Bioflavonoids are known to inhibit
enzymes in the glycolytic pathway and have been reported to decrease tumour blood flow. The
antineoplastic capabilities of
flavone acetic acid (FAA), dimethylaminoethyl-flavone-8-acetate (
FAA ester) and quercitin (Q) as a function of pH, level of oxygenation and in conjunction with
hyperthermia or
SR-4233. In vitro, exposure of FSaIIC murine
fibrosarcoma cells to various concentrations of FAA or
FAA ester for 1 h demonstrated that both drugs were slightly more toxic toward hypoxic cells at 37 degrees C and pH 7.40 (but were somewhat less cytotoxic at pH 6.45 and 37 degrees C) than towards normally oxygenated cells. The cytotoxicity of FAA and
FAA ester increased only minimally by concomitant treatment of cells at 42 degrees C or 43 degrees C. When temperatures of tumour-bearing mice anaesthetized with
chloral hydrate and
pentobarbital were measured both FAA (200 mg/kg) and Q (200 mg/kg) caused a more rapid drop in tumour versus core temperature, indicating a relative shutdown of tumour blood flow had been produced by these
flavonoids. In
Hoechst 33342 dye-defined subpopulations, both FAA and Q were only minimally cytotoxic in the subpopulation enriched in euoxic (bright) cells, producing surviving fractions of 0.70 and 0.29, respectively but were approximately 2-fold and 3-fold respectively more toxic towards the subpopulation enriched in hypoxic (dim) cells. When FAA preceded
hyperthermia approximately a 3-4-fold increase in cell kill resulted from the combination in both subpopulations. Finally, when
SR-4233, a selective hypoxic cell
cytotoxic agent, was administered prior to FAA or Q and followed by
hyperthermia the level of tumour cell killing increased so that the surviving fractions were 0.009 and 0.0055, respectively, in the dim cell subpopulation. These results indicate that FAA,
FAA ester and Q may be most effectively used in a setting involving a combined modality regimen with a focus on the hypoxic tumour cell population.