Biomedical subjects

Martin E Eichhorn

Publications and source records attributed to Martin E Eichhorn.

7 recordsLinked to original sources

PubMed2006

Antiangiogenic combination tumor therapy blocking alpha(v)-integrins and VEGF-receptor-2 increases therapeutic effects in vivo.

Anti-angiogenesis is a promising strategy for cancer therapy currently evaluated in clinical trials. The aim of the study was to investigate the effects of an antiangiogenic combination therapy inhibiting alpha(v)-integrins by a c(yclic)RGD-peptide (EMD270179) and blocking VEGFR-2 by SU5416 on tumor angiogenesis and progression in vivo. Experiments were performed in dorsal skinfold chamber preparations of Syrian golden hamsters (60 +/- 5 g) bearing A-Mel-3 tumors. From day 3-10 after tumor-cell implantation, animals (n = 6 per group) were treated by monotherapies using the cRGD-peptide (114 mg/kg/day; i.p.), the VEGFR-2 antagonist (6 mg/kg/day; i.p.) or by the combination of both monotherapies. A control group received only the solvent DMSO. Using intravital microscopy parameters of intratumoral microcirculation were analyzed on day 5, 7 and 10. In separate experiments subcutaneous tumor growth and metastasis formation was evaluated starting therapy on day 0. Functional vessel density was significantly reduced by the combination therapy compared to that by all other groups on day 10. Although intratumoral red blood cell velocity and vessel diameters were less affected, blood flow in vessel segments and the microcirculatory perfusion index were lower after combined therapy compared to controls. In addition, we observed a significantly stronger inhibition of subcutaneous tumor growth and metastasis formation using the combination therapy. These data clearly support the concept of antiangiogenic combination therapy and demonstrate that it may especially be effective when scheduled as an early or prophylactic treatment regimen, thus avoiding angiogenesis-dependent tumor and metastasis initiation or tumor recurrence.

Angiogenesis Inhibitors↗

PubMed2005

A new animal model to assess angiogenesis and endocrine function of parathyroid heterografts in vivo.

BACKGROUND: It is still a matter of investigation how angiogenesis and restoration of gland perfusion determine graft function after free parathyroid autotransplantation. We provide a new animal model allowing simultaneous and repetitive in vivo assessment of angiogenesis and endocrine function of parathyroid transplants. METHODS: Fresh human parathyroid tissue from patients with secondary hyperparathyroidism was grafted into dorsal skinfold chamber preparations of athymic nude mice (CD1-nu; n=8). Equivalent pieces of the same human donor specimens were heat-inactivated and served as control grafts (n=7). RESULTS: In all animals receiving parathyroid transplants, intact human parathyroid hormone levels were detectable by species-specific enzyme-linked immunosorbent assay analysis of plasma samples on day 5 after transplantation and increased by 2.5-fold over the observation period (19 days) in contrast with controls. Plasma Ca levels revealed no differences between the groups. On day 5 after transplantation, intravital fluorescence microscopy revealed murine angiogenic microvessels sprouting along nonperfused human donor vessels, and 1 week later functional microvasculature was established in all parathyroid transplants. Histologic analysis revealed well-vascularized endocrine tissue. In contrast, control grafts were necrotic and partly resorbed; they exhibited no angiogenic activity or well-vascularized fat cells indicating fatty degeneration. In addition, species-specific Western blot analysis revealed vascular endothelial growth factor expression of parathyroid transplants rather than functional vessel density as the functional parameter of angiogenesis determining transplant function in vivo. CONCLUSION: This model may serve to understand mechanisms associated with specific parathyroid transplant angiogenesis and its significance for transplant function to optimize clinical success of autotransplantation in therapy-resistant patients.

Animals↗

PubMed2005

Rapamycin induces tumor-specific thrombosis via tissue factor in the presence of VEGF.

Therapeutic strategies that target and disrupt the already-formed vessel networks of growing tumors are actively pursued. The goal of these approaches is to induce a rapid shutdown of the vascular function of the tumor so that blood flow is arrested and tumor cell death occurs. Here we show that the mammalian target of rapamycin (mTOR) inhibitor rapamycin, when administered to tumor-bearing mice, selectively induced extensive local microthrombosis of the tumor microvasculature. Importantly, rapamycin administration had no detectable effect on the peritumoral or normal tissue. Intravital microscopy analysis of tumors implanted into skinfold chambers revealed that rapamycin led to a specific shutdown of initially patent tumor vessels. In human umbilical vein endothelial cells vascular endothelial growth factor (VEGF)-induced tissue factor expression was strongly enhanced by rapamycin. We further show by Western blot analysis that rapamycin interferes with a negative feedback mechanism controlling this pathologic VEGF-mediated tissue factor expression. This thrombogenic alteration of the endothelial cells was confirmed in a one-step coagulation assay. The circumstance that VEGF is up-regulated in most tumors may explain the remarkable selectivity of tumor vessel thrombosis under rapamycin therapy. Taken together, these data suggest that rapamycin, besides its known antiangiogenic properties, has a strong tumor-specific, antivascular effect in tumors.

Angiogenesis Inhibitors↗

PubMed2004

Neovascular targeting chemotherapy: encapsulation of paclitaxel in cationic liposomes impairs functional tumor microvasculature.

Cationic liposomes have been shown to be internalized selectively by angiogenic tumor endothelial cells after intravenous injection. Therefore, encapsulation of cytotoxic substances in cationic liposomes is a new approach to target tumor vasculature. It was the aim of our study to quantify the effects of paclitaxel encapsulated in cationic liposomes (MBT-0206) on tumor microvasculature and growth in vivo. Experiments were performed in the dorsal skinfold chamber preparation of Syrian Golden hamsters bearing syngeneic A-Mel-3 melanomas. Tumors were treated with intravenous infusion of MBT-0206 (20 mM) resulting in an effective paclitaxel dose of 5 mg/kg body weight (b.w.). Control animals received conventional paclitaxel in Cremophor EL (Taxol(R); 5 mg/kg b.w.), unloaded cationic liposomes (20 mM) or the solvent 5% glucose, respectively. Using intravital microscopy, tumor growth and effects on intratumoral microvasculature were analyzed. Tumor growth was significantly retarded after treatment with MBT-0206 compared to the treatment with paclitaxel. Analysis of intratumoral microcirculation revealed a reduced functional vessel density in tumors after application of liposomal paclitaxel. At the end of the observation time, vessel diameters were significantly smaller in animals treated with paclitaxel encapsulated in cationic liposomes while red blood cell velocity was less affected. This resulted in a significantly reduced blood flow in vessel segments and a reduced microcirculatory perfusion index in these animals. Histochemical TUNEL stain was vessel-associated after treatment with liposomal paclitaxel in contrast to few apoptotic tumor cells in the control groups. Our data demonstrate that encapsulation of paclitaxel in cationic liposomes significantly increased the antitumoral efficacy of the drug. Remarkable microcirculatory changes indicate that encapsulation of paclitaxel in cationic liposomes resulted in a mechanistic switch from tumor cell toxicity to an antivascular therapy.

Animals↗

PubMed2004

Novel temperature-sensitive liposomes with prolonged circulation time.

Hyperthermia increases the efficiency of various chemotherapeutic drugs and is administered as an adjunct to chemotherapy for the treatment of cancer patients. The temperature-dependent effect can be strongly increased by the use of temperature-sensitive liposomes in combination with regional hyperthermia, which specifically releases the entrapped drug in the heated tumor tissue. The novel lipid 1.2-dipalmitoyl-sn-glycero-3-phosphoglyceroglycerol (DPPGOG), which is closely related to the naturally occurring 1.2-dipalmitoyl-sn-glycero-3-phosphoglycerol, in combination with 1.2-dipalmitoyl-sn-glycero-3-phosphocholine and 1.2-distearoyl-sn-glycero-3-phosphocholine provides long-circulating temperature-sensitive liposomes with favorable properties under mildly hyperthermic conditions (41-42 degrees C). DPPGOG facilitates temperature-triggered drug release from these liposomes (diameter, 175 nm) and leads to a substantially prolonged plasma half-life for the encapsulated drug with t(1/2) = 9.6 h in hamsters and t(1/2) = 5.0 h in rats. Quantitative fluorescence microscopy of amelanotic melanoma grown in the transparent dorsal skin fold chamber of hamsters demonstrated a favorable drug accumulation in heated tissue after i.v. application of these liposomes (42 degrees C for 1 h). The mean area under the curve for tissue drug concentration was increased by more than sixfold by application of the new liposomes compared with nonliposomal drug delivery. In summary, we present a new DPPGOG-based liposomal formulation enabling long circulation time combined with fast and efficient drug release under mild hyperthermia. This adds positively to the results with lipid-grafted polyethylenglycol used thus far in temperature sensitive liposomes and widens the possibilities for clinical applications.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed2004

Anti-vascular tumor therapy: recent advances, pitfalls and clinical perspectives.

Anti-vascular tumor therapy represents a promising new strategy for cancer treatment. Anti-vascular treatment may be divided in anti-angiogenic and vascular targeting therapy. Whereas anti-angiogenic drugs aim on the inhibition of new vessel formation, vascular targeting compounds are designed to selectively destruct preexisting tumor blood vessels leading to secondary tumor cell death. Both anti-angiogenic drugs and vascular targeting agents have proven effective anti-tumoral activity in numerous preclinical studies over the last decade. In vivo, a combination with anti-vascular tumor therapy enhances the effects of other treatment modalities as chemo- and radiotherapy. Phase I clinical studies revealed a number of well-tolerated candidates. As monotherapy, however, anti-angiogenic treatment lacked efficacy in randomized clinical studies so far. In contrast, combination of anti-angiogenic therapy with chemotherapy was highly effective in an encouraging, large randomized phase III trial on metastatic colorectal cancer. This review will outline recent advances in the preclinical and clinical development of anti-vascular therapy with focus on vascular targeting. Conceptual differences between anti-angiogenic and vascular targeting therapies will be discussed with emphasis on specific problems and pitfalls in the conversion into the clinic.

Animals↗

PubMed2003

Effect of the surface charge of liposomes on their uptake by angiogenic tumor vessels.

Recently, cationic liposomes have been shown to preferentially target the angiogenic endothelium of tumors. It was the aim of our study to investigate the influence of liposomal surface charge on the uptake and kinetics of liposomes into solid tumors and tumor vasculature. Experiments were performed in the amelanotic hamster melanoma A-Mel-3 growing in the dorsal skinfold chamber preparation of male Syrian golden hamsters. Fluorescently labeled liposomes with different surface charge were prepared. Accumulation of i.v. injected liposomes was assessed by quantitative intravital fluorescence microscopy of tumor and surrounding host tissue. The histological distribution of liposomes was analyzed by double-fluorescence microscopy 20 min after application of fluorescently labeled lectin as a vascular marker. After i.v. application of anionic and neutral liposomes, we observed an almost homogeneous distribution of liposome-induced fluorescence throughout the chamber preparation without specific targeting to tumor tissue. In contrast, cationic liposomes exhibited a significantly enhanced accumulation in tumor tissue and tumor vasculature up to 3-fold compared to surrounding tissue (p<0.05). The histological distribution of neutral and anionic liposomes revealed extravasation 20 min after i.v. injection, while cationic liposomes displayed a highly selective accumulation on the vascular endothelium. In conclusion, cationic liposomes exhibited a preferential uptake in angiogenic tumor vessels and therefore may provide an efficient tool for the selective delivery of diagnostic or therapeutic agents to angiogenic blood vessels of solid tumors. On the other hand, anionic and neutral liposomes may be used as carriers of drugs to the extravascular compartment of tumors due to their extravasation.

Animals↗