ZD6126 is a novel vascular-targeting agent that acts by disrupting the
tubulin cytoskeleton of an immature
tumor endothelium, leading to an occlusion of
tumor blood vessels and a subsequent
tumor necrosis. We wanted to evaluate
ZD6126 in primary and metastatic
tumor models of human
pancreatic cancer. Nude mice were injected orthotopically with L3.6pl
pancreatic cancer cells. In single and multiple dosing experiments, mice received
ZD6126,
gemcitabine, a combination of both agents, or no treatment. For the induction of metastatic diseases, additional groups of mice were injected with L3.6pl cells into the spleen. Twenty-four hours after a single-dose treatment,
ZD6126 therapy led to an extensive central
tumor necrosis, which was not seen after
gemcitabine treatment. Multiple dosing of
ZD6126 resulted in a significant growth inhibition of primary
tumors and a marked reduction of spontaneous liver and
lymph node metastases. Experimental metastatic diseases could be significantly controlled by a combination of
ZD6126 and
gemcitabine, as shown by a reduction of the number and size of established liver
metastases. As shown by additional in vitro and in vivo experiments, possible mechanisms involve antivascular activities and subsequent antiproliferative and proapoptotic effects of
ZD6126 on
tumor cells, whereas direct activities against
tumor cells seem unlikely. These data highlight the antitumor and antimetastatic effects of
ZD6126 in human
pancreatic cancer and reveal benefits of adding
ZD6126 to standard
gemcitabine therapy.