Biomedical subjects

Marc Dellian

Publications and source records attributed to Marc Dellian.

14 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 concurrent chemotherapy with vinorelbine and mitomycin C in combination with radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck.

OBJECTIVE: The purpose of this pilot study was to evaluate the feasibility and toxicity of concurrent chemotherapy with vinorelbine and mitomycin C in combination with accelerated radiotherapy (RT) in patients with locally advanced cancer of the head and neck. PATIENTS AND METHODS: Between January 2003 and March 2004, 15 patients with T4/N2-3 squamous cell carcinoma (12/15) and with N3 cervical lymph node metastases of carcinoma of unknown primary (3/15) were treated with chemotherapy and simultaneous accelerated RT. RESULTS: 11 patients completed therapy without interruption or dose reduction. Grade 3-4 acute mucosal toxicity was observed in 9/15 patients, grade 4 hematologic toxicity in 6/15 patients. At a median follow-up of 7.5 months, 2 patients have died of intercurrent disease, 2 patients have experienced local relapse; 5 patients are alive with no evidence of disease at the primary tumor site. DISCUSSION: The described regimen is highly effective, but led to remarkable side effects.

Aged↗

PubMed2005

[Mass in the neck--the view of the ENT specialist].

A swelling in the neck is a common finding. Underlying causes may be enlarged lymph nodes and cysts, but also benign and malignant tumors. The clinical presentation, however, often gives rise to a fear of a malignant process. In children, more than 95% of such swellings are due to infection. In adults older than 40, however, a malignant tumor may be expected in more that 50% of the cases. Sine early detection is associated with a good prognosis, every mass in the neck must be considered to be potentially malignant. In particular when there is additional difficulty in swallowing or hoarseness, indicative of concomitant involvement of the airways or upper alimentary canal, a further careful diagnostic workup is indicated. Cervical lymph nodes measuring appreciably more than 1 cm in diameter, or additional fever, night sweats or loss of weight must immediately prompt the diagnostic steps necessary to diagnose a malignant lymphoma or carcinoma.

Adult↗

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↗

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↗

PubMed2004

Dynamic intravital fluorescence microscopy--a novel method for the assessment of microvascular permeability in acute pancreatitis.

Edema formation is the first manifestation of acute pancreatitis. Microcirculatory derangements like leukocyte-endothelial cell interaction and perfusion failure result in enhancement of microvascular permeability to large molecules playing a pivotal role in the progression of the acutely altered pancreatic tissue. Due to the lack of suitable methods the crucial mechanisms of enhanced permeability in vivo are not very well investigated. Sprague-Dawley rats were randomly assigned to three groups: (a) sham operated animals with normal pancreas, (b) the pancreatitis group induced by 60 min temporary occlusion of the arterial supply followed by reperfusion and (c) the histamine group in which the pancreas was superfused with 10(-5)M histamine. The pharmacokinetics of tetramethylrhodamine-labelled BSA in the intravital microscopic images of a capillary network of the pancreas were densitometrically quantified over 20 min. From these data the effective microvascular permeability was calculated taking also into account morphology of microvessels, elimination rate of the tracer from the intravascular space and capillary microhematocrit. In addition macromolecular leakage of gold-labelled BSA was investigated by electron microscopy. Microvascular permeability was 0.10 +/- 0.02 x 10(-7) cm/s, 0.49 +/- 0.04 x 10(-7) cm/s and 1.21 +/- 0.29 x 10(-7) cm/s for control, ischemia and histamine group, respectively (P < 0.05 ischemia, histamine vs. control and ischemia vs. histamine). Electron microscopy revealed albumin extravasation in the last two groups. We established a technique allowing to quantify microvascular permeability in pancreatic tissue by dynamic intravital microscopy being independent of the investigator. This technique enabling accurate pathophysiologic characterisation in terms of edema formation can form the basis for evaluating in the future novel treatment strategies directed against acute pancreatitis.

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↗

PubMed2003

Platelet-endothelial interaction in tumor angiogenesis and microcirculation.

Activated platelets release angiogenic growth factors and have therefore been proposed to contribute to tumor angiogenesis within a potentially prothrombotic tumor microcirculation. The aim of the study was to investigate interactions of platelets with the angiogenic microvascular endothelium of highly vascularized solid tumors during growth and in response to endothelial stimulation in comparison with normal subcutaneous tissue. Experiments were performed in the dorsal skinfold chamber preparation of C57BL/6J mice bearing the Lewis lung carcinoma (LLC-1) or methylcholanthrene-induced fibrosarcoma (BFS-1). Fluorescently labeled rolling and adherent platelets, red blood cell velocity, and vessel diameters were assessed by intravital fluorescence microscopy on days 1, 3, 8, and 14 after tumor cell implantation. Slightly elevated numbers of rolling platelets were observed in the early stages of tumor angiogenesis at day 1 (control, 1.7 +/- 0.6; LLC-1, 3.4 +/- 1.8; BFS-1, 3.0 +/- 0.7 [1/mm/s], P <.05) and day 3 (control, 1.6 +/- 0.6; LLC-1, 4.1 +/- 1.7, P <.05; BFS-1, 2.3 +/- 0.5 [1/mm/s]) after tumor cell implantation. Endothelial stimulation with calcium ionophore A23187 at day 14 after tumor cell implantation resulted in a minor increase to 2.1 +/- 0.4 (LLC-1) and 1.8 +/- 0.8 (BFS-1) rolling platelets (1/mm/s) in tumor microvessels compared with 4.9 +/- 0.9 in controls (P <.05). Platelet adherence was not observed. We therefore conclude that in the 2 experimental tumors under study, (1) slightly increased platelet rolling is a transient phenomenon after tumor cell implantation, and (2) platelet-endothelial interaction in response to endothelial stimulation is reduced in tumor microvessels.

Animals↗

PubMed2003

Depressive symptoms during and after radiotherapy for head and neck cancer.

BACKGROUND: Patients with head and neck cancer are extraordinarily susceptible to depressive traits. Thus, a general screening of these patients at their first admission to the ital is desirable. METHODS: From 1997-2001, 133 patients with head and neck tumors filled in the Self-Rating-Depression-Scale (SDS) at the beginning and end of radiotherapy (ti1/ti2), 6 weeks, and 6 months after radiotherapy (ti3/ti4). RESULTS.: The SDS index increased significantly from 46.44 (ti1) to 48.91(ti2) (p =.025) and then remained stable. The subdomain "somatic-eating-related symptoms" at ti1 was significantly lower than ti2 (p <.001). In contrast to inpatients, outpatients and those with conventional instead of hyperfractionated-accelerated radiotherapy were less impaired by eating-related symptoms. Patients with higher education showed a lower SDS index and cognitive scale. Marital status, tumor stage, histologic grading, and substance abuse had no influence. CONCLUSIONS: Patients with a higher risk of depression should receive long-term monitoring during and after the end of radiotherapy, and prompt intervention strategies should be applied.

Adolescent↗

PubMed2003

Hyperthermia induces T1 relaxation and blood flow changes in tumors. A MRI thermometry study in vivo.

Regional hyperthermia in combination with chemotherapy and/or radiotherapy has proven to be an effective treatment concept for locally advanced deep-seated tumors. Simultaneous MR-imaging could be a promising approach for therapy optimization. Purpose of this study was the in vivo investigation of temperature induced longitudinal relaxation time (T(1)) and blood flow changes in a tumor model. Using a 1.5 Tesla MR system, the T(1) sensitivity on temperature and the onset of tissue changes at temperatures >44 degrees C were investigated in muscle samples. Also, fourteen Syrian Golden Hamsters with amelanotic melanoma A-MEL-3 were examined during heating of the tumors. Temperature induced blood flow and T(1) changes were determined continuously during hyperthermia. Changes of T(1) correlated linearly with temperature over a wide range (27-44 degrees C) in the tissue sample. Tissue changes became notable above 44 degrees C. In the tumor model, relative changes of T(1) (unlike blood flow) showed linear correlation with temperature over the entire range of hyperthermia relevant temperatures (32-44 degrees C). For a low thermal dose, T(1) allows the assessment of temperature changes in tumors in vivo. At higher thermal doses, in addition to temperature changes, T(1) also shows tissue changes. Both temperature and tissue changes supply important information for hyperthermia.

Animals↗

PubMed2003

Neovascular targeting therapy: paclitaxel encapsulated in cationic liposomes improves antitumoral efficacy.

PURPOSE: Cationic liposomes have been shown to selectively target tumor endothelial cells. Therefore, the encapsulation of antineoplastic drugs into cationic liposomes is a promising tool to improve selective drug delivery by targeting tumor vasculature. It was the aim of our study to evaluate tumor selectivity and antitumoral efficacy of paclitaxel encapsulated in cationic liposomes in comparison with the free drug paclitaxel (Taxol(R)) in vivo. EXPERIMENTAL DESIGN: Experiments evaluating tumor selectivity were carried out in male Syrian golden hamsters bearing the amelanotic hamster melanoma A-Mel-3 in dorsal skinfold preparations. Growth of tumor cells was observed after s.c. inoculation (day 0). On days 5, 7, 9, 12, 14, and 16, animals were treated by continuous i.v. infusion over 90 min with 5% glucose, Taxol(R), unloaded cationic liposomes, or paclitaxel encapsulated into cationic liposomes (LipoPac), respectively (lipid dose, 150 mg/kg body weight; paclitaxel dose, 5 mg/kg body weight). Tumor volumes and presence of regional lymph node metastases were quantified. RESULTS: Vascular targeting of rhodamine-labeled cationic liposomes was maintained after encapsulation of paclitaxel as revealed by in vivo fluorescence microscopy (ratio of dye concentration, tumor:normal tissue = 3:1). The s.c. tumor growth revealed a remarkable retardation of tumor growth after treatment with LipoPac (1.7 +/- 0.3 cm(3)). In contrast, control tumors showed exponential tumor growth [tumor volume at the end of the observation period (mean +/- SE): 5% glucose, 17.7 +/- 1.9 cm(3); unloaded cationic liposomes, 10.0 +/- 1.6 cm(3); Taxol(R), 10.7 +/- 1.7 cm(3)]. In addition, the appearance of regional lymph node metastases was significantly delayed by treatment with paclitaxel encapsulated into cationic liposomes in comparison with all other groups. CONCLUSIONS: The data suggest that cationic liposomes are a powerful tool for selective and efficient drug delivery to tumor microvessels. This may serve as proof of the concept of neovascular tumor targeting therapy by cationic liposomes.

Animals↗

PubMed2002

Acid production in glycolysis-impaired tumors provides new insights into tumor metabolism.

PURPOSE: Low extracellular pH is a hallmark of solid tumors. It has long been thought that this acidity is mainly attributable to the production of lactic acid. In this study, we tested the hypothesis that lactate is not the only source of acidification in solid tumors and explored the potential mechanisms underlying these often-observed high rates of acid production. EXPERIMENTAL DESIGN: We compared the metabolic profiles of glycolysis-impaired (phosphoglucose isomerase-deficient) and parental cells in both in vitro and two in vivo models (dorsal skinfold chamber and Gullino chamber). RESULTS: We demonstrated that CO(2), in addition to lactic acid, was a significant source of acidity in tumors. We also found evidence supporting the hypothesis that tumor cells rely on glutaminolysis for energy production and that the pentose phosphate pathway is highly active within tumor cells. Our results also suggest that the tricarboxylic acid cycle is saturable and that different metabolic pathways are activated to provide for energy production and biosynthesis. CONCLUSIONS: These results are consistent with the paradigm that tumor metabolism is determined mainly by substrate availability and not by the metabolic demand of tumor cells per se. In particular, it appears that the local glucose and oxygen availabilities each independently affect tumor acidity. These findings have significant implications for cancer treatment.

Acids↗