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At least 487 records · Page 27Linked to original sources
PubMed1990

Recombinant interleukin-2 (rIL-2) with flavone acetic acid (FAA) in advanced malignant melanoma: immunological studies.

Natural killer (NK) cell activity and lymphokine activated killer (LAK) cell cytotoxicity were measured in patients receiving recombinant interleukin 2 (rIL-2) and flavone acetic acid (FAA) for treatment of progressing metastatic melanoma. NK activity was increased in 23 of 26 patients and LAK activity induced in 13 of 26 patients. However, levels of cytotoxicity in the present study were not significantly greater than a previous study using rIL-2 alone. LAK cell precursors demonstrated by in vitro incubation of pretreatment lymphocytes with IL-2 and subsequent cytotoxicity were no different in the patients compared to normal controls. Analysis of cell surface phenotypes failed to reveal any significant changes in the cell populations examined, including IL-2R and Leu 19. Although five patients had tumour response, one being complete, there was no correlation with the immunological parameters examined.

Adjuvants, Immunologic↗
PubMed1990

Recombinant interleukin-2 (rIL-2) with flavone acetic acid (FAA) in advanced malignant melanoma: a phase II study.

Recombinant interleukin 2 (rIL-2) and flavone acetic acid (FAA) were used to treat 34 patients with progressing metastatic melanoma. Five patients had solely non-visceral disease and the median number of organ sites involved was two. Five doses of rIL-2 were given, the first dose intrasplenically via a femoral artery catheter with a further dose 4 h later i.v. and the other doses i.v. on alternate days. The rIL-2 dose was 11 x 10(6) Cetus units m-2; the day before rIL-2, FAA (4.8 G m-2) was given as a 6 h i.v. infusion, in order to enhance further killer cell activity. A total of three courses at 21-day intervals was planned and 74 courses in all were given. Despite the high dose of rIL-2 and the potential overlapping toxicity affecting blood pressure with the addition of FAA, side-effects were generally mild. There were only five episodes of grade 4 toxicity: one of ventricular tachycardia and four other episodes of transient biochemical or haematological disturbance. Grade 3 hypotension or hypertension occurred on 22 courses but again was transient. No patient required intensive care facilities. Five patients had tumour response, one being complete. Responses occurred in pulmonary and hepatic metastases, but mainly in non-visceral sites. Eleven patients remain alive at 6-17 months and in five there is no relapse or progression of disease. Despite the impressive results in animal tumour models, the addition of FAA to rIL-2 in the present study has not markedly improved results over rIL-2 alone.

Adjuvants, Immunologic↗
PubMed1990

The use of vascularised spheroids to investigate the action of flavone acetic acid on tumour blood vessels.

EMT6 multicellular spheroids were introduced into the peritoneal cavities of mice and allowed to become vascularised, resulting in solid spherical tumours. The necrotic cores of the initially avascular spheroids were replaced by vascularised tumour tissue but the outer zones of the spheroids failed to become vascularised. The presence of both vascular and avascular components in each spheroid allowed the role of the vasculature in the antitumour action of flavone acetic acid (FAA) to be determined. Eighteen hours after treatment with FAA 0.8 mmol kg-1, the vascularised core became necrotic and haemorrhagic, while the outer avascular zone remained viable. Tumour cells which were infiltrating superficial sub-mesothelial fat did not become necrotic despite the presence of numerous thrombi in associated vessels. Injection of two fluorescent vascular markers, the first (Hoechst 33342) together with FAA, and the second (10-nonyl acridine orange) 4 h later, demonstrated that there is a marked loss of blood flow in the spheroids. These results provide further evidence that FAA kills blood vessel-dependent tumour cells by interrupting the tumour blood supply.

Acridine Orange↗
PubMed1991

Anti-tumour activity of flavone acetic acid (NSC 347512) in mice--influence of immune status.

Flavone acetic acid (FAA) is a synthetic flavonoid with dramatic pre-clinical anti-tumour activity involving a vascular component in its mechanism but no clinical effects have been seen to date. As FAA also has immunomodulatory activity, immunological factors might explain differences in activity between mouse and man. This study examines the influence of host immune status on the anti-tumour activity of FAA. Two human colon tumour xenografts (COBA, HT-29) fail to respond to FAA in nude mice. The lack of activity of FAA against HT-29 xenografts cannot be explained on the basis of limited drug bioavailability as achievable plasma, and tumour levels of FAA are similar to those seen in sensitive murine colon tumours. The immune status of the host also influences the activity of FAA against two transplantable tumours of the mouse colon. Both these tumours are highly responsive to FAA in their normal NMRI hosts, but neither tumours exhibited significant growth delay in thymectomised NMRI or nude hosts. Histological examination of treated tumours revealed significant areas of haemorrhagic necrosis in all three hosts. These data suggest a clear immunological component in the mechanism of action of FAA which is separate from the previously described haemorrhagic necrosis.

Adenocarcinoma↗
PubMed1991

The relationship between tissue levels of flavone acetic acid (NSC 347512) and site dependent anti-tumour activity in murine colon tumours.

Flavone acetic acid (FAA) is extremely active against subcutaneous transplantable tumours in mice, but disappointingly there has been no demonstrable clinical activity. Previous studies have shown that lung tumour deposits are less responsive than the same cells implanted subcutaneously. The aim of this study is to examine the tissue disposition of FAA in an attempt to explain this site-dependent activity. The data show clearly that FAA clearance curves are influenced by the presence of MAC 15A tumours growing either subcutaneously or systemically. The decreased clearance of FAA from MAC 15A tumour bearing animals does not however explain the resistance of lung deposits. Neither can this be explained by differences in metabolism in these different sites. Cytotoxic metabolites have not been detected either in vitro or in vivo and their role in the mechanism of action of FAA is questionable.

Adenocarcinoma↗
PubMed1991

Divergent effects of flavone acetic acid on established versus developing tumour blood flow.

Flavone Acetic Acid (FAA) exerts much of its effect by reducing tumour blood flow. Previous studies on FAA-induced changes in blood flow have used established tumours with a functional microvasculature. Using radioactive Xenon(133Xe) clearance to monitor local blood flow we show that the effects of FAA are dependent on the presence of this functional microvasculature with no evidence that FAA inhibits the actual development of tumour microcirculation. Thus, administration of multiple doses of FAA around the time of tumour cell injection failed to diminish t1/2 values of 133Xe (e.g. t1/2 16 min for FAA vs 14 min for saline controls at 10 days) or to affect tumour volumes (5.55 +/- 0.06 cm3 in FAA-treated animals vs 5.7 +/- 1.3 cm3 in controls at 25 days). In marked contrast a single dose of FAA (200 mg kg-1 body weight) 2 weeks after tumour cell injection dramatically extended t1/2 times (47 min for FAA vs 7 min for controls; P less than 0.001) and significantly reduced tumour burden. This effect is specific for tumour microvasculature and is not directed simply at new vessels since a similar treatment of animals with implanted-sponge-induced granulation tissue had no effect on t1/2 times (6.8 +/- 1.1 min for FAA at 200 mg kg-1 vs 7.2 +/- 1.0 min for saline-treated controls.

Animals↗
PubMed1991

Anticoagulant treatment does not affect the action of flavone acetic acid in tumour-bearing mice.

Flavone acetic acid (FAA) is a novel antitumour agent that has a profound effect on the vasculature in murine tumour models. Previously we have shown that FAA induces a coagulopathy and thrombocytopaenia in tumour-bearing mice, and the purpose of the present study was to determine the significance of the FAA-induced intravascular coagulation in the antitumour action of FAA. Several anticoagulant agents were tested for their effectiveness in altering ex vivo coagulation of murine plasma; heparin and ancrod were found to be most effective. These agents were administered to tumour-bearing mice prior to FAA and TNF treatment with little effect on the induced regrowth delay. However: the FAA-induced consumption of platelets in tumour-bearing mice was not blocked by anticoagulant treatment. These data suggest that platelet consumption occurs independently of the normal coagulation pathway, and further that fibrin deposition may not be a major factor in the antitumour action of FAA.

Adenocarcinoma↗
PubMed1992

Tumour concentrations of flavone acetic acid (FAA) in human melanoma: comparison with mouse data.

Flavone acetic acid (FAA) showed impressive effects against murine solid tumours but no activity in clinical studies. The mechanism of action in mice may involve damage to tumour vasculature or immunomodulation, and these effects may be species-specific. Alternatively, concentrations of FAA achieved in mouse tumours may be higher than in human tumours. It is important to resolve this issue since it raises important questions about the relevance of in vitro versus in vivo tumour screens and the development of FAA analogues. As part of a Cancer Research Campaign Phase II study of metastatic melanoma in which 8.4 g m-2 FAA was given as a 6 h infusion, six tumour biopsies were obtained from four patients. FAA tumour concentrations were determined by HPLC and compared with subcutaneous murine solid tumours within the same analytical laboratory. Tumour/plasma percentages (range 26-61%; mean +/- SD, 43.9 +/- 11.4%) were similar to those in mice, as was the area under the curve (AUC) extrapolated to infinity and the AUC above the putative activity threshold of 100 micrograms ml-1. We conclude that the exposure of drug-refractory human melanoma tissue to FAA was comparable to that of sensitive mouse tumours. This suggests that reduced penetration of FAA into human tumours is unlikely to explain the lack of antitumour activity observed in clinical studies and that differences in mechanism of action are predominant.

Adult↗
PubMed1992

Flavone acetic acid (FAA) with recombinant interleukin-2 (TIL-2) in advanced malignant melanoma. II: Induction of nitric oxide production.

Plasma samples were collected from 20 patients undergoing phase I clinical trial with flavone-8-acetic acid (FAA; 4.8 g m-2 per dose) in combination with recombinant human interleukin-2 (rhIL-2; 6-18 i.u. m-2 per day) for the treatment of metastatic melanoma. Samples were analysed for nitrate content as an indication of the oxidation of L-arginine to nitric oxide. Pretreatment plasma nitrate levels (53 +/- 4 microM) were significantly above those of healthy volunteers (19 +/- 4 microM). The maximum plasma nitrate concentration obtained after treatment, 190 +/- 29 microM (range 49 to 655 microM), was comparable to that of mice treated with FAA. Most of the increases occurred 3-5 days after initiation of a 5 day infusion of rhIL-2, but three of the increases occurred within 2 days of a 1 h infusion of FAA alone. The maximum plasma nitrate concentrations of the three patients which underwent remission (two complete, one partial) following treatment (368 +/- 143 microM) were significantly higher (P < 0.05) than those of patients with progressive disease. Hypotension was the major dose-limiting side effect, and there was no relationship between the degree of hypotension and the rise in plasma nitrate. The results provide evidence that treatment of patients with FAA and rhIL-2 induce the synthesis of nitric oxide, a physiological mediator and potential cytotoxic agent.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Flavone acetic acid (FAA) with recombinant interleukin-2 (rIL-2) in advanced malignant melanoma. III: Cytokine studies.

Twelve patients undergoing IL-2 and flavone acetic acid (FAA) combination immunotherapy for advanced melanoma were studied throughout treatment for the induction of measurable levels of bioactive TNF, GM-CSF and IL-6 in their serum. This was to assess the extent of secondary cytokine induction in these patients and the possible role of such cytokines in both the toxic and therapeutic responses. The nature of the treatment schedule enabled these cytokines to be measured in response to FAA alone, FAA/IL-2 and FAA alone following IL-2/FAA activation of target cells. A small rise in the serum levels of these cytokines was seen on the initial course of FAA/IL-2 but this was minor compared to the marked elevation in levels 2-8 h following the initiation of the third course of FAA given with or without IL-2 and at a time point which coincided with maximum toxicity in those patients who experienced it. These results show that FAA alone can induce cytokine release from primed target cells. This may be associated with the therapeutic effect and/or toxicity of the agent.

Adult↗
PubMed1999

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.

Animals↗
PubMed1998

Benzodiazepine binding site-interactive flavones from Scutellaria baicalensis root.

A benzodiazepine binding assay directed separation led to the identification of 3 flavones baicalein (1), oroxylin A (2), and skullcapflavone II (3) from the water extract of Scutellaria baicalensis root. Compounds 1, 2, and 3 interacted with the benzodiazepine binding site of GABAA receptors with a Ki value of 13.1, 14.6 and 0.36 micromol/L, respectively.

Animals↗
PubMed2001

Novel CFTR chloride channel activators identified by screening of combinatorial libraries based on flavone and benzoquinolizinium lead compounds.

The flavonoid genistein and the benzo[c]quinolizinium MPB-07 have been shown to activate the cystic fibrosis transmembrane conductance regulator (CFTR), the protein that is defective in cystic fibrosis. Lead-based combinatorial and parallel synthesis yielded 223 flavonoid, quinolizinium, and related heterocyclic compounds. The compounds were screened for their ability to activate CFTR at 50 microm concentration by measurement of the kinetics of iodide influx in Fisher rat thyroid cells expressing wild-type or G551D CFTR together with the green fluorescent protein-based halide indicator YFP-H148Q. Duplicate screenings revealed that 204 compounds did not significantly affect CFTR function. Compounds of the 7,8-benzoflavone class, which are structurally intermediate between flavones and benzo[c]quinoliziniums, were effective CFTR activators with the most potent being 2-(4-pyridinium)benzo[h]4H-chromen-4-one bisulfate (UCcf-029). Compounds of the novel structural class of fused pyrazolo heterocycles were also strong CFTR activators with the most potent being 3-(3-butynyl)-5-methoxy-1-phenylpyrazole-4-carbaldehyde (UCcf-180). A CFTR inhibitor was also identified. The active compounds did not induce iodide influx in null cells deficient in CFTR. Short-circuit current measurements showed that the CFTR activators identified by screening induced strong anion currents in the transfected cell monolayers grown on porous supports. Compared with genistein, the most active compounds had up to 10 times greater potency in activating wild-type and/or G551D-CFTR. The activators had low cellular toxicity and did not elevate cellular cAMP concentration or inhibit phosphatase activity, suggesting that CFTR activation may involve a direct interaction. These results establish an efficient screening procedure to identify CFTR activators and inhibitors and have identified 7,8-benzoflavones and pyrazolo derivatives as novel classes of CFTR activators.

Animals↗
PubMed1994

The morphological effects of the anti-tumor agents flavone acetic acid and 5,6-dimethyl xanthenone acetic acid on the colon 38 mouse tumor.

Flavone acetic acid and 5,6-dimethyl xanthenone acetic acid have a broad spectrum of anti-tumor activity in mice, and act by stimulating immune cells and inhibiting tumor blood flow, resulting in hemorrhagic necrosis within 24 hrs. To study the evolution of hemorrhagic necrosis, subcutaneous Colon 38 tumors were examined by light and electron microscopy from 30 min to 24 hrs after treatment with these agents, and measurements of tumor energy metabolites made. The results show that both agents cause apoptosis beginning at 30 min, and that by 4 hrs necrosis supervenes, accompanied by rupture of tumor blood vessels. The absence of early endothelial cell damage or thrombosis suggests that vessel rupture, and consequent loss of blood flow and energy metabolite depletion, is caused by loss of extravascular mechanical support by the tumor parenchyma.

Adenocarcinoma↗
PubMed2001

A new flavone glycoside, 5-hydroxy 7,3',4',5'-tetra-methoxyflavone 5-O-beta-D-xylopyranosyl-(1-->2)-alpha-L-rhamnopyranoside from Bauhinia variegata Linn.

A new flavone glycoside m.f. C(30)H(36)O(15) m.p. 252-253 degrees C, [M]+ 636 (EIMS) was isolated from the acetone soluble fraction of the concentrated 95% ethanolic extract of the seeds of Bauhinia variegata (Linn). It was identified as 5-hydroxy7,3',4',5'-tetra-methoxyflavone 5-O-beta-D-xylopyranosyl-(1-->2)-alpha-L-rhamnopyranoside (1) by various colour reactions, chemical degradations and spectral techniques.

Aspartic Acid Endopeptidases↗
PubMed2003

Two new flavone glycosides from Valeriana jatamansi.

From the rhizomes and roots of Valeriana jatamansi Jones, two new flavone glycosides, acacetin 7-O-beta-sophoroside (1), and acacetin 7-O-(6"-O-alpha-L-rhamnopyranosyl)-beta-sophoroside (2), have been isolated together with fifteen known compounds. Their structures were determined by spectroscopic and chemical means.

Flavonoids↗
PubMed1998

A new flavone 2'-glucoside from Andrographis alata.

A new flavone glucoside, 5,2',6'-trihydroxy-7-methoxyflavone 2'-O-beta-D-glucopyranoside has been isolated from the whole plant of Andrographis alata. The structure was elucidated on the basis of spectral and chemical evidence.

Flavonoids↗