Antiangiogenetische Therapie beim humanen Pankreaskarzinom nach orthotoper Implantation in die Nacktmaus durch einen Mikrotubuli-Inhibitor

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.