Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “FLAVONES”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 559 records · Page 31Linked to original sources
PubMed1991

Flavone acetic acid directly induces expression of cytokine genes in mouse splenic leukocytes but not in human peripheral blood leukocytes.

Flavone-8-acetic acid (FAA) is a flavonoid drug that augments mouse natural killer activity, induces cytokine gene expression, and synergizes with recombinant interleukin 2 for the treatment of murine renal cancer. However, FAA has been largely inactive in human clinical trials. In the present study we investigated the ability of FAA treatment to directly induce cytokine mRNA expression in total mouse splenic leukocytes and selected leukocyte subsets, as well as in total human peripheral blood leukocytes. Analysis of RNA isolated from FAA-treated mouse splenic leukocytes demonstrated that treatment with greater than or equal to 100 micrograms/ml of FAA induced expression of tumor necrosis factor alpha (TNF-alpha) mRNA by 1 h and induced maximal expression of TNF-alpha, alpha-interferon, and gamma-interferon mRNA within 3 h. The expression of all cytokine genes was diminished by 6 h. Interferon biological activity was detected in the supernatants of mouse splenic or peripheral blood leukocytes after treatment with FAA. These results correlate well with the previously reported induction of cytokine mRNA genes and biological activity by FAA in vivo. In contrast, FAA did not induce detectable mRNA expression or cytokine protein secretion by human peripheral blood leukocytes under similar conditions. These results demonstrate that FAA can directly stimulate cytokine gene expression in mouse but not in human leukocytes. Further studies performed with highly purified positively selected mouse CD4+ or CD8+ splenic T-lymphocytes, as well as purified B-cells, demonstrated that the FAA-induced expression of gamma-interferon mRNA was mainly induced in the CD8+ lymphocyte subset. alpha-Interferon mRNA was expressed largely in the B-cell population, while TNF-alpha mRNA was induced in all leukocyte subsets tested. Therefore, these results suggest that the immunomodulatory effects of FAA in mice are direct, but different cytokines are induced from different leukocyte subsets. Further, the data suggest that flavonoid compounds or analogues that stimulate cytokine gene expression in human cells might be therapeutically active in cancer patients.

Animals↗
PubMed1991

Tumor-dependent increased plasma nitrate concentrations as an indication of the antitumor effect of flavone-8-acetic acid and analogues in mice.

The antitumor agent flavone-8-acetic acid (FAA) is remarkable because it induces hemorrhagic necrosis, altered tumor blood flow, and cytokine synthesis. We show here that FAA and structurally related analogues increase plasma nitrite plus nitrate (NO2-/NO3-) levels in mice. Dose-dependent increases in plasma NO2-/NO3- concentrations, which reached maximum levels at 12 h, were found following administration of FAA. Furthermore, the presence of a palpable s.c. Colon 38 tumor significantly enhanced the response. Tumor-dependent increases were also observed with the active FAA analogues xanthenone-4-acetic acid, 5-methyl XAA, and 5,6-dimethyl XAA, while the inactive analogue 8-methyl XAA failed to increase plasma NO2-/NO3- concentrations substantially above basal levels. Increased plasma NO2-/NO3- levels were also observed in response to endotoxin (100 micrograms/mouse) and to recombinant human tumor necrosis factor alpha (4 to 16 micrograms/mouse). NO2-/NO3- levels may signify nitric oxide production as a result of stimulation of the L-arginine-dependent pathway in activated macrophages. The tumor dependence of the response may reflect the immunological stimulus imposed by tumor implantation. A clear relationship was found between increased plasma NO2-/NO3- levels and tumor growth delays induced by FAA and xanthenone-4-acetic acid analogues. It is suggested that nitric oxide may contribute to tumor cell death by two mechanisms, alteration of blood flow contributing to tumor ischemia and direct tumor cell killing. Plasma NO2-/NO3- concentrations may be a sensitive indication of the antitumor response to this class of compounds.

Adenocarcinoma↗
PubMed1990

Evidence for the production of nitric oxide by activated macrophages treated with the antitumor agents flavone-8-acetic acid and xanthenone-4-acetic acid.

Activated peritoneal macrophages, obtained from mice pretreated with Bacillus Calmette-Guérin, after exposure in vitro to flavone-8-acetic acid (FAA; NSC 347512) at a concentration of 890 microM, produce nitrite (3.7 nmol/10(6) cells), as measured 20 h later by the Griess reaction. Stimulation of nitrite production was inhibited at least 90% by NG-monomethylarginine (125 microM), suggesting that nitrite was formed via nitric oxide as a product of arginine metabolism. Stimulation was only partially inhibited by dexamethasone (0.1 microM). The ability of xanthenone-4-acetic acid (XAA) and three of its analogues to stimulate nitrite production was also investigated. 5,6-Dimethyl-XAA stimulated nitrite production (12.6 nmol/10(6) cells) at an optimal concentration of 80 microM, 8-methyl-XAA was without effect, and XAA and 5-methyl-XAA showed intermediate activity. The optimal in vitro drug concentrations for stimulation by FAA, XAA, and active XAA analogues correlated with the optimal in vivo dose required for the induction of either hemorrhagic necrosis or growth delay of s.c. Colon 38 tumors. These results strongly imply that FAA and active XAA derivatives function as low molecular weight stimulators of nitric oxide formation in macrophages, possibly acting on the same differentiation pathway as do endotoxin and tumor necrosis factor alpha. We suggest that nitric oxide, which is known to be toxic to tumor cells, contributes to the cytotoxic action of FAA and its analogues.

Animals↗
PubMed1990

Immunological effects of flavone acetic acid.

Flavone acetic acid (FAA) enhances natural killer and lymphokine-activated killer (LAK) cell activity in mice. We examined the immunological effects of FAA on human blood cells both in vivo and in vitro. Peripheral blood natural killer and LAK activity and lymphocyte subsets were evaluated in cancer patients after receiving 3-h infusion of FAA at either 8.5 or 10 g/m2 with alkalinization. Natural killer cell activity and the number of Leu-19 (CD56) positive cells decreased at 24 h after infusion; significant changes in LAK activity and the number of Leu-1 (CD5), Leu-3 (CD4), Leu-2 (CD8) cells were not observed. Peripheral blood mononuclear cells and peripheral blood lymphocytes collected from healthy volunteers were exposed in vitro to FAA, interleukin 2, and FAA plus interleukin 2. FAA, alone or in combination, failed to enhance LAK activity at any time point or concentration from peripheral blood mononuclear cells and peripheral blood lymphocytes. Concentrations of greater than or equal to 100 micrograms/ml antagonized the generation of LAK activity from interleukin 2 treated peripheral blood lymphocytes. These data suggest that FAA may not be useful in enhancing immunological responses in humans.

Adult↗
PubMed1990

Systemic alkalinization inhibits the ability of flavone acetic acid to augment natural killer activity, induce cytokine gene expression, and synergize with interleukin 2 for the treatment of murine renal cancer.

Flavone acetic acid (FAA) is an investigational drug that augments natural killer activity, induces the genes for alpha- and gamma-interferon (IFN) and tumor necrosis factor alpha, and synergizes with recombinant interleukin 2 for the successful treatment of murine renal cancer. However, in most clinical studies of FAA only minimal immunomodulatory effects have been reported. Most of the patients in these studies have also been given sodium bicarbonate to prevent possible nephrotoxicity. The current study was performed to determine whether alkalinization had any effects on FAA-induced immune modulation and therapeutic activity in mice. The results showed that alkalinization inhibited the treatment of murine renal cancer by FAA plus recombinant interleukin 2 such that the survival rate of 84% in nonalkalinized mice was reduced to 0 in mice that were alkalinized during treatment. Alkalinization also significantly inhibited the ability of FAA to augment both splenic and hepatic natural killer activity in a dose-dependent manner. In contrast, alkalinization did not inhibit the ability of polyinosinic:polycytidylic acid and poly-L-lysine stabilized in carboxymethyl cellulose, maleic anhydride divinyl ether, or Propionibacterium acnes to augment liver-associated natural killer activity. By Northern blot analysis, it was shown that the induction of mRNA for IFN-alpha, IFN-gamma, and tumor necrosis factor alpha by FAA in the spleen cells of mice was significantly reduced in alkalinized mice. Consistent with a reduction in the FAA-induced expression of the cytokine genes, alkalinization also resulted in a significant decrease in both the peak serum concentration and duration of detectable IFN activity following FAA treatment. Increasing the dose of FAA in alkalinized mice to 300 mg/kg overcame the deleterious effects of alkalinization for treatment of murine renal cancer by FAA plus recombinant interleukin 2. These results demonstrate that the process of alkalinization inhibits the immunomodulatory and immunotherapeutic effects of FAA in mice and suggest that alkalinization might have similar deleterious effects on FAA-induced immune stimulation in human clinical trials.

Adenocarcinoma↗
PubMedDate not supplied

Flavone acetic acid pharmacokinetics in nude mice.

The pharmacokinetics of flavone acetic acid (FAA) were comparatively studied in Balb-c mice and in immunocompetent nude mice treated with i.v. doses of 100 and 300 mg/kg. In both strains of mice, FAA kinetics appear to be dose-dependent, since the AUC values increased disproportionally to the dose. FAA protein binding and the pattern of distribution were similar in Balb-c and nude mice, the highest drug concentrations being found in liver and small intestine and the lowest in brain. Renal excretion appears to be the major route of FAA elimination in both strains, accounting for about 75% of the total drug administered after a dose of 100 mg/kg and 50-60% after a dose of 300 mg/kg. We conclude that FAA pharmacokinetics are comparable in Balb-c and nude mice so that the previously investigated FAA dosage schedules in inbred mice can also be employed in nude mice bearing human tumors.

Animals↗
PubMed1990

Role of tumor necrosis factor in flavone acetic acid-induced tumor vasculature shutdown.

Flavone acetic acid (FAA), a novel investigational antitumor agent, has been shown to cause early vascular shutdown in several experimental murine tumors, and this phenomenon is believed to be crucial to FAA's antitumor effects. However, the basis of this FAA-induced tumor vascular shutdown is unknown. In this study a radioactive tracer-clearance technique has been used as an objective indication of tumor blood flow to show that i.p. administered FAA induces a progressive and sustained reduction in blood flow in a colon 26 tumor growing s.c. in syngeneic mice. As early as 1 h after administration, there was a significant increase in the t1/2 clearance value for intratumorally injected 133Xe, reaching a peak at 3 h (117.3 +/- 36.4 versus 7.8 +/- 0.85 min for controls). Significant inhibition of blood flow was still apparent 48 h after a single injection of drug. This FAA-induced vascular shutdown was virtually abolished in tumor-bearing mice pretreated with an antiserum against tumor necrosis factor, while no such effect was observed in controls pretreated with nonimmune serum (t1/2 of 10.8 +/- 1.2 versus 65.6 +/- 8.0 min for controls). Furthermore, in vitro FAA was seen to induce tumor necrosis factor secretion from murine peritoneal cells and splenocytes. These studies suggest that FAA-induced tumor vascular shutdown in the colon 26 tumor is mediated by tumor necrosis factor.

Animals↗
PubMed1988

Augmentation of natural killer activity, induction of IFN and development tumor immunity during the successful treatment of established murine renal cancer using flavone acetic acid and IL-2.

The investigational drug flavone acetic acid (FAA) has been previously shown to systemically augment NK activity in vivo in normal mice within 24 h of i.p. or i.v. administration. The current study investigates the ability of FAA, and/or rIL-2, to augment NK activity and antitumor responses in mice bearing murine renal cancer (Renca). The results demonstrate that FAA potently augments NK activity in the blood, spleen, and liver of Renca-bearing mice and that the administration of rIL-2 in addition to FAA results in a further augmentation of NK activity over that observed with FAA alone. Renca-bearing mice treated with FAA (200 to 250 mg/kg) plus rIL-2 exhibited a significantly increased incidence of long term survivors (59%) over that observed following treatment with FAA (0%) or rIL-2 (5%) alone. Therapeutic synergy between FAA and rIL-2 was observed against primary tumors, minimal residual disease, and experimental-induced pulmonary metastases. Mice cured of Renca by FAA plus rIL-2 treatment were largely resistant to rechallenge with Renca suggesting a role for T lymphocytes. The augmentation of NK activity and the therapeutic effects of FAA coincided with the rapid induction of high titers of serum IFN of the alpha/beta type within 4 h of FAA administration. Subsequent studies demonstrated that the contribution of FAA could be partially replaced by the administration of several doses of human rIFN-alpha A/D Bg1 before the initiation of rIL-2 administration. The observed synergistic antitumor effects of FAA plus rIL-2 coincided with the augmentation of NK activity, induction of IFN-alpha/beta, and induction of long lasting tumor immunity. Overall, these results suggest that this approach may obviate the need for adoptive immunotherapy in association with rIL-2 administration for at least some tumor types.

Adjuvants, Immunologic↗
PubMed1989

Enhancement of the antitumor effect of flavone acetic acid by the bioreductive cytotoxic drug SR 4233 in a murine carcinoma.

Flavone acetic acid (FAA, NSC 347512) is a new anticancer drug currently undergoing clinical investigation. Although the precise mechanism for its broad spectrum of activity against transplanted murine solid tumors is unknown, it has been reported that FAA reduces tumor blood flow and produces hemorrhagic necrosis. We have confirmed this finding with the murine transplanted carcinoma SCCVII: 200 mg/kg FAA reduced tumor blood flow to 20-30% of normal for 1-2 days as determined by rubidium 86 extraction. In an attempt to exploit the tumor hypoxia produced by FAA, we have combined it with the novel bioreductive drug SR 4233, a benzotriazine dioxide with high selective toxicity for hypoxic cells. Marked enhancement of the antitumor effect of FAA (200 mg/kg) was observed when it was combined with SR 4233 (0.1 and 0.2 mmol/kg). This was seen using tumor cell survival, regrowth delay, and histological endpoints, with the best results obtained when the two agents were injected simultaneously. These data suggest that targeting bioreductive cytotoxic agents to tumors by producing tumor hypoxia may be a valid way of increasing the tumor cell killing of these agents.

Animals↗
PubMed1988

Flavone-8-acetic acid augments systemic natural killer cell activity and synergizes with IL-2 for treatment of murine renal cancer.

The investigational drug flavone-8-acetic acid (FAA) potently augments NK activity in the spleen, liver, lungs, and peritoneum in a dose-dependent manner after i.v. or i.p. administration. Augmented NK activity peaks by 24 h after FAA injection and returns to normal after 6 days. Combined treatment of established murine renal cancer with FAA and rIL-2 results in up to 80% long term survival whereas FAA or rIL-2 alone were unable to induce any long term survivors. The optimal dose of rIL-2 required for use with FAA was in the range of 10,000 to 30,000 U/day. Further studies demonstrated that the regimen of FAA plus rIL-2 administration that was effective in treating established murine renal cancer also induced a more potent augmentation of NK activity than did either FAA or rIL-2 alone. Subsequent studies revealed that the therapeutic effectiveness of FAA plus rIL-2 was significantly reduced when tumor-bearing mice were treated with anti-asialo GM1 serum. These results are consistent with a role for augmented NK activity in the therapeutic effects of FAA plus rIL-2 murine renal cancer. In addition, these studies demonstrate that FAA and rIL-2 is a useful approach for cancer treatment in that subtoxic doses of rIL-2 can be used and significant anti-tumor efficacy occurs even without accompanying adoptive immunotherapy.

Animals↗
PubMed1988

Flavone acetic acid (NSC 347512)-induced modulation of murine tumor physiology monitored by in vivo nuclear magnetic resonance spectroscopy.

Flavone acetic acid (FAA), a new drug with broad activity against transplanted solid tumors of mice, induces nonrepairable DNA single strand breaks that correlate with therapeutic efficacy. To test the hypothesis that the inability of the cells to repair single strand breaks is associated with a disruption of tumor energy metabolism, in vivo 31P nuclear magnetic resonance (NMR) spectra were acquired from s.c. implanted Glasgow osteogenic sarcomas in C57BL/6 x DBA/2 F1 mice both before and after treatment with FAA i.v. at 100, 150, or 200 mg/kg and from a control (no treatment) group (n = 4 in each group). While FAA produced a dose-dependent decrease in both the nucleoside triphosphates level and pH, only treatment with an efficacious dose of 200 mg/kg resulted in both a reduction in pH and a complete loss of nucleoside triphosphates from the NMR spectrum at 4 h with no recovery until 48 h and little recovery out to 72 h. The ATP concentration determined by high pressure liquid chromatography in a parallel set of experiments was 5.59 +/- 1.16 (SE) mumol/g (wet weight) in control tumors (n = 9) and 0.24 +/- 0.12 mumol/g (wet weight) at 4 h after 200 mg/kg FAA (n = 7). To examine the possibility that the loss of ATP and decreased pH are associated with a reduction in tumor blood flow, we used 2H NMR to monitor the washout of D2O injected directly into the tumor both before and 4 h after treatment with 200 mg/kg FAA. The pretreatment tumor blood flow of 12.4 +/- 1.7 ml/min/100 g was reduced to 1.9 +/- 0.5 ml/min/100 g at 4 h after treatment (n = 3). The FAA-induced reduction of both tumor blood flow and ATP may play an important role in its mechanism of action and should be considered in the combination of FAA with other drugs or therapeutic modalities. In addition, because 31P NMR can be used clinically, it should provide a nonambiguous early indicator of activity for clinical trials of FAA.

Adenosine Triphosphate↗
PubMed1988

Flavone acetic acid (NSC 347512)-induced DNA damage in Glasgow osteogenic sarcoma in vivo.

Flavone acetic acid (FAA) is a new antitumor agent with broad activity against transplantable solid tumors of mice but with only scant or no activity against leukemias and lymphomas. The technique of alkaline elution was used to study DNA lesions in s.c. implanted Glasgow osteogenic sarcoma in C57BL/6 x DBA/2 F1 mice treated i.v. with FAA. At efficacious dosages (235 and 200 mg/kg), FAA produced extensive single strand breakage. Formation of single strand breaks was dependent on time of assay after exposure to FAA with only minimal damage occurring prior to 5 h posttreatment. Apparently Glasgow osteogenic sarcoma had no capacity to repair single strand breaks for at least 45 h after drug administration. Thus, FAA differs in its mechanism from other scission agents (e.g., VP-16). Neither interstrand cross-links nor DNA-protein cross-links were detected. DNA single strand breaks did not occur in the bone marrow cells or in the unresponsive P388 leukemia cells at dosages causing extensive DNA damage in solid tumor cells.

Animals↗
PubMed1994

Synthesis of new derivatives of flavone-8-acetic acid.

The synthesis of new flavone-8-acetic acid derivatives is described. It is studied the influence of a dialkylaminomethyl group in the 3-position on the activity. None of the new compounds showed cytostatic activity.

Antineoplastic Agents↗
PubMed1994

Electrophysiologic effects of total flavones of Hippophae rhamnoides L on guinea pig papillary muscles and cultured rat myocardial cells.

The effects of total flavones of Hippophae rhamnoides L (TFH) were evaluated using conventional microelectrode technic. After administration of TFH 100-200 mg.L-1, the action potential duration of 50% repolarization (APD50) was shortened both in cultured rat myocardial cells and in guinea pig papillary muscles. The slope of phase 4 of depolarization (SP4) in cultured rat myocardial cells was decreased and the contractile force (CF) in guinea pig papillary muscles was weakened. Arrhythmias evoked by strophantin G in guinea pig papillary muscles were suppressed by TFH 100 mg.L-1. These findings suggested that the influence of TFH on myocardial cells may be resulted mainly from its inhibition of Ca2+ influx and its interference with intracellular Ca2+ reservoir.

Action Potentials↗
PubMed1994

[Demonstration of the anti-lipid peroxidation effect of 3',5,7-trihydroxy-4'-methoxy flavone rutinoside: in vitro study].

Diosmin (DI) 3'5,7-trihydroxy-4'-methoxy flavone rutinoside is a member of the flavonoid family, some of whom have antioxidant or free radical scavenger properties. Paw oedema induced by doxorubicin in rats is reduced by DI as observed by SAUVAIRE et al (1989). This suggests a free radical scavenger activity for DI. In this work we demonstrate that such activity is able to protect isolated human LDL from oxidation in vitro. The study of the electrophoretic mobility of oxidized LDL and of total-MDA values as lipoperoxidation-marker indicates an oxidation inhibiting effect higher than 70% for 0.16 mM DI in LDL mixtures containing 50 mM Cu2+ or 4.3 mU/ml xanthine-oxidase and incubated during 20 and 6 hours respectively. Owing to the high level of the oxidizing conditions and the vitamin E (48 mM), vitamin A (1.4 mM) and beta-carotene (2.4 mM) content of the LDL mixtures, it is concluded that DI is clearly able to complement the antioxidant effect of isoprenoids which are naturally present in LDL mixtures.

Adult↗
PubMedDate not supplied

Enhancement of chlorambucil cytotoxicity by combination with flavone acetic acid in a murine tumour.

Previous studies using murine tumours have shown enhanced action of certain chemotherapeutic compounds when combined with agents that reduce tumour blood flow. In the majority of cases the compounds used were cytotoxic to the induced hypoxic cells but in this study we have investigated the relative importance of changes in tumour pH following blood flow reductions. The role of tumour pH was investigated by using combinations of the cytotoxic alkylating agent Chlorambucil (CHL) with the vascular occluding agent Flavone Acetic Acid (FAA). Chlorambucil is a weak acid (pKa = 3.7) and is concentrated within cells exposed to culture media at low pH or to the acidic microenvironment in vivo. In vitro incubations showed that greater cytotoxicity was obtained when cells were incubated at low pH and that the cytotoxicity was independent of the level of oxygenation at the time of the drug incubation. Combination of both CHL and FAA in vivo resulted in greater reductions in cell survival and growth delay than when either agent was given alone. Simultaneous administration of the two agents were very effective, potentially due to two factors; firstly, that the pH of the tumour changes during ischaemia and secondly, that the reduced blood flow potentially alters the pharmacokinetic distribution of CHL resulting in 'drug-trapping' within the tumour. Since the action of CHL is independent of the induced hypoxia which results from blood flow reduction it is suggested that the increased in vivo action is due in part to the changes in tumour pH.

Adenocarcinoma↗
PubMed1994

In vivo skin penetration studies of camomile flavones.

In vivo skin penetration studies of the Camomile flavones apigenin, luteolin and apigenin 7-O-beta-glucoside were carried out with nine healthy, female volunteers. During seven hours the decline of flavonoid concentration in a saturated aqueous alcoholic solution filled in glass application chambers were repeatedly measured by spectrophotometry at fixed time periods. The maximal fluxes were calculated. From the graph of the maximal flux values as a function of time it was concluded, that the flavonoids are not only adsorbed at the skin surface, but penetrate into deeper skin layers. This is important for their topical use as antiphlogistic agents.

Administration, Topical↗