Vascular targeting in pancreatic cancer: the novel tubulin-binding agent ZD6126 reveals antitumor activity in primary and metastatic tumor models.
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.
Kleespies
Axel
A
Department of Surgery, Klinikum Grosshadern, Ludwig-Maximilian-University, Munich, Germany. axelkleespies@aol.com
Köhl
Gudrun
G
Friedrich
Michael
M
Ryan
Anderson J
AJ
Barge
Alan
A
Jauch
Karl-Walter
KW
Bruns
Christiane J
CJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D049109:Cell Proliferation; D002478:Cells, Cultured; D004396:Coloring Agents / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008956:Models, Chemical; D009336:Necrosis; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000473:pathology*; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014404:Tubulin / Q000737:chemistry*; D014471:Umbilical Veins / Q000166:cytology; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D004396:Coloring Agents; C455219:N-acetylcochinol-O-phosphate; D009943:Organophosphorus Compounds; D013778:Tetrazolium Salts; D013844:Thiazoles; D014404:Tubulin; D003841:Deoxycytidine; C022616:thiazolyl blue; D000093542:Gemcitabine