No abstract

Cationic lipid complexed paclitaxel (EndoTAG TM -1) is a novel vascular targeting agent for the treatment of cancer. Here, the aim was to investigate intratumoral drug distribution after EndoTAG TM -1 therapy and analyze the impact of EndoTAG TM -1 scheduling on antitumoral efficacy. The therapeutic effect of EndoTAG TM -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 TM -1 to the tumor endothelium, whereas Oregon Green paclitaxel dissolved in cremophor displayed an interstitial distribution pattern. The therapeutic efficacy of EndoTAG TM -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 TM -1 therapy and cytotoxic chemotherapy significantly enhanced antitumoral efficacy in both tumor models. Interestingly, only EndoTAG TM -1 in combination with gemcitabine was able to inhibit the incidence of metastasis in pancreatic cancer. In conclusion, vascular targeting tumor therapy by EndoTAG TM -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.Angiogenesis, the formation of new blood vessels from the endothelium of the existing vasculature, is fundamental in tumor growth, progression and metastasis. 1 The complex network of tumor blood microvessels guarantees an adequate supply of tumor cells with nutrients and oxygen and provides efficient drainage of metabolites.Therapeutic strategies that target and disrupt already formed vessel networks of growing tumors are therefore actively pursued. In contrast with the antiangiogenesis approach, the aim of vascular targeting is to destroy the established tumor vasculature thus causing a rapid and extensive decrease in tumor blood flow, followed by secondary tumor cell death. 2,3 Ligand-directed vascular targeting agents and small molecular tubulin-binding agents have been successfully developed to induce a vascular shutdown of tumor microvessels. 4 In addition to these compounds, drug delivery systems are of considerable interest in realizing such a new therapeutic concept: cationic lipid complexes have been described to target angiogenic endothelial cells in tumor preferentially. [5][6][7] This property potentially enables selective delivery of cytotoxic drugs to tumor endothelial cells and thus vascular targeting chemotherapy. We have previously shown that vascular targeting therapy can be realized by paclitaxel or camptothecin encapsulated in cationic lipid complexes. 8,9 Treatment with these liposomal compounds significantly retarded primary tumor growth and delayed metastatic disease by an antivascular...

Purpose: Paclitaxel encapsulated in cationic liposomes (EndoTAG-1) is a vascular targeting formulation for the treatment of solid tumors. It triggers intratumoral microthrombosis, causing significant inhibition of tumor perfusion and tumor growth associated with endothelial cell apoptosis. Here, we quantified the effects of repeated EndoTAG-1therapy on tumor microvascular leakiness with respect to leukocyte-endothelial cell interactions, the targeting property of cationic liposomes, and the therapeutic combination with conventional cisplatin chemotherapy. Experimental Design: Using dorsal skinfold chamber preparations in Syrian Golden hamsters, in vivo fluorescence microscopy experiments were done after repeated EndoTAG-1 treatment of A-Mel-3 tumors. Controls received glucose, paclitaxel alone, or cationic liposomes devoid of paclitaxel. Extravasation of rhodamine-labeled albumin was measured to calculate microvessel permeability, and intratumoral leukocyte-endothelial cell interactions were quantified. Subcutaneous tumor growth was evaluated after combination therapy followed by histologic analysis. Results: Microvascular permeability was significantly increased only after treatment with EndoTAG-1, whereas intratumoral leukocyte-endothelial cell interactions were not affected by any treatment. In separate skinfold chamber experiments, fluorescently labeled cationic liposomes kept their targeting property for tumor endothelial cells after repeated EndoTAG-1 treatment and no signs of extravasation were observed. Subcutaneous A-Mel-3 tumor growth was significantly inhibited by the combination of cisplatin and EndoTAG-1. Conclusions: These data show that vascular targeting with EndoTAG-1increases tumor microvessel leakiness probably due to vascular damage. This mechanism is not mediated by inflammatory leukocyte-endothelial cell interactions. Manipulating the blood-tumor barrier by repeated tumor microvessel targeting using EndoTAG-1 can effectively be combined with tumor celld irected conventional cisplatin chemotherapy.

Cationic lipid complexes have been shown to be bound and internalized selectively by angiogenic tumor endothelial cells after intravenous injection. Based on this phenomenon, the chemotherapeutic agent paclitaxel was encapsulated into these lipid complexes providing a vascular targeting agent (MBT-0206). As noninvasive imaging techniques are of critical importance for optimizing antivascular cancer treatment in the clinic, we have evaluated the antivascular effects of MBT-0206 in the A-MEL-3 solid tumor model using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI).Twenty-four hours after three intravenous applications of MBT-0206, tumors of treated animals demonstrated a significant decrease of intratumoral blood volume and an increase of vascular permeability in comparison to size-matched control tumors. In contrast, animals treated with conventional paclitaxel given as Taxol ® at equal drug dose did not show any significant differences in vascular parameters acquired by DCE-MRI in comparison to controls. Immunohistological analysis confirmed a significant reduction of microvessel density in MBT-0206 treated tumors. Moreover, a significant increase of intratumoral microvascular occlusion following MBT-0206 treatment was observed compared to controls and paclitaxel treated animals.In conclusion, antivascular tumor therapy with MBT-0206 significantly impairs functional tumor microcirculation. DCE-MRI is a promising tool to quantify the antivascular effects of MBT-0206 during treatment.

Problem Paclitaxel encapsulated in cationic liposomes (EndoTAG-1) is a vascular targeting formulation for the treatment of solid tumors. It triggers intratumoral microthrombosis causing significant inhibition of tumor perfusion and tumor growth associated with endothelial cell apoptosis. Here, we quantified the effects of repeated EndoTAG-1 therapy on tumor microvascular leakiness with respect to leukocyte-endothelial cell interactions, the targeting property of cationic liposomes and the therapeutic combination with conventional cisplatin chemotherapy. Methods Using dorsal skinfold chamber preparations in Syrian Golden hamsters in vivo fluorescence microscopy experiments were performed after repeated EndoTAG-1 treatment of A-Mel-3 tumors. Controls received glucose, paclitaxel alone or cationic liposomes devoid of paclitaxel. Extravasation of rhodamine-labelled albumin was measured to calculate microvessel permeability and intratumoral leukocyte-endothelial cell interactions were quantified. Subcutaneous tumor growth was evaluated after combination therapy followed by histological analysis. Results Microvascular permeability was significantly increased only after treatment with EndoTAG-1, while intratumoral leukocyte-endothelial cell interactions were not affected by any treatment. In separate skinfold chamber experiments fluorescently-labeled cationic liposomes kept their targeting property for tumor endothelial cells after repeated EndoTAG-1 treatment and no signs of extravasation were observed. Subcutaneous A-Mel-3 tumor growth was significantly inhibited by the combination of cisplatin and EndoTAG-1. Conclusion These data show that vascular targeting with EndoTAG-1 increases tumor microvessel leakiness probably due to vascular damage. This mechanism is not mediated by inflammatory leukocyte-endothelial cell interactions. Manipulating the blood-tumor barrier by repeated tumor microvessel targeting using EndoTAG-1 can effectively be combined with tumor cell-directed conventional cisplatin chemotherapy. Significance Antivascular therapy using liposomal paclitaxel (EndoTAG-1) is currently undergoing Phase II clinical studies in human cancer patients. Referring to the present experimental data showing increased permeability of intratumoral microvessels combination therapy with conventional therapy appears to be a very promising strategy. Support This study was supported by grants of Munich Biotech AG, Neuried, Germany and by grants of the Novartis Foundation for Therapeutic Research, Nürnberg, Germany.