Flavone acetic acid (FAA) is a synthetic
flavonoid with a remarkable spectrum of anticancer activities in mouse tumours, but with no anticancer activity in humans. The mechanism of action of this
drug is complex and involves a tumour vasculature action similar to the effects of tumour
necrosis factor (TNF). To assess directly the role of TNF in FAA mechanism of action, this
cytokine was assayed in both mouse and human plasma after
intravenous administration of the
drug. In mouse, a species particularly sensitive to FAA antitumour action, FAA plasma concentrations reached 268 micrograms/ml at 0.5 h and remained high (165 micrograms/ml) at 6 h following the
intravenous administration of an anticancer efficacious dose (540 mg/m2). After FAA administration in mouse, TNF activity (L929 mouse cell bioassay) increased to 300 pg/ml
TNF-alpha-equivalent at 2 h, reached a maximum concentration of 600 pg/ml at 4 h, and declined thereafter to 220 pg/ml at 6 h. TNF activity in mouse plasma was completely abrogated in the presence of mouse
TNF-alpha antibodies. FAA added directly to blank mouse plasma did not show TNF activity. In patients receiving the
drug as a 6-h
intravenous infusion at doses ranging from 3.6 to 8.1 g/m2, FAA plasma levels ranged from 58 to 449 micrograms/ml at the end of infusion. Human
TNF-alpha levels assayed with an immunoradiometric assay were either not detectable or very low (< 25 pg/ml) before FAA administration. At completion of the FAA infusion,
TNF-alpha remained near background levels in 20 of the 21 courses. A slight increase in plasma
TNF-alpha was observed in 1 patient at the 8.1 g/m2 dose level of FAA, from 13 pg/ml before
intravenous infusion, to 70 pg/ml at completion of
intravenous infusion. Taken together, these data demonstrate a marked interspecies difference with regard to
TNF-alpha secretion after FAA treatment, as this
cytokine is produced in mice, whereas it is not significantly secreted in pretreated patients. Although the low
TNF-alpha levels achieved in mice probably do not explain all of FAA antitumour activity in that species, the observed interspecies difference in
TNF-alpha secretion after FAA administration could partly explain the marked difference in FAA antitumour activity observed between mice and humans.