Disease relevance of Dimethyloxoxanthene acetic acid

• Scintigraphic imaging of the hypoxia marker (99m)technetium-labeled 2,2'-(1,4-diaminobutane)bis(2-methyl-3-butanone) dioxime (99mTc-labeled HL-91; prognox): noninvasive detection of tumor response to the antivascular agent 5,6-dimethylxanthenone-4-acetic acid [1].
• Activation of tumor-associated macrophages by the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid induces an effective CD8+ T-cell-mediated antitumor immune response in murine models of lung cancer and mesothelioma [2].
• The results suggest an important role for tumour necrosis factor in mediating both the host toxicity and antitumour activity of 5,6-dimethylxanthenone-4-acetic acid, but also suggest that tumour necrosis factor can be replaced by other vasoactive factors in its antitumour action, an observation of relevance to current clinical studies [3].
• PURPOSE: To measure host responses to the antivascular agent DMXAA (5,6-dimethylxanthenone-4-acetic acid) and to compare them with those of other antivascular agents.Methods: Induction of tumor necrosis was measured in s.c. murine Colon 38 carcinomas growing in normal or tumor necrosis factor (TNF) receptor-1 knockout mice [4].
• The effects of two anti-vascular agents, combretastatin A4 phosphate (CA4P), and 5,6-dimethylxanthenone-4-acetic acid (DMXAA), on the perfusion of two human colon adenocarcinomas implanted in SCID mice, were assessed for up to 3 h using non-invasive magnetic resonance imaging (MRI) and spectroscopy techniques (MRS) [5].

High impact information on Dimethyloxoxanthene acetic acid

• 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is a small molecule in the flavanoid class that has antitumor activity thought to be due to ability to induce high local levels of tumor necrosis factor (TNF)-alpha that disrupt established blood vessels within tumors [2].
• Treatment with the tumor necrosis factor-alpha-inducing drug 5,6-dimethylxanthenone-4-acetic acid enhances the antitumor activity of the photodynamic therapy of RIF-1 mouse tumors [6].
• Effects of 5,6-dimethylxanthenone-4-acetic acid on human tumor microcirculation assessed by dynamic contrast-enhanced magnetic resonance imaging [7].
• Vascular attack by 5,6-dimethylxanthenone-4-acetic acid combined with B7.1 (CD80)-mediated immunotherapy overcomes immune resistance and leads to the eradication of large tumors and multiple tumor foci [8].
• Stimulation of tumors to synthesize tumor necrosis factor-alpha in situ using 5,6-dimethylxanthenone-4-acetic acid: a novel approach to cancer therapy [9].

Chemical compound and disease context of Dimethyloxoxanthene acetic acid

• In addition, the antitumour effects of the conventional cytotoxic drug cyclophosphamide and the tumour necrosis factor inducer 5,6-dimethylxanthenone-4-acetic acid (DMXAA) were found to be potentiated by thalidomide in mice bearing colon 38 adenocarcinoma tumours [10].

Biological context of Dimethyloxoxanthene acetic acid

• Mechanisms of tumor vascular shutdown induced by 5,6-dimethylxanthenone-4-acetic acid (DMXAA): Increased tumor vascular permeability [11].
• The pharmacokinetics of 5,6-dimethylxanthenone-4-acetic acid, as well as the degree of induced plasma and tissue tumour necrosis factor, were similar in tumour necrosis factor receptor-1(-/-) and wild-type mice [3].
• Induction of endothelial cell apoptosis by the antivascular agent 5,6-Dimethylxanthenone-4-acetic acid [12].
• However, the maximum tolerated dose of 5,6-dimethylxanthenone-4-acetic acid was considerably higher in tumour necrosis factor receptor-1(-/-) mice (>100 mg kg(-1)) than in wild-type mice (27.5 mg kg(-1)) [3].
• Predicting pharmacokinetics and drug interactions in patients from in vitro and in vivo models: the experience with 5,6-dimethylxanthenone-4-acetic acid (DMXAA), an anti-cancer drug eliminated mainly by conjugation [13].

Anatomical context of Dimethyloxoxanthene acetic acid

• We conclude that 5,6-Dimethylxanthenone-4-acetic acid can induce vascular endothelial cell apoptosis in some murine and human tumours [12].
• The new antitumour drug 5,6-dimethylxanthenone-4-acetic acid (5,6-MeXAA; NSC 640488) was 14-fold more potent than the investigational chemotherapeutic drug flavone-8-acetic acid (NSC 347512) in stimulating tumouricidal activity in cultures of resident murine peritoneal macrophages [14].
• Induction of STAT and NFkappaB activation by the antitumor agents 5,6-dimethylxanthenone-4-acetic acid and flavone acetic acid in a murine macrophage cell line [15].
• An anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid (5,6-MeXAA) induced nitric oxide synthase (NOS) in the tumour, spleen, thymus and small intestine, but not in the lung, liver, kidney, heart or skeletal muscle in B6D2F1 mice bearing subcutaneous colon 38 tumours [16].
• Positive TUNEL staining of tumour vascular endothelium was evident in one patient in a Phase I clinical trial, from a breast tumour biopsy taken 3 and 24 h after infusion of 5,6-Dimethylxanthenone-4-acetic acid (3.1 mg x m(-2)) [12].

Associations of Dimethyloxoxanthene acetic acid with other chemical compounds

• The investigational antitumor agent, 5,6-dimethylxanthenone-4-acetic acid (5,6-MeXAA; NSC 640488) induced greater expression of tumor necrosis factor-alpha (TNF-alpha) mRNA in murine spleen cells in vivo at its optimal dose of 27.5 mg/kg than flavone acetic acid (FAA; NSC 347512) at its optimal dose of 220 mg/kg [17].
• Induction of intratumoral tumor necrosis factor (TNF) synthesis and hemorrhagic necrosis by 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in TNF knockout mice [18].
• Effects of the serotonin receptor antagonist cyproheptadine on the activity and pharmacokinetics of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) [19].
• 5,6-Dimethylxanthenone-4-acetic acid (DXAA) is a synthetic xanthenone derivative that is active against murine solid tumors and is being formulated for clinical trials [20].
• Comparative effects of combretastatin A-4 disodium phosphate and 5,6-dimethylxanthenone-4-acetic acid on blood perfusion in a murine tumour and normal tissues [21].
• Coadministration of ASA404 with docetaxel did not affect total systemic exposure of either drug [22].

Gene context of Dimethyloxoxanthene acetic acid

• 6-methylhydroxylation of the anti-cancer agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by flavin-containing monooxygenase 3 [23].
• The involvement of flavin-containing monooxygenase (FMO) in the 6-methylhydroxylation of the experimental anti-cancer drug 5,6-dimethylxanthenone-4-acetic acid (DMXAA) was investigated by use of human liver microsomes and microsomes containing cDNA-expressed FMOs [23].
• The aim of this study was to determine, using a human liver bank (N=14), the interindividual variations in the expression and activity of liver enzymes that metabolize the investigational anticancer drug 5,6-dimethylxanthenone-4-acetic acid (DMXAA), i.e cytochrome P450 (CYP1A2) and uridine diphosphate glucuronosyltransferase (UGT1A9/2B7) [24].
• NF-kappa B activation in vivo in both host and tumour cells by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) [25].
• The antitumour activity of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in TNF receptor-1 knockout mice [3].

Analytical, diagnostic and therapeutic context of Dimethyloxoxanthene acetic acid

• A single i.p. dose (27.5 mg/kg) of the drug 5,6-dimethylxanthenone-4-acetic acid (DMXAA), given to nude mice bearing the LS174T colorectal xenograft, destroyed all but a peripheral rim of tumor cells, without enhancing survival [26].
• The synthetic flavone analogue 5,6-dimethylxanthenone-4-acetic acid (5,6-MeXAA) has shown promise as an antitumor agent and is currently a candidate for clinical trials [27].
• PURPOSE: To compare the ability of combretastatin A-4 disodium phosphate (CA4DP) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) to change tissue blood perfusion [21].
• To determine whether there is a therapeutic interaction between the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and nine chemotherapy drugs against an early-passage mouse mammary tumour (MDAH-MCa-4), and to investigate the mechanism of any such interaction [28].
• PURPOSE: 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), an anticancer drug with an antivascular action, has recently completed phase I clinical trials [29].

References