Vascular targeting by EndoTAG-1 enhances therapeutic efficacy of conventional chemotherapy in lung and pancreatic cancer

Int J Cancer. 2010 Mar 1;126(5):1235-45. doi: 10.1002/ijc.24846.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Carcinoma, Lewis Lung
  • Cisplatin / administration & dosage
  • Cricetinae
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Drug Administration Schedule
  • Drug Delivery Systems
  • Humans
  • Immunohistochemistry
  • Lipopeptides
  • Liposomes
  • Lung Neoplasms / blood supply
  • Lung Neoplasms / drug therapy*
  • Male
  • Mice
  • Neovascularization, Pathologic / drug therapy*
  • Paclitaxel / administration & dosage*
  • Pancreatic Neoplasms / blood supply
  • Pancreatic Neoplasms / drug therapy*

Substances

  • Antineoplastic Agents
  • Lipopeptides
  • Liposomes
  • Deoxycytidine
  • gemcitabine
  • Paclitaxel
  • Cisplatin