Tumor-selective vessel occlusions by platelets after vascular targeting chemotherapy using paclitaxel encapsulated in cationic liposomes.
Paclitaxel encapsulated in cationic liposomes (EndoTAG-1) significantly impairs tumor growth by a significant reduction of functional tumor microcirculation and induction of endothelial cell apoptosis. The aim of the study was to analyze whether platelet activation within the tumor microcirculation contributes to the antivascular effects of vascular targeting chemotherapy using EndoTAG-1. In vitro, FACS analysis revealed a significant activation of platelets upon treatment with EndoTAG-1. In vivo, using A-Mel-3 tumors in Syrian Golden hamsters equipped with dorsal skinfold chamber preparations, the contribution of platelets to the antivascular effects of EndoTAG-1 was evaluated by fluorescence and laser-scanning microscopy. Immediately after a single treatment with EndoTAG-1 or cationic liposomes devoid of paclitaxel, an increase of platelet adherence in tumor microvessels was observed. This was accompanied by an acute impairment of the microcirculation within the treated tumors leading to reduced tumor perfusion. After repetitive therapy, an increase of platelet adherence and subsequent tumor microvessel occlusions occurred only after treatment with EndoTAG-1. Comparing to "tumor free" normal tissue controls these microthromboses were tumor selective. Significantly disbalancing the coagulation system within tumors by targeted induction of microthromboses within the tumor microcirculation appears to be an important mechanism of EndoTAG-1 therapy.
Strieth
Sebastian
S
Institute for Surgical Research, University of Munich (LMU), Germany. sebastian.strieth@med.uni-muenchen.de
Nussbaum
Claudia F
CF
Eichhorn
Martin E
ME
Fuhrmann
Martin
M
Teifel
Michael
M
Michaelis
Uwe
U
Berghaus
Alexander
A
Dellian
Marc
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001792:Blood Platelets / Q000378:metabolism*; D006224:Cricetinae; D016503:Drug Delivery Systems; D042783:Endothelial Cells / Q000473:pathology; D005434:Flow Cytometry; D008081:Liposomes / Q000737:chemistry*; D008647:Mesocricetus; D008833:Microcirculation; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D017239:Paclitaxel / Q000008:administration & dosage* / Q000494:pharmacology; D010973:Platelet Adhesiveness
D000970:Antineoplastic Agents; D008081:Liposomes; D017239:Paclitaxel