Glioma tropism of lentivirally transduced hematopoietic progenitor cells.

Experimental gliomas attract hematopoietic progenitor cells (HPC) in vivo. HPC are therefore promising candidates for a cell-based delivery of therapeutic molecules to experimental gliomas. A therapeutic application requires efficient genetic manipulation of the cellular vector and a lack of tumorigenicity.

Combined treatment with lexatumumab and irradiation leads to strongly increased long term tumour control under normoxic and hypoxic conditions.

Purpose: The combination of ionizing radiation with the pro-apoptotic TRAIL receptor antibody lexatumumab has been shown to exert considerable synergistic apoptotic effects in vitro and in short term growth delay assays. To clarify the relevance of these effects on local tumour control long-term experiments using a colorectal xenograft model were conducted.

Materials And Methods: Colo205-xenograft bearing NMRI (nu/nu) nude mice were treated with fractionated irradiation (5x 3 Gy, d1-5) and lexatumumab (0.

Combination of the pro-apoptotic TRAIL-receptor antibody mapatumumab with ionizing radiation strongly increases long-term tumor control under ambient and hypoxic conditions.

Purpose: Mapatumumab, an agonistic tumor necrosis factor-related apoptosis inducing ligand-receptor antibody, exerts highly synergistic apoptotic effects in vitro and in short-term growth delay assays when combined with irradiation. Because it remained unclear in how far these effects influence local tumor control, long-term experiments using a colorectal xenograft model were undertaken.

Material And Methods: Experiments were performed with irradiation (5 x 3 Gy, d1-5) and mapatumumab (10 mg/kg) in Colo205-xenograft-bearing NMRI (nu/nu) nude mice.

Aurora kinase inhibitor ZM447439 induces apoptosis via mitochondrial pathways.

ZM447439 (ZM) is a potent and selective inhibitor of aurora-A and -B kinase with putative anti-tumoral activity. Inhibitors of aurora kinases were shown to induce apoptosis in vitro and in vivo. To investigate the underlying mechanisms, cell death pathways triggered by ZM was analysed in HCT-116 colorectal cancer cells.

Efficacy of triple therapies including ionising radiation, agonistic TRAIL antibodies and cisplatin.

The detection of molecular targeted agents is a milestone in cancer treatment. Despite the achievements, the efficacy of single targeted agents in combination with radiotherapy is limited by putative treatment resistance. We therefore tested a rationally designed triple therapy consisting of an agonistic antibody against either TRAIL-R1 (mapatumumab/HGS-ETR1) or TRAIL-R2 (lexatumumab/HGS-ETR2) in combination with the established chemotherapeutic drug cisplatin in a panel of solid tumour cell lines derived from head and neck as well as colorectal carcinomas.

Efficacy of a triple treatment with irradiation, agonistic TRAIL receptor antibodies and EGFR blockade.

Background And Purpose: : Since the efficacy of a single targeted agent in combination with ionizing radiation is limited by putative treatment resistances, a rationally designed triple treatment consisting of an agonistic antibody targeting either TRAIL-R1 (mapatumumab) or TRAIL-R2 (lexatumumab), radiation and an epidermal growth factor receptor-(EGFR-)inhibiting antibody (cetuximab) was tested.

Material And Methods: : Induction of apoptosis after triple treatment was determined in Colo205, HCT116 and FaDu cells by Hoechst 33342 stain. The degree of interaction was determined by isobologram analysis.

Drug evaluation: lexatumumab, an intravenous human agonistic mAb targeting TRAIL receptor 2.

Human Genome Sciences Inc, under license from Cambridge Antibody Technology Ltd, is developing lexatumumab, an intravenous human agonistic mAb to TNF-related apoptosis-inducing ligand (TRAIL) receptor 2, for the potential treatment of cancer. Phase II clinical trials of lexatumumab are underway.

Irradiation specifically sensitises solid tumour cell lines to TRAIL mediated apoptosis.

Background: TRAIL (tumor necrosis factor related apoptosis inducing ligand) is an apoptosis inducing ligand with high specificity for malignant cell systems. Combined treatment modalities using TRAIL and cytotoxic drugs revealed highly additive effects in different tumour cell lines. Little is known about the efficacy and underlying mechanistic effects of a combined therapy using TRAIL and ionising radiation in solid tumour cell systems.

Influence of hypoxia on TRAIL-induced apoptosis in tumor cells.

Purpose: Tumor hypoxia reduces the efficacy of radiotherapy, many types of chemotherapy, and tumor necrosis factor-alpha (TNF-alpha). TRAIL (TNF-alpha-related apoptosis-inducing ligand) is a ligand for death receptors of the TNF superfamily shown to be selectively toxic for tumor cells and thereby a promising antineoplastic tool. The impact of hypoxia on TRAIL-induced apoptosis was examined in this study.

Molecular requirements for the combined effects of TRAIL and ionising radiation.

Background And Purpose: Previously it was shown that combination of death ligand TRAIL and irradiation strongly increases cell kill in several human tumour cell lines. Since Bcl-2 overexpression did not strongly interfere with the efficacy, components of the mitochondrial death pathway are not required for an effective combined treatment. In the present study the minimal molecular prerequisites for the efficacy of a combined treatment were determined.

Death receptor ligands: new strategies for combined treatment with ionizing radiation.

The major goal of modern radiation oncology is the achievement of a maximal tumor control with minimal normal tissue damage. However, normal tissue tolerance may preclude the application of tumoricidal radiation doses. In order to overcome this limitation, strategies either to increase normal tissue tolerance or to reduce the radiation dose required may prove beneficial.

[Death inducing ligands in combination with ionizing radiation: objective and current knowledge].

Background: Apart from optimization of the radiation technology, future new strategies in radiation oncology will focus on the biological optimisation leading to improved adaptation of the tumor therapy on each tumor entity. In this regard, different areas of biological research may be distinguished: prediction, development of new cytotoxic agents, improvement of the tolerance of normal tissue and the optimisation of radiochemotherapy.

Material And Method: For the development of new strategies the knowledge of molecular mechanisms of radiation induced cell death is essential.