 [10].
• An evaluation of combinations of diaziquone, etoposide and mitoxantrone in the treatment of adults with relapsed or refractory acute myeloid leukemia: results of 8722, a randomized phase II study conducted by Cancer and Leukemia Group B [11].
• The antitumor quinones diaziquone and doxorubicin have been shown to produce a time- and concentration-dependent inhibition of TR when incubated for up to 24 hr with intact A204 human rhabdomyosarcoma cells [12].
• Combination of aziridinylbenzoquinone and cis-platinum with radiation therapy in the 9L rat brain tumor model [13].

Biological context of CI 904

• Phase I evaluation and pharmacokinetics of aziridinylbenzoquinone using a weekly intravenous schedule [14].
• Aziridinylbenzoquinone demonstrated activity against acute nonlymphocytic leukemia with maximal tolerated doses of 30 mg/sq m daily for 5 days [15].
• Sister chromatid exchange induction by diaziquone in human and mouse lymphocytes following both in vivo and in vitro exposures [16].
• Metabolism of diaziquone by NAD(P)H:(quinone acceptor) oxidoreductase (DT-diaphorase): role in diaziquone-induced DNA damage and cytotoxicity in human colon carcinoma cells [17].
• Diaziquone, 2,5-diaziridinyl-3,6-biscarboethoxyamino-1,4-benzoquinone, plasma and cerebrospinal fluid kinetics [18].

Anatomical context of CI 904

• Aziridinylbenzoquinone is designed to have adequate lipid solubility to attain useful drug concentrations in the central nervous system [14].
• We investigated the in vitro interaction with and antitumor effect on several murine and human leukemic cell lines of diaziquone (AZQ) [19].
• The cerebrospinal fluid (CSF) pharmacokinetics of aziridinylbenzoquinone (AZQ) was studied following i.v. and intraventricular drug administration [20].
• Trenimon belongs to a class of aziridinylbenzoquinone anticancer drugs that cross the blood-brain barrier [21].
• Diaziquone-induced cytotoxicity in isolated rat hepatocytes [22].

Associations of CI 904 with other chemical compounds

• Diaziquone, doxorubicin, methotrexate, and mitomycin C gave a 25% or greater increase in lifespan and diaziquone and mitomycin C gave some long-term survivors [23].
• The diaziquone free radical produced electrochemically in dimethyl sulfoxide exhibited an 11-line electron spin resonance spectrum [24].
• In the follow-up study reported here, the activities of cisplatin, AZQ (diaziquone), pazelliptine and retelliptine have been evaluated against a panel of 40 established tumor lines grown subcutaneously in nude mice [25].
• A poor response to vincristine (Vcr), cis-platin (CDDP), hydroxyurea (HU) or diaziquone (AZQ) (no responders), and cytosine arabinoside (AraC) (1/12), was seen [26].
• 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 [27].

Gene context of CI 904

• Role of p53 in aziridinylbenzoquinone-induced p21waf1 expression [28].
• NQO1 can also be exploited in the design of NQO1-directed antitumor agents such as the new aziridinylbenzoquinone RH1 and Hsp90 inhibitors such as 17AAG [29].
• The activity of ribonucleotide reductase, which catalyzes the first unique step of DNA synthesis and which obtains its reducing equivalents from TR through thioredoxin, was decreased in diaziquone- and doxorubicin treated A204 cells [12].
• In vitro multidrug resistance of P388 murine leukemia selected for resistance to diaziquone [30].
• PURPOSE: Because there is a compelling need to develop new agents for intrathecal use, we investigated the safety, efficacy, and CSF pharmacokinetics of diaziquone (AZQ) following intrathecal administration in patients with refractory meningeal malignancies [31].

Analytical, diagnostic and therapeutic context of CI 904

• A phase I trial of high-dose diaziquone and autologous bone marrow transplantation: an Illinois Cancer Council study [32].
• Plasma and cerebrospinal fluid (CSF) kinetics of diaziquone, 2,5-diaziridinyl-3,6-biscarboethoxyamino-1,4-benzoquinone (AZQ), were evaluated after intravenous injection in patients with implanted Ommaya reservoirs [18].
• A total of 359 xenograft tumors in 229 experimental animals were monitored after treatment with intraperitoneal cyclophosphamide, intraperitoneal diaziquone, or local diaziquone [33].
• Local diaziquone was as effective as intraperitoneal injection in producing tumor responses [33].
• A marked similarity in kinetic parameters was found for BZQ and diaziquone (AZQ, NSC 182986), another diaziridinylbenzoquinone that has recently completed phase II clinical trials [34].

References