5,6-Di-methylxanthenone-4-acetic
acid (
DMXAA) is a small molecule in the flavanoid class that has antitumor activity. Although classified as a "vascular disrupting agent," we have recently conducted studies showing that
DMXAA has remarkable efficacy in a range of
tumors, working primarily as an immune modulator that activates tumor-associated macrophages and induces a subsequent CD8(+) T-cell-mediated response. To more completely analyze the effect of
DMXAA on CD8(+) T-cell generation, we treated mice bearing
tumors derived from EG7
thymoma cells that express the well-characterized chicken
ovalbumin neotumor
antigen. Treatment with
DMXAA led to
cytokine release,
tumor cell
necrosis, and ultimately reduction in
tumor size that was lymphocyte dependent. Within 24 h of administration, we observed dendritic cell activation in
tumor-draining lymph nodes (TDLN). This was followed by a rapid and marked increase in the number of tetramer-specific CD8(+) T cells in the spleens of treated animals. In contrast, the vascular disrupting agent
combretastatin A4-phosphate, which caused a similar amount of immediate
tumor necrosis, did not activate dendritic cells, nor induce an effective antitumor response. Using in vitro systems, we made the observation that
DMXAA has the ability to directly activate mouse dendritic cells, as measured by increased expression of costimulatory molecules and proinflammatory
cytokine release via a pathway that does not require the
Toll-like receptor adaptor molecule MyD88.
DMXAA thus has the ability to activate
tumor-specific CD8(+) T cells through multiple pathways that include induction of
tumor cell death, release of stimulatory
cytokines, and direct activation of dendritic cells.