Antiproliferative properties of flavone acetic acid (NSC 347512) (LM 975), a new anticancer agent

Capolongo, Laura; Balconi, Giovanna; Ubezio, Paolo; Giavazzi, Raffaella; Taraboletti, Giulia; Regonesi, Antonella; Yoder, Omar C.; D’Incalci, Maurizio

doi:10.1016/0277-5379(87)90096-4

Cited by 39 publications

(14 citation statements)

References 3 publications

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“…Previous in vitro studies with a variety of tumour cell lines indicate that high drug concentrations and long exposure times are necessary to achieve direct cytotoxicity (Bibby et al, 1987a;Capolonga et al, 1987;Schroyens et al, 1987 Smith et al (1987) have described the induction of haemorrhagic necrosis in mouse colon 26 and colon 38 tumours and suggest that FAA may work in a similar fashion to tumour necrosis factor (TNF). Ching and Baguley (1987) and Wiltrout (1987) have also suggested that natural killer (NK) cells may be involved in the mechanisms of action of FAA as it activates NK cell activity in mice.…”

Section: Chemotherapymentioning

confidence: 99%

Unique chemosensitivity of MAC 16 tumours to flavone acetic acid (LM975, NSC 347512)

Bibby

Double²,

Loadman³

1988

Br J Cancer

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Summary MAC 16 is one of a series of mouse colon tumours originally induced by dimethylhydrazine. It is a relatively slow growing subcutaneous adenocarcinoma which becomes necrotic as it grows and causes severe body wasting in the host. This study has indicated that the tumour is resistant to a large number of standard anti-cancer drugs but is highly responsive to the investigational agent flavone acetic acid (FAA). The levels of FAA achieved in tumours are lower than those necessary for activity in vitro suggesting its mechanism of action in vivo is not (Corbett et al., 1986;Plowman et al., 1986;Bibby et al., 1987a concentrations for a desired dose to be administered in 0.1 ml per lOg body weight. Drugs were made up immediately before use and all injections were i.p. TumoursThe development of several transplantable adenocarcinomas of the large bowel in mice from primary tumours induced by prolonged administration of 1,2,dimethylhydrazine has been described elsewhere (Double et al., 1975). MAC 16 tumours were excised from donor animals and placed in sterile 0.9% saline containing streptomycin (2mg ml -') and penicillin (2000 U ml-1) and cut into small fragments 1 x 2mm in size. Fragments were implanted s.c. into the flank by means of a trocar. Take rates are variable with good rates being dependent on careful implantation of viable tumour fragments. Positive takes can only be identified 2-3 weeks after implantation. ChemotherapyTumour bearing animals were allocated by restricted randomisation into groups of 10. Chemotherapy did not commence until the tumours could be reliably measured, i.e. until they achieved minimum dimensions of 4 x 5 mm. Therapeutic effects were assessed by twice weekly 2-dimensional caliper measurements of the tumour. Tumour volume was calculated from the formula a2 x b/2 where a is the smaller diameter and b is the larger (Geran et al., 1972

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Section: Chemotherapymentioning

confidence: 99%

Unique chemosensitivity of MAC 16 tumours to flavone acetic acid (LM975, NSC 347512)

Bibby

Double²,

Loadman³

1988

Br J Cancer

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“…However, contrary to its potent antitumor activity reported in mice, FAA has not shown anticancer activity in humans (Weiss et al, 1988;Kerr et al, 1989;de Forni et al, 1995). This interspecies difference in FAA anticancer activity has been hypothesized to be, at least partially, due to a possible metabolic activation of this flavonoid in vivo in mice (Capolongo et al, 1987;Chabot et al, 1989).…”

mentioning

confidence: 94%

“…Because FAA is weakly cytotoxic in vitro in murine and human cancer cell lines (Drewinko and Yang, 1986;Capolongo et al, 1987;Schroyens et al, 1987), which are otherwise responsive to FAA when these tumor cells are implanted in mice, several indirect mechanisms of anticancer action have therefore been suggested: augmentation of natural killer activity and induction of interferon (Hornung et al, 1988); antiangiogenic properties (Lindsay et al, 1996); and tumor blood flow shut down and induction of extensive hemorrhagic necrosis (Corbett et al, 1986;Evelhoch et al, 1988;Bibby et al, 1989;Hill et al, 1989;Zwi et al, 1989). At the molecular level, FAA has been reported to induce DNA damage in Glasgow osteogenic sarcoma after in vivo administration, which could indicate the in vivo formation of reactive metabolites in mice .…”

mentioning

confidence: 99%

Identification of New Flavone-8-Acetic Acid Metabolites Using Mouse Microsomes and Comparison with Human Microsomes

Pham¹,

Auzeil²,

Regazzetti³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Flavone-8-acetic acid (FAA) is a potent anticancer agent in mouse but has not shown activity in humans. Because FAA metabolism could play a role in this interspecies difference, our aim was to identify the metabolites formed in vitro using mouse microsomes compared with those in human microsomes. Mouse microsomes produced six metabolites as detected by reversed-phase highperformance liquid chromatography-mass spectrometry (MS). Three metabolites were identified as the 3-, 4-, or 6-hydroxy-FAA, by comparison with retention times and UV and MS spectra of standards. Two metabolites presented a molecular weight of 296 (FAA ‫؍‬ 280) indicating the presence of one oxygen but did not correspond to any monohydroxylated FAA derivative. These two metabolites were identified as epoxides because they were sensitive to epoxide hydrolase. The position of the oxygen was determined by the formation of the corresponding phenols under soft acidic conditions: one epoxide yielded the 3-and 4-hydroxy-FAA, thus corresponding to the 3,4-epoxy-FAA, whereas the other epoxide yielded 5-and 6-hydroxy-FAA, thus identifying the 5,6-epoxy-FAA. The last metabolite was assigned to the 3,4-dihydrodiol-FAA because of its molecular weight (314) and sulfuric acid dehydration that indicated that the 3-and 4-positions were involved. Compared with mouse microsomes, human microsomes (2 pools and 15 individual microsomes) were unable to metabolize FAA to a significant extent. In conclusion, we have identified six new FAA metabolites formed by mouse microsomes, whereas human microsomes could not metabolize this flavonoid to a significant extent. The biological importance of the new metabolites identified herein remains to be evaluated.

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“…against advanced experimental colon tumors in mice [4]. Additionally, FAA has a different toxicity profile to most anticancer drugs, with no significant myelo suppression observed [5]. The related compounds MFAA (6-methyl-4-oxo-2-aryl-4H-chromen-8-yl)acetic acid) containing a 6-methyl substituent in FAA showed antitumor activity comparable to FAA in vitro but were essentially inactive in vivo [6].…”

Section: Introductionmentioning

confidence: 99%

The Influence of some Xanthone Derivatives on the Activity of J-774A.1 Cells

Marona¹,

Pękala²,

Gunia³

et al. 2009

Sci. Pharm.

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The chemiluminescence of stimulated cells with phorbol myristate acetate and the production of nitric oxide after stimulation with lipopolisaccharide in the presence of the parent compounds FAA (flavone-8-acetic acid = (4-oxo-2-phenyl-4H-chromen-8-yl)acetic acid), XAA (xanthone-4-acetic acid = (9-oxo-9H-xanthen-4-yl)acetic acid), and appropriate xanthone derivatives (1-7) was determined. Also the toxicity of the FAA, MFAA ((6-methyl-4-oxo-2-aryl-4H-chromen-8-yl)acetic acid), XAA and 1-7 against J-774A.1 cultured cells was evaluated. Compound 5 (2-methyl-2-{[(9-oxo-9H-xanthen-2-yl)methyl]sulfanyl}-propanoic acid) was effective in inhibiting chemiluminescence of J-774A.1 cells but most of the other tested compounds stimulated the reaction. FAA and two xanthones with a methoxycarbonyl moeity slightly decreased the generation of nitric oxide at 50 μM. Most of the tested compounds (1-7) showed weak toxicity at concentration of 100 μM.

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Antiproliferative properties of flavone acetic acid (NSC 347512) (LM 975), a new anticancer agent

Cited by 39 publications

References 3 publications

Unique chemosensitivity of MAC 16 tumours to flavone acetic acid (LM975, NSC 347512)

Unique chemosensitivity of MAC 16 tumours to flavone acetic acid (LM975, NSC 347512)

Identification of New Flavone-8-Acetic Acid Metabolites Using Mouse Microsomes and Comparison with Human Microsomes

The Influence of some Xanthone Derivatives on the Activity of J-774A.1 Cells

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