Vascular targeting by EndoTAG-1 enhances therapeutic efficacy of conventional chemotherapy in lung and pancreatic cancer.
Cationic lipid complexed paclitaxel (EndoTAG-1) is a novel vascular targeting agent for the treatment of cancer. Here, the aim was to investigate intratumoral drug distribution after EndoTAG-1 therapy and analyze the impact of EndoTAG-1 scheduling on antitumoral efficacy. The therapeutic effect of EndoTAG-1 in combination with conventional gemcitabine or cisplatin therapy was evaluated in L3.6pl orthotopic pancreatic cancer and a subcutaneous Lewis lung (LLC-1) carcinoma model. Oregon Green paclitaxel encapsulated in cationic liposomes in combination with intravital fluorescence microscopy clearly exhibited delivery of the drug by EndoTAG-1 to the tumor endothelium, whereas Oregon Green paclitaxel dissolved in cremophor displayed an interstitial distribution pattern. The therapeutic efficacy of EndoTAG-1 was critically dependent on the application schedule with best therapeutic results using a metronomic rather than a maximum tolerated dose application sequence. The combination of EndoTAG-1 therapy and cytotoxic chemotherapy significantly enhanced antitumoral efficacy in both tumor models. Interestingly, only EndoTAG-1 in combination with gemcitabine was able to inhibit the incidence of metastasis in pancreatic cancer. In conclusion, vascular targeting tumor therapy by EndoTAG-1 combined with standard small molecular chemotherapy results in markedly enhanced antitumoral efficacy. Therefore, this combination represents a promising novel strategy for clinical cancer therapy.
Eichhorn
Martin E
ME
Department of Surgery, Klinikum Grosshadern, University of Munich, Munich, Germany. martin.eichhorn@med.uni-muenchen.de
Ischenko
Ivan
I
Luedemann
Siiri
S
Strieth
Sebastian
S
Papyan
Armine
A
Werner
Alexander
A
Bohnenkamp
Hermann
H
Guenzi
Eric
E
Preissler
Gerhard
G
Michaelis
Uwe
U
Jauch
Karl-Walter
KW
Bruns
Christiane J
CJ
Dellian
Marc
M
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D018827:Carcinoma, Lewis Lung; D002945:Cisplatin / Q000008:administration & dosage; D006224:Cricetinae; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004334:Drug Administration Schedule; D016503:Drug Delivery Systems; D006801:Humans; D007150:Immunohistochemistry; D055666:Lipopeptides; D008081:Liposomes; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage*; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D055666:Lipopeptides; D008081:Liposomes; D003841:Deoxycytidine; D017239:Paclitaxel; D002945:Cisplatin; D000093542:Gemcitabine