Small-molecule cytokine inducers causing tumor necrosis.

The capillary networks of solid tumors are more permeable and less well organized than those of normal tissue. This review explores the hypothesis that these differences might be exploited as a selective antitumor strategy. Both high and low molecular weight compounds have been found to induce cytokines such as tumor necrosis factor (TNF) and to inhibit tumor blood flow in experimental tumors, with consequent induction of necrosis. Flavone acetic acid (FAA) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) are of particular interest. Accumulating evidence implicates the enzyme IkappaB kinase, which leads to the activation of the transcription factor, NFkappaB, as a target for these drugs. The downstream effects of FAA and DMXAA on the tumor microcirculation are complex, involving both direct and indirect effects on vascular endothelial cells. Induced changes in the shape and organization of vascular endothelial cells may lead to the activation of blood platelets and the release of 5-HT. Cytokines, 5-HT and nitric oxide (NO) released in response to FAA and DMXAA may induce a sustained increase in the permeability of tumor vascular cells, leading to cessation of blood flow and induction of tumor necrosis. Exploitation of this principle to clinical anticancer therapy represents an important challenge for the future.