Enhancement of mitomycin-C cytotoxicity by combination with flavone acetic acid in a murine tumour.
The antitumour activity of a combination of Mitomycin C (MMC), a prototypical bioreductive agent, with the vascular occluding agent, flavone acetic acid (FAA), was examined in a murine tumour. Flavone acetic acid induced a long lived reduction of blood flow in the tumour thereby inducing hypoxia and cell death by ischaemia. Dose response curves for tumour cell survival and regrowth delay were constructed after each agent administered alone or when combined. The greatest antitumour effect was measured when the two agents were administered simultaneously. The reduced tumour perfusion induced by the combination was not lower than that for FAA alone indicating that the greater in vivo effect was not due to enhancement of the vascular occluding effect of the FAA. The role of the tumour microenvironment in determining the MMC cytotoxicity was examined using in vitro incubations of MMC under controlled oxygenation and pH. MMC cytotoxicity was increased in hypoxia (enhancement ratio = 2.0) and also when extracellular pH was reduced from 7.4 to 6.4 (enhancement ratio = 1.5). Since the microenvironmental consequences of induced ischaemia are reductions in both oxygenation and pH these parameters are probably responsible in large part for the enhancement of cytotoxicity observed when MMC and FAA are combined.