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PubMed1991

Haematological effects in mice of the antitumour agents xanthenone-4-acetic acid, 5,6-dimethyl-xanthenone-4-acetic acid [correction of 5,6-methyl-] and flavone acetic acid.

Treatment of C57Bl/6 x DBA/2 mice with the maximal tolerated dose of flavone-8-acetic acid (FAA, 1300 mumol/kg), xanthenone-4-acetic acid (XAA, 1090 mumol/kg), or its dose-potent derivative 5,6-dimethyl-xanthenone-4-acetic acid (5,6-MeXAA, 100 mumol/kg) resulted within 24 h in a dramatic reduction in the number of circulating lymphocytes, an elevation in haemoglobin concentrations and a reduction in platelet numbers. Neutrophil counts either remained unchanged or were slightly elevated. All three compounds caused a marked loss of cells in the thymus. Examination of histological sections of thymus at 48 h following treatment with XAA revealed a selective depletion of cortical thymocytes and no effects on the epithelium or other thymic structures. A transient decrease in cell numbers was seen in the spleen and femoral bone marrow, with recovery to normal levels occurring within 3 days. The number of haemopoietic stem cells, colony-forming units in culture (CFU-c), in the femoral bone marrow increased after drug administration despite the occurrence of a decrease in the overall number of cells in the femur. In contrast to the increase in CFU-c numbers seen in vivo, 2 h exposure of bone-marrow cells to FAA, XAA or 5,6-MeXAA in vitro resulted in a decrease in the surviving fraction of CFU-c. The results are consistent with the hypothesis that the in vivo haematological effects of these compounds are indirect, perhaps being mediated through the induction of cytokines, and contrast with the haematological effects of conventional antitumour agents. The biochemical and haematological effects are unlikely to be the cause of the acute toxicity observed for these compounds.

Animals↗
PubMed1992

A phase I and pharmacokinetic study of 12-h infusion of flavone acetic acid.

This phase I study investigated flavone acetic acid (FAA) given as a 12-h intravenous infusion every 3 weeks in the absence of urinary alkalinisation. Cohorts of three patients were treated at doses of 7, 10 and 13 g/m2. One subject had colon cancer; 5, renal cancer; and 3, lung cancer. The Eastern Cooperative Oncology Group (ECOG) performance status was 0 in four patients, 1 in two subjects and 2 in three cases. The maximum tolerated dose was 13 g/m2. The dose-limiting toxicities were WHO grade 3 hypotension and grade 3 diarrhoea. Other toxicities included lethargy and dizziness, nausea, temperature fluctuation, myalgia and dry mouth, but no significant myelosuppression was encountered. One patient receiving 10 g/m2 for renal cancer showed a partial response that lasted for 3 months and included the resolution of pulmonary and cutaneous metastases. The pharmacokinetics showed large interpatient variability. At 12-16 h post-infusion, the plasma elimination profile entered a plateau phase, with frequent increases in concentration suggesting enterohepatic recycling. Neither peak FAA levels nor AUC values were dose-dependent at the doses studied. Peak plasma levels were 101-402 micrograms/ml and AUC (0-48 h) values were 75-470 mg ml-1 min. Plasma protein binding varied with total concentration. Two metabolites were detected in the plasma, and both also underwent apparent enterohepatic recycling. Repeat dosing resulted in decreases of up to 48% in peak levels and AUC values for FAA in three of six patients. Of the total FAA dose, 39%-77% was excreted in the urine as FAA or metabolites within 2 days. The dose recommended for further phase II studies is 10 g/m2.

Adult↗
PubMed1993

Serotonin involvement in the antitumour and host effects of flavone-8-acetic acid and 5,6-dimethylxanthenone-4-acetic acid.

The relationship of serotonin (5-HT) receptors to the action of the experimental antitumour drugs flavone-8-acetic acid (FAA) and 5,6-dimethylxanthenone-4-acetic acid (5,6-MeXAA) was studied. Both FAA and 5,6-MeXAA are known to induce the synthesis of tumour necrosis factor-alpha (TNF) and to stimulate nitric oxide synthesis in vivo, as measured by elevation of plasma nitrate. Serotonin potentiated the effect of a subtherapeutic dose of 5,6-MeXAA (20 mg/kg) as measured both by plasma nitrate increase and by growth delay of s.c. implanted colon 38 tumours. On the other hand, administration of the serotonin 5-hydroxytryptamine-2 (5-HT2) antagonist cyproheptadine (20 mg/kg) inhibited both the plasma nitrate response and, to a lesser extent, the induction of tumour haemorrhagic necrosis by 5,6-MeXAA, FAA and TNF. Reduction of circulating plasma serotonin by pre-treatment with p-chlorophenylalanine and reserpine reduced the plasma nitrate response, but not the tumour necrosis response, to 5,6-MeXAA (30 mg/kg). It is suggested that serotonin is necessary for the induction of nitric oxide synthases and acts, either directly or indirectly, in concert with TNF. Serotonin agonists may have utility in increasing nitric oxide synthesis in response to TNF or to agents that induce TNF as part of their antitumour action.

Animals↗
PubMed1995

Phase I and pharmacology study of flavone acetic acid administered two or three times weekly without alkalinization.

Flavone acetic acid (FAA, NSC 347512) is a synthetic flavonoid compound with a unique form of preclinical antitumor activity, but its mechanism of action is still not known. In an attempt to exploit the remarkable preclinical activity of this compound in such a way as to allow its use as a clinically useful agent, we performed a phase I and pharmacology study with frequent administration and no hyperhydration or alkalinization. Sixteen patients (9 men, 7 women) were given FAA as 6-h i.v. infusions 2 or 3 times a week (10 and 6 patients, respectively), at doses ranging from 2.5 to 8.1 g/m2. A total of 130 doses were administered during this study. Sedation, arterial hypotension, vomiting and diarrhea were the predominant toxicities observed at the highest dose (8.1 g/m2. One patient developed severe but reversible multiple organ failure. No treatment-related deaths occurred. Pharmacokinetics was linear for the doses studied, with peak plasma levels ranging from 39 to 449 micrograms/ml and a mean terminal half-life of 3.1 h. No drug accumulation was observed with this frequent-administration schedule. No objective response was observed. Three FAA infusions per week at 8.1 g/m2 could be recommended as an optimal and tolerable schedule.

Adult↗
PubMed1990

Flavone acetic acid and plasma protein binding.

Both the capacity of healthy human, cancer patient, and mouse plasma proteins to bind flavone acetic acid (FAA) and the qualitative differences in the plasma protein-binding site were studied. The binding capacity of plasma proteins for FAA was saturated within the therapeutic range in both species. The binding of FAA to plasma protein was significantly greater in both healthy human and cancer patient plasma than in mouse plasma. Plasma from patients with cancer bound on the average less FAA than did healthy patient plasma. The concentration of albumin in the plasma varied between healthy humans, cancer patients, and mice, being 5.3 +/- 0.7, 4.7 +/- 0.8, and 3.9 +/- 0.3 g/100 ml, respectively. The protein binding of FAA was found to be dependent on the plasma albumin concentration, but albumin concentration alone was not adequate for the accurate prediction of the percentage of FAA protein bound. Scatchard plots indicated that healthy human plasma had a greater number of high-affinity binding sites than did mouse plasma. FAA binds at the indolebenzodiazepine binding area on albumin and can be displaced from this site by salicylic acid and clofibric acid, but only at supratherapeutic concentrations. Our results indicate that alterations in plasma albumin could contribute to a variable effect with FAA. Therefore, the influence of serum albumin concentration and the nonlinearity of FAA protein binding should be considered in assessment of the appropriateness of a dose schedule for FAA.

Animals↗
PubMed1993

Saturable elimination and saturable protein binding account for flavone acetic acid pharmacokinetics.

Flavone acetic acid (FAA) is an antineoplastic agent that has undergone extensive study in Phase I trials. Concentration-dependent plasma protein binding has been demonstrated in vitro at concentrations of total drug that are achieved in vivo. Moreover, dose-dependent total systemic clearance has been described when FAA has been administered as a short iv infusion. When administered as a prolonged 24-hr infusion, total FAA (bound plus unbound) plasma pharmacokinetics are well described with a first-order two-compartment model. However, measurement of unbound FAA intra- and post-intravenous infusion in eight patients revealed a twofold increase in fraction of FAA unbound in plasma intrainfusion. We attempted to fit pharmacokinetic structural models of varying complexity to the unbound concentrations alone and simultaneously to the unbound and bound FAA plasma concentrations. The data were adequately described only by a model that incorporated simultaneous saturable plasma protein binding and a Michaelis-Menten process for elimination. A comparison among models is presented, as well as pharmacokinetic parameter estimates for FAA in children. These clinical data are consistent with predictions of the clearance model in which both saturable protein binding (resulting in a dynamically increasing unbound fraction) and saturable elimination (resulting in gradually decreasing unbound intrinsic clearance) are operative.

Antineoplastic Agents↗
PubMed1993

Determination of flavone C-glycosides in tea.

An HPLC method for the determination of flavone C-glycosides (FCG) from black tea has been developed. Sample clean-up was accomplished by means of polyamide column chromatography, followed by enzyme hydrolysis of interfering compounds such was flavonol glycosides and a second polyamide column chromatographic step. Using HPLC with gradient elution and photodiode array detection eight FCG were separated. Seven FCG were isolated by means of preparative HPLC. Identification was carried out using co-chromatography, FAB(Fast Atom Bombardment)-mass spectrometry and various nuclear magnetic resonance techniques. Apigenin 6-C-glucosyl-8-arabinoside (schaftoside) and apigenin 6-C-arabinosyl-8-C-glucoside (isoschaftoside) as well as luteolin 8-C-glucoside (orientin) and luteolin 6-C-glucoside (isoorientin) have been detected in tea for the first time. Three of the other compounds have been identified as apigenin 8-C-glucoside (vitexin), apigenin 6-C-glucoside (isovitexin) and apigenin 6,8-di-C-glucoside (vicenin-2). Their occurrence in tea has been previously reported. From its UV spectrum another compound was concluded to be an apigenin glycoside. The FCG were quantified in a variety of teas of different origins (16 black, two green and one oolong). The total amounts of the FCG were 0.48-2.69 g/kg dry weight. The FCG pattern of teas of different origins were similar to each other and no origin-dependent characteristics have yet been observed. Small amounts of FCG (1.2-2.2 mg/kg) were detected in hydrolysates of high relative molecular mass fractions (Mr > 5000) of a black tea liquor.

Apigenin↗
PubMed1996

Thermospray-LC-MS analysis of various groups of polyphenols in tea. I. Catechins, flavonol O-glycosides and flavone C-glycosides.

This paper describes the application of thermospray-HPLC-MS (buffer ionization mode, single-stage MS, positive ion detection) to the analysis of flavanols (catechins), flavonol O-glycosides, flavone C-glycosides as well as caffeine, theobromine, theogallin and theanine from tea. All compounds are detected as pseudo-molecular ions [M+H]+. Other molecular ion species are adducts with sodium, potassium, ammonium and solvent clusters. The catechin gallates and the flavonol glycosides are fragmented. The fragmentation is temperature dependent. The glycoside bond is labile and consequently the flavonol glycosides have the protonated aglycone as this base peak. The ester bonds in the catechin gallates are more stable and the fragmentation is limited. The fragment pattern contributes to the structural information. LC-thermospray-MS is a good analytical tool for identifying the polyphenols mentioned above both in tea and other foodstuffs, especially in method development and structural elucidation.

Carbohydrate Sequence↗
PubMed1990

Flavone acetic acid antitumour activity against a mouse pancreatic adenocarcinoma is mediated by natural killer cells.

Flavone acetic acid (FAA) is one of the most active antitumour agents against mouse solid tumours. A number of reports favour the hypothesis that FAA could behave as a biological response modifier; in fact FAA stimulates natural killer (NK) cells, induces secretion of type I interferon and synergizes with interleukin-2 to increase NK/lymphokine-activated killer (LAK) activity in vivo. However, there is no conclusive evidence that the antitumour activity of FAA is mediated via the modulation of NK/LAK cells. The present study was designed to evaluate whether the reported activation of NK cells is instrumental in FAA antitumour activity. FAA (180 mg/kg, i.v. on days 3, 7 and 11 after tumour implant) was significantly effective in inhibiting the subcutaneous growth of the pancreatic adenocarcinoma PAN/03 in C57/Bl mice. After 132 days the number of tumour-free survivors was 36%, whereas in the control group receiving no treatment, or in the group of mice treated with 10 micrograms/mouse of alpha-asialo-GM1 the value was only 0 or 6.7%, respectively. The combination of FAA and alpha-asialo-GM1 resulted in only 6% tumour-free mice. In parallel experiments, splenocytes and peritoneal cells from C57/B1 mice were tested in a standard cytotoxicity NK assay. While animals treated with FAA showed a significant increase in NK activity, those injected with alpha-asialo-GM1 had very low levels, and the combined treatment of FAA and alpha-asialo-GM1 resulted in a lower or similar NK activity compared to that in untreated mice. The fact that the abrogation of the NK-stimulating effect of FAA is accompanied by a lack of anti-tumour activity indicates that, at least in this experimental model, FAA is likely to act via an immunomodulatory mechanism.

Adenocarcinoma↗
PubMed1994

A new flavone glycoside from the fern Pteris cretica.

A new flavone glycoside isolated from the fern Pteris cretica has been shown to be luteolin 7-O-robinobioside (1) by chemical and spectral methods. In addition luteolin 7-O-rutinoside (2) and luteolin 7-O-glucoside (3) have been isolated from this plant. Flavonoid 2 is reported for the first time in ferns.

Flavonoids↗
PubMed1993

Phospholipid and fatty acid compositions of Rhizobium leguminosarum biovar trifolii ANU843 in relation to flavone-activated pSym nod gene expression.

The phospholipid and associated fatty acid compositions of the bacterial symbiont of clover, Rhizobium leguminosarum biovar trifolii wild-type ANU843, was analyzed by two-dimensional silica thin-layer chromatography, fast atom bombardment-mass spectrometry, flame-ionization detection gas-liquid chromatography and combined gas-liquid chromatography/mass spectrometry. The phospholipid composition included phosphatidylethanolamine (15%), N-methylphosphatidylethanolamine (47%), N,N-dimethylphosphatidylethanolamine (9%), phosphatidylglycerol (19%), cardiolipin (5%) and phosphatidylcholine (2%). Fatty acid composition included predominantly cis-11-octadecenoic acid, lower levels of cis-9-hexadecenoic acid, hexadecanoic acid, 11-methyl-11-octadecenoic acid, octadecanoic acid, 11,12-methyleneoctadecanoic acid, eicosanoic acid and traces of branched, and di- and triunsaturated fatty acids. The influence of expression of the "nodulation" genes encoding symbiotic functions on the composition of these membrane lipids was examined in wild-type cells grown with or without the flavone inducer, 4',7-dihydroxyflavone and in mutated cells lacking the entire symbiotic plasmid where these genes reside, or containing single transposon insertions in selected nodulation genes. No significant changes in phospholipid or associated fatty acid compositions were detected by the above methods of analysis.

Fatty Acids↗
PubMed1990

Flavone acetic acid distribution in human malignant tumors.

The pharmacokinetics of flavone acetic acid (FAA) after a dose of 4.8 mg/m2 given i.v. over 1 h was investigated in 13 patients with different solid tumors. The mean volume of distribution and clearance were 52 +/- 4 l/m2 and 2.6 +/- 0.2 l/h x m2, respectively. A tumor or metastasis biopsy was obtained from six patients 2 h after the end of infusion. Tumor FAA levels ranged from 39.6 to 148.8 micrograms/g and were similar to those obtained after a therapeutic i.v. dose of 200 mg/kg FAA in animals bearing Pan/03 tumor, which is very sensitive to the drug. Although FAA tumor concentration could be detected only during one interval and we therefore cannot draw a definitive conclusion, differences in the agent's antitumor activity in mice and patients (i.e. very active in the former and inactive in the latter) are apparently not due to discrepancies in drug distribution and pharmacokinetics.

Adult↗
PubMed1994

Synthesis of dibenzoylmethanes as intermediates for flavone synthesis by a modified Baker-Venkataraman rearrangement.

1-Polyoxyphenyl-3-(2,6-dioxyphenyl)propane-1,3-diones have been synthesized as intermediates for flavone synthesis by condensation of 2-(2,6-dioxybenzoyloxy)polyoxyacetophenone in the presence of phase transfer catalyst. The average yields of 1-polyoxyphenyl-3-phenylpropane-1,3- diones, 1-polyoxyphenyl-3-(2-benzyloxyphenyl)propane-1,3-diones and 1-polyoxy-3-(2,6-dibenzyloxyphenyl)propane-1,3-diones were 79%, 74% and 71%, respectively. The bulkiness of the benzyloxy groups or methoxy groups exerted steric hindrance and reduced the yield. Nevertheless, the yields were higher than the previously reported ones.

Benzoates↗
PubMedDate not supplied

Antioxidant action of a new flavonic derivative in acute carbon tetrachloride intoxication.

The antioxidant potential of a new flavonic derivative named conventionally theophylline-rutoside [TR-1722] was estimated by the measurement of G-6-Pase activity (marker enzyme for the endoplasmic reticulum), catalase activity (enzyme involved in the antioxidant defence process), and total -SH groups from the hepatic homogenate, using CCl4 as a free radical generating model. To show changes in the permeability of the hepatocyte membrane, the activity of lactate dehydrogenase (LDH) in plasma was determined. The obtained results suggest that TR-1722 acts by curtailing both lipid peroxidation and alkylation processes.

Animals↗
PubMed2000

HPLC separation of flavonols, flavones and oxidized flavonols with UV-, DAD-, electrochemical and ESI-ion trap MS detection.

The cation-induced or electrochemical oxidation of flavonols has been reported to yield 2-(hydroxybenzoyl)-2-hydroxy-3(2H)-benzofuranone. Two new gradient reversed phase HPLC methods are presented which allow the determination of those oxidized flavonols simultaneously with flavonols and flavones. UV and electrochemical detection are used because of their high sensitivity. Qualitative detection together with quantification of all compounds is achieved with photodiode-array detection. An electrospray ionization ion trap mass spectrometric method is presented for unique identification of the benzofuranones after HPLC separation.

Chromatography, High Pressure Liquid↗
PubMed2005

Preliminary safety evaluation of the putative cancer chemopreventive agent tricin, a naturally occurring flavone.

PURPOSE: Naturally occurring flavonoids such as quercetin and genistein possess cancer chemopreventive properties in experimental models. However, adverse effects such as their mutagenicity confound their potential clinical usefulness. Furthermore in leukaemia cells some flavonoids cleave the breakpoint cluster region of the mixed lineage leukaemia (MLL) gene as a consequence of inhibition of topoisomerase II. The choice of flavonoids to be developed as cancer chemopreventive agents depends crucially on their safety. Here, we explored safety aspects of the novel flavone tricin, a constituent of rice bran and other grass species, which has recently been found to interfere with murine gastrointestinal carcinogenesis. METHODS: Evidence of pathological or morphological changes in liver, lung, heart, spleen, kidney, adrenal gland, pancreas or thymus tissues was studied in mice which received tricin, genistein or quercetin 1,000 mg/kg daily by the oral route on five consecutive days. The ability of tricin (50 microM) to cleave the MLL gene was studied in human leukaemia cells by Southern blotting, and its effect on human topoisomerase II activity was investigated in incubations with supercoiled DNA. The mutagenicity of tricin was assessed in the Salmonella/Escherichia coli assay, and its clastogenicity was adjudged by chromosomal aberrations in Chinese hamster ovary cells and occurrence of micronuclei in bone marrow erythrocytes in Swiss-Webster mice. RESULTS: Neither tricin, quercetin, or genistein caused pathological or morphological changes in any of the murine tissues studied. Tricin (50 microM) failed to cause MLL gene breakage, and it inhibited topoisomerase II only at 500 microM, but not at 10, 50 or 100 microM. Tricin lacked genotoxic properties in the systems studied here. CONCLUSION: The results tentatively suggest that tricin may be considered safe enough for clinical development as a cancer chemopreventive agent.

Animals↗
PubMed1996

Flavone acetic acid increases the cytotoxicity of mitomycin C when combined with hyperthermia.

Flavone acetic acid (FAA, NSC 347512) is known to selectively reduce tumor blood flow. Taking advantage of this pharmacodynamic effect, we have previously shown that FAA in combination with hyperthermia (HT) can produce a marked improvement in antitumor response in mice. In the present study, we investigated whether FAA could increase the cytotoxicity of mitomycin C (MMC), a bioreductive drug with selective cytotoxicity against hypoxic cells, under either normothermic or hyperthermic conditions. In vitro, the cytotoxicity of MMC against B16 melanoma cells was not enhanced with exposure to FAA at concentrations less than 100 microgram/ml, even when combined with HT (43 degrees C, 60 min). The cytotoxicity of MMC (1 microgram/ml) at pH 6.5, however, was enhanced by exposure of cells to hypoxia in combination with HT. In vivo, the tumor growth time, calculated as the time required to double the initial tumor volume, was 5.2, 6.8, 8.5, and 15.0 days with FAA (150 mg/kg) alone, MMC (4 mg/kg) alone, FAA + MMC, or FAA + MMC + HT (43 degrees C, 15 min) treatment groups, respectively. Antitumor response obtained in animals treated with FAA plus MMC with HT was clearly better than that obtained in any of the other groups. Scheduling of FAA, MMC, and HT was found to be important in producing optimal antitumor response. Administration of MMC (4 mg/kg) prior to FAA (150 mg/kg) and subsequent HT treatment was superior to administration of FAA before MMC. In an attempt to explain these findings, the influence of FAA on blood flow in skeletal muscle and in tumor was examined using a laser blood flowmeter. FAA administration to mice produced a 75% reduction in blood flow to the tumor for up to 2 h but had no detectable effect on normal skeletal blood flow. Our current explanation of the increased antitumor response achieved with the combination of MMC, FAA, and HT is as follows. The FAA-mediated decrease in blood flow to the tumor, when combined with HT, may produce sufficiently hypoxic conditions to significantly increase the antitumor efficacy of the bioreductive drug, MMC. We believe that clinical testing of this combined drug treatment with hyperthermia is warranted.

Animals↗
PubMed2006

Fluorometric detection of adenosine triphosphate with 3-hydroxy-4'-(dimethylamino)flavone in aqueous solutions.

An effect of appearance of new band in the excitation spectra of 3-hydroxy-4'-(dimethylamino)flavone (FME probe) in presence of adenosine triphosphate (ATP) is described. Considerable shift of new band up to the red and increase of fluorescence intensity points to the formation of FME-ATP associate, in which FME molecule undergoes to a strong electrostatic stabilization by tetra-charged ATP anion. It is shown the FME anion formation is possible under influence of ATP in the studied conditions. The dynamics of the observed effect is studied in mitochondria. The registered phenomenon allows the quantitative evaluation of ATP concentration in the range of 10(-3)-10(-5) M. In contrast to ATP, other nucleoside phosphates do not give a new band in the excitation spectra of FME probe. This implies the possibility of the in vivo determination of the ATP concentration.

Adenosine Triphosphate↗