The effect of 5,6-dimethylxanthenone-4-acetic acid on tumour necrosis factor production by human immune cells.
5,6-dimethylxanthenone-4-acetic acid (5,6-MeXAA) is a potent anti-tumour agent which is undergoing early clinical evaluation. It was developed as an improved analogue of flavone acetic acid (FAA) which failed in clinical trial although it had impressive anti-tumour activity in mice. It has been postulated that one possible reason for the clinical failure of FAA was its inability to induce cytokines, especially tumour necrosis factor (TNF) in humans whereas this was seen as an important component of its mechanism of action in mice. Previous studies have demonstrated that 5,6-MeXAA induces mRNA for TNF in the human HL-60 cell line although the protein was not detected. This study has demonstrated mRNA for TNF alpha by RT-PCR in human and murine immune cells incubated with either 5,6-MeXAA, FAA or in culture medium alone. Using a bioassay technique 5,6-MeXAA and FAA were shown to induce TNF production in vitro by murine macrophages but TNF was not detected when human or murine peripheral blood mononuclear cells were stimulated with these agents. A small but significant production of TNF was seen in the HL-60 cell line after 5,6-MeXAA treatment suggesting 5,6-MeXAA can directly stimulate human cells to produce TNF albeit at low levels.
Patel
S
S
Clinical Oncology Unit, University of Bradford, West Yorkshire, UK.
Parkin
S M
SM
Bibby
M C
MC
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D016207:Cytokines / Q000235:genetics; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D051379:Mice; D009000:Monocytes / Q000378:metabolism; D016133:Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D014966:Xanthenes / Q000494:pharmacology; D044004:Xanthones
D000970:Antineoplastic Agents; D016207:Cytokines; D005419:Flavonoids; D014409:Tumor Necrosis Factor-alpha; D014966:Xanthenes; D044004:Xanthones; C066668:vadimezan; C049328:flavone acetic acid