TUMOR-NECROSIS-FACTOR-ALPHA PLASMA-LEVELS AFTER FLAVONE ACETIC-ACID ADMINISTRATION IN MAN AND MOUSE

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 mug/ml at 0.5 h and remained high (165 mug/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 mug/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.