Flavone Acetic Acid Research Articles

Improving local tumor control by combining vascular targeting drugs, mild hyperthermia and radiation.

Improvement in local control in a foot-implanted (200 mm3) C3H mouse mammary carcinoma by combining vascular targeting drugs, mild hyperthermia and radiation was investigated. The vascular targeting drug was flavone acetic acid (FAA; 150 mg/kg) intraperitoneally injected either 3 h before local tumor water-bath heating or 1 h after local tumor irradiation. For untreated tumors, the average (+/- 1 S.E.) tumor growth time (TGT; time to reach 5 x treatment volume) was 7.1 days (+/- 0.4). This was increased to 9.2 days (+/- 0.7) by using FAA. Heating also increased TGT, the effect being temperature and time dependent, and this heat response was further increased by FAA. The radiation dose (+/- 95% confidence interval) to control 50% of tumors (TCD50) 90 days after irradiation was 52 Gy (50-55) for radiation alone. This was decreased to 42 Gy (39-45) by FAA, 47 Gy (45-50) by heating (41.5 degrees C; 60 min) 4 h after irradiation, and to 28 Gy (22-35) by combining FAA and heat. Thus, vascular targeting drugs can improve the efficacy of mild hyperthermia and radiation.

ChemInform Abstract: Synthesis and Antitumor Activity of New Derivatives of Flavone-8-acetic Acid (FAA). Part 4. Variation of the Basic Structure.

ChemInform Abstract: Synthesis and Antitumor Activity of New Derivatives of Flavone-8-acetic Acid (FAA). Part 4. Variation of the Basic Structure.

Synthesis and antitumour activity of new derivatives of flavone-8-acetic acid (FAA). Part 4: Variation of the basic structure.

A range of 11 derivatives of flavone-8-acetic acid (FAA) in which the structure has been substantially altered in different ways have been prepared and their anti-tumour activity evaluated in vitro against a panel of human and murine tumour cell lines and in vivo against MAC 15A. The generally poor activity observed shows that the basic structure cannot be altered much without destroying the activity.

Synthesis and Antitumour Activity of New Derivatives of Flavone-8-acetic Acid (FAA). Part 4 1) : Variation of the Basic Structure

A range of 11 derivatives of flavone-8-acetic acid (FAA) in which the structure has been substantially altered in different ways have been prepared and their anti-tumour activity evaluated in vitro against a panel of human and murine tumour cell lines and in vivo against MAC 15A. The generally poor activity observed shows that the basic structure cannot be altered much without destroying the activity.

Induction of STAT and NFκB activation by the antitumor agents 5,6-dimethylxanthenone-4-acetic acid and flavone acetic acid in a murine macrophage cell line

The antitumor agents flavone-8-acetic acid (FAA) and its dose-potent analogue 5,6-dimethylxanthenone-4-acetic acid (DMXAA), currently in clinical trials, have a novel mechanism of action that is mediated through their ability to induce a spectrum of cytokines. Since NFκB and STAT transcription factors participate in the regulation of a number of genes involved in immune and cytokine responses, we investigated whether these transcription factors were activated in the ANA-1 murine macrophage cell line by DMXAA and FAA compared with lipopolysaccharide (LPS), a bacterial component that induces an overlapping spectrum of cytokines. Activation of STAT1 and STAT3 was observed distinctly 4 hr after DMXAA and FAA stimulation. DMXAA and FAA induced NFκB translocation with slower kinetics of activation compared with LPS. STAT activation by DMXAA and FAA was inhibited by cycloheximide, indicating a requirement for de novo protein synthesis. The ANA-1 cells produced high titres of interferons (IFNs) in the culture supernatant after stimulation with DMXAA and FAA, and the addition of antibodies to IFNα/β inhibited STAT activation, indicating that IFNs mediated STAT activation. NFκB activation, on the other hand, was not inhibitable with cycloheximide or with antibodies to IFNα/β. NFκB activation appeared to be a direct action of the anticancer agents, whereas activation of the STAT proteins was due, in part, to the high titres of IFNs induced. These results demonstrate the significance of the IFN response in initiating the cascade of secondary events that may contribute to the overall antitumor efficacy of DMXAA and FAA in murine models.

Flavone acetic acid induces a G2/M cell cycle arrest in mammary carcinoma cells.

Flavone acetic acid (FAA) is a synthetic flavonoid that demonstrated extraordinary anti-tumour properties in murine models but was not effective in clinical trials. In an effort to better understand the molecular mechanisms by which FAA asserts its tumouricidal activities, we have examined the effect of FAA on the cell cycle. We observed FAA-mediated G2/M cell cycle arrest in mammary carcinoma cells at a concentration previously demonstrated to have anti-tumour effects in rodent models. The cell cycle arrest was accompanied by an increase in the P34cdc2 (cdc2) cyclin-dependent kinase activity. Morphological cytogenetic analysis demonstrated a colcemid-like effect of FAA on cytokinesis by causing accumulation of condensed C-metaphases of a sustained mitotic block. The cell cycle effect was blocked by the antioxidants ADPC and ascorbate, the superoxide scavenger Tiron, and the sphingosine kinase inhibitor L-cycloserine, but not by inhibitors of nitric oxide synthase. Based on these data, we propose that FAA may induce cell cycle arrest by stimulating the activity of acidic sphingomyelinase leading to the generation of reactive oxygen species. © 1999 Cancer Research Campaign

Inhibition of DT-diaphorase (NAD(P)H:Quinone oxidoreductase, ec 1.6.99.2) by 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and flavone-8-acetic acid (FAA): implications for bioreductive drug development

The tumour blood flow inhibitors 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and flavone-8-acetic acid (FAA) have been shown to potentiate the antitumour activity of several bioreductive drugs in vivo. Whilst the induction of hypoxia as a result of blood flow inhibition is presumed to be responsible for enhancing the activity of bioreductive drugs, no studies have examined potential interactions between DMXAA or FAA and enzymes involved in bioreductive drug activation. Both FAA and DMXAA are competitive inhibitors of the enzyme DT-diaphorase (NAD(P)H:Quinone oxidoreductase EC 1.6.99.2) with respect to NADH, with K i values of 75 and 20 μM, respectively. Cytochromes P450 reductase and b 5 reductase activities are not significantly inhibited by FAA, whereas DMXAA partially inhibits cytochrome b 5 reductase activity. The cytotoxicity of the indoloquinone EO9 (3-hydroxymethyl-5-aziridinyl-1-methyl-2-[1 H-indole-4,7-dione] prop-β-en-α-ol) against DLD-1 ( ic 50 = 0.32 ± 0.08 μM) was significantly reduced when combinations of EO9 and FAA ( ic 50 = 12.26 ± 5.43 μM) or DMXAA ( ic 50 > 40 μM) were used. In the case of menadione (which is detoxified by DT-diaphorase), combinations of menadione with FAA or DMXAA were more toxic ( ic 50 = 7.46 ± 2.22 and 9.46 ± 1.70 μM, respectively) than menadione alone ( ic 50 = 22.02 ± 1.59 μM). Neither DMXAA nor FAA potentiated the activity of tirapazamine in vitro. These results suggest that the use of DMXAA and FAA to potentiate the activity of bioreductive drugs where DT-diaphorase plays a central role in either activation or detoxification may be inappropriate. The fact that FAA in particular does not inhibit other key enzymes involved in bioreductive activation suggests that it may be useful in terms of identifying DT-diaphorase-activated prodrugs.

ChemInform Abstract: Synthesis and Antitumor Activity of New Derivatives of Flavone‐8‐acetic Acid (FAA). Part 3. 2‐Heteroaryl Derivatives.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis and antitumour activity of new derivatives of flavone-8-acetic acid (FAA). Part 3: 2-Heteroaryl derivatives.

A range of 14 derivatives of flavone-8-acetic acid (FAA) with a heterocyclic substituent in place of the 2-phenyl group have been prepared and their anti-tumour activity evaluated in vitro against a panel of human and murine tumour cell lines and in vivo against MAC 15A. Some of the compounds, notably 2c,d and s, showed significant in vivo activity and these require further studies in order to evaluate their potential for development.

Synthesis and Antitumour Activity of New Derivatives of Flavone-8-acetic Acid (FAA). Part 31): 2-Heteroaryl Derivatives

A range of 14 derivatives of flavone-8-acetic acid (FAA) with a heterocyclic substituent in place of the 2-phenyl group have been prepared and their anti-tumour activity evaluated in vitro against a panel of human and murine tumour cell lines and in vivo against MAC 15A. Some of the compounds, notably 2c, d and s, showed significant in vivo activity and these require further studies in order to evaluate their potential for development.

Effects of boron neutron capture therapy using borocaptate sodium in combination with a tumor-selective vasoactive agent in mice.

Boron neutron capture therapy (BNCT) destroys tumor cells by means of α particles and recoil protons emitted by 10B(n,α)7Li reaction. For BNCT to be effective, the tumor/normal tissue concentration ratio of 10B must be larger than 1.0, because neutron distribution is not selective. We examined the combination of 10B‐enriched borocaptate sodium (BSH) with flavone acetic acid (FAA) as a model compound which causes vascular collapse in squamous cell carcinoma in mice (SCCVII tumors) and would increase the tumor/normal tissue concentration ratio of 10B. FAA (200 mg/kg, i.p.) was injected, and 5 min later BSH (75 mg/kg, i.v.) was administered, followed 15 to 180 min later by irradiation with thermal neutrons. The 10B concentrations were measured by prompt gamma ray spectrometry. Without FAA, tumor 10B concentrations were less than or equal to normal tissue concentrations at all time intervals, except that the concentrations were 1.7‐ to 2.7‐fold greater in tumor than muscle at 15 and 180 min after injection of BSH. With FAA, 10B concentrations 2.1‐ to 6.9‐fold greater in tumor than in muscle were achieved at all intervals tested. For blood and skin, significant differential accumulations were found in tumors at 120 and 180 min. Tumor/liver ratios were less than 1 at all times. Cell survival was determined by in vivo/in vitro colony assay, and increasing radiosensitization correlated with increasing tumor 10B concentrations, whether or not they were achieved with FAA. Tumor control rates, determined at 180 days after BNCT, similarly appeared to depend only on 10B levels at the time of irradiation. Because 10B levels correlate with the radiation response of tissues, a therapeutic gain would be expected whenever the tumor levels exceed normal tissue levels, such as in tumors located in muscle irradiated at 15–180 min after FAA+BSH, or in those in skin irradiated at 120 and 180 min.

ChemInform Abstract: Synthesis and Antitumor Activity of New Derivatives of Flavone‐8‐ acetic Acid (FAA). Part 2. Ring‐Substituted Derivatives

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Production of tumour necrosis factor-alpha by cultured human peripheral blood leucocytes in response to the anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid (NSC 640488).

The investigative anti-tumour agent 5,6-dimethylxanthenonone-4-acetic acid (DMXAA, NSC 640488), developed in this laboratory as an improved analogue of flavone acetic acid (FAA, NSC 347512), is currently in clinical trial. The ability of DMXAA to up-regulate tumour necrosis factor (TNF) mRNA and protein synthesis in cultured human peripheral blood leucocytes (HPBLs) has been investigated and compared with that of flavone acetic acid (FAA) and of bacterial lipopolysaccharide (LPS). Human peripheral blood leucocytes were isolated from buffy coats obtained from a blood transfusion centre and also from blood samples from laboratory volunteers. At a concentration of 400 microg ml(-1) and an incubation time of 2 h, DMXAA up-regulated mRNA synthesis in six of eight individuals tested, as measured by Northern blotting. The degree of up-regulation varied in different individuals from one to nine times that of control levels. In contrast, FAA caused no induction above that of control levels and in some cases suppressed expression relative to controls, extending previous data that DMXAA but not FAA up-regulates TNF mRNA in the human HL-60 tumour cell line. At the same concentration but with longer incubation times (6-12 h), DMXAA induced increases in TNF protein in 11 of 15 samples of HPBLs from buffy coats and also in 11 of 15 samples of HPBLs from volunteers, as measured by cytotoxicity assays with L929 cells. FAA caused no increase in TNF protein, while LPS induced TNF to approximately 20-fold higher levels than did DMXAA. Considerable heterogeneity of response was observed with both sources of HPBLs, and there was little or no correlation between the extent of TNF induction by DMXAA and LPS in individual samples. In vitro analysis of the response of human peripheral blood leucocytes to DMXAA may be a useful test in clinical trials of agents such as DMXAA.

Immunomodulatory Actions of Xanthenone Anticancer Agents

Derivatives of xanthenone-4-acetic acid (XAA) were developed as analogues of flavone-8-acetic acid (FAA), a drug with excellent activity against experimental tumours in mice but no clinical activity. XAA derivatives were found to differ from conventional cytotoxic agents by having little direct cytotoxic activity against cultured cells. However, they exhibit pronounced immunomodulatory activity, inducing natural killer activity in mice and stimulating peritoneal macrophages to kill cultured tumour cells. They also induce selective reduction in tumour blood flow, leading to tumour haemorrhagic necrosis. The key to these actions appears to be the induction of cytokines, including tumour necrosis factor (TNF) and interferons. Cytokines are thought to mediate the increase in natural killer activity, the in vitro killing of tumour cells, and, through effects on vascular endothelial cells, the reduction of tumour blood flow and consequent onset of tumour necrosis. Although the target of XAA derivatives is not known, there is evidence for species differences. In particular, FAA induces messenger RNA for TNF in cultured mouse cells but not in cultured human cells, whereas one of the XAA derivatives, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), induces it in both murine and human cells. DMXAA is also more active and 12 times more dose potent than FAA in the mouse, and on this basis has been selected for clinical trials as a novel low molecular weight immunomodulatory antitumour agent.

Flavone Acetic Acid Stimulates Nitric Oxide and Peroxynitrite Production in Subcutaneous Mouse Tumors

Flavone acetic acid (FAA) has powerful anti-tumor activity against many types of solid murine tumors, but its biochemical mechanism of action is not understood. The present study examined the role of tumor vasculature and nitric oxide in mediating the anti-tumor effects of FAA. Athymic nude mice bearing subcutaneous RJ2-14 tumors were treated with a single dose of FAA, 200 mg/kg i.p., and euthanized at various times. Apoptosis within tumors was apparent during the first six hours of FAA treatment. We found that Type III, endothelial nitric oxide synthase (NOS) activity was significantly increased in tumors, but not in other tissues, as early as two hours after FAA dosing. FAA also stimulated the formation of the toxic peroxynitrite radical in tumors within two hours of treatment as assessed by immunostaining for nitrotyrosine. Staining was observed in dilated tumor vessels and surrounding tumor cells and correlated with the presence of apoptosis. Tumor endothelium may therefore be a critical target for FAA activity via stimulation of the nitric oxide pathway.

ChemInform Abstract: Synthesis and Antitumor Activity of New Derivatives of Flavone‐8‐ acetic Acid (FAA). Part 1. 6‐Methyl Derivatives.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis and antitumour activity of new derivatives of flavone-8-acetic acid (FAA). Part 2: Ring-substituted derivatives.

A range of 18 derivatives of flavone-8-acetic acid (FAA) with substituents on the 2-phenyl group have been prepared and their anti-tumour activity evaluated in vitro against a panel of human and murine tumour cell lines and in vivo against MAC 15A. There was no clear-cut relationship between in vitro and in vivo activity but the activity in each situation was found to be very sensitive to the precise substitution pattern with closely related isomers giving widely different activities. Some of the compounds, notably 10b,c,j, and r, were active in vivo and these require further studies in order to evaluate their potential for development.

Hydrogen-bonding effects, electrostatic potential, and the antitumor activity of flavone acetic acid and related compounds. III. Ab initio studies on the conformation space

Hydrogen-bonding effects, electrostatic potential, and the antitumor activity of flavone acetic acid and related compounds. III. Ab initio studies on the conformation space

Hydrogen-bonding effects, electrostatic potential, and the antitumor activity of flavone acetic acid and related compounds. II. Ab initio studies on the second stable conformations

We previously studied the first stable conformations of flavone acetic acid and related compounds. In this article, a similar investigation was carried out on the second stable conformation of the same compounds. Emphasis is on the conformation dependence of the hydrogen-bonding effects, the molecular electrostatic potential (MEP), and the antitumor activity shown by these compounds. The results show that the second conformation is about 7.0 kcal mol−1 higher in energy and possibly is an inactive conformation as no correlation has been found between the antitumor activity and the MEP features. In addition, a detailed comparison with the first conformation, which is probably the active conformation, has been made of the geometry, the total energy, the Mulliken charges on some important atoms, hydrogen-bonding effects, and the MEP minima and isosurfaces. The role of the hydrogen-bonding effects, which was unclear in our previous work, is clarified in this work. The possible molecular basis of the antitumor activity is suggested. © 1996 John Wiley & Sons, Inc.

Tumor necrosis factor-alpha suppresses the regrowth of fractionated irradiated endothelial cells in vitro.

Cytokines from two sources may affect endothelial cells (ECs) in tumor therapy: endogenously from cells in tumors and exogenously from therapeutic applications. These cytokines could modulate the influence of other therapy on tumor ECs. We use the colorimetric MTT method to assess the growth of irradiated ECs isolated from bovine pulmonary artery (CPAEC) and human umbilical cord vein (HUVEC) treated by cytokines. CPAECs given a single radiation dose of 2.5 to 15 Gy showed a small reduction in viable cells 2 to 3 days post-treatment. Neither tumor necrosis factor-alpha (TNF), interleukin-1 alpha (IL-1), nor interferon-gamma (INF) altered the growth of CPAECs treated by single radiation doses. HUVECs irradiated by a single dose of 12 Gy showed continuous reduction in viable cell numbers while those treated by 3 fractions of 4 Gy in 3 days or 6 fractions of 2 Gy in 3 days began to regrow 7 to 8 days after irradiation. Addition of TNF during the fractionated irradiation period limits the regrowth of HUVECs. Addition of IL-1 does not have the same effect. We have also tested the combined effect of another EC active agent flavone acetic acid (FAA), which has also been shown to stimulate the expression of TNF, with radiation, FAA (200 micrograms/ml) has a greater inhibitory effect on the growth and regrowth of fractionatedly irradiated HUVECs than TNF. These data suggest that TNF or FAA should be explored along with radiotherapy for their anti-tumor effect.