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Biomedical subjects

R Mertelsmann

Publications and source records attributed to R Mertelsmann.

365 records · Page 21Linked to original sources
PubMedDate not supplied

Dacarbazine and interferon alpha for stage IV malignant melanoma.

Based on encouraging reports of improved response rates with the use of dacarbazine (DTIC) in combination with recombinant interferon alpha-2a (rIFN-alpha-2a) in patients with metastatic malignant melanoma, we conducted a phase II study to determine the efficacy and feasibility of this treatment regimen. 31 patients were treated with an induction dose of rIFN-alpha-2a at 15 MIU/ m2 intravenously (i.v.) daily for 5 days per week for 3 consecutive weeks followed by a continuous maintenance dose of 10 MIU/m2 subcutaneously (s.c.) given 3 days per week; starting on day 22, in conjunction with rIFN-alpha-2a s.c., DTIC was started at a dose of 200 mg/m2 i.v. for 5 continuous days completing a 28-day cycle. Therapy was continued until progression was evidenced. Of the 29 evaluable patients, 7 (24.1%) achieved an objective response (complete plus partial remission) with the highest responses occurring in those patients assessed with pulmonary metastases. The median duration to treatment failure was 2.6 months, while the median survival was 6.9 months. Our data reveal that using rIFN-alpha-2a plus DTIC in combination does not yield better results than those achieved when using DTIC alone. However, 3 of the 7 responders experienced long-term survival ranging up to 42 months. Whether this benefit is achieved by the addition of rIFN-alpha-2a can only be answered by large randomized clinical trials. Conflicting results with some of the current literature are discussed.

Adult↗
PubMedDate not supplied

In vivo administration of recombinant human interleukin-3 elicits an acute phase response involving endogenous synthesis of interleukin-6.

Interleukin-6 has been shown to stimulate in vitro synthesis of C-reactive protein (CCRP) in hepatocytes by enhancing the transcriptional rate of the CRP gene. It has also been demonstrated that IL-6 spurs the terminal differentiation of B-cells into immunoglobulin secreting cells when synergizing with IL-3. IL-6 may therefore act as a prime molecule in the acute phase and immune response. We have administered rh IL-3 to cancer patients in a phase I/II clinical trial. Endogenous IL-6 levels increased in a dose-dependent fashion upon i.v. bolus injection of rh IL-3 and continued to be significantly elevated above pretreatment levels when IL-3 was further administered by the s.c. route. Increases of IL-6 levels were associated with enhanced production of CRP in vivo detected after 24 h of injection. At day 14 of rh IL-3 treatment plasma immunoglobulin concentrations were measured and IgM was found to be increased by greater than 2.5 fold above starting levels. These results indicate that rh IL-3 also augments the acute phase response in vivo and contributes to increased synthesis of IgM and that induction of endogenous IL-6 is involved in these events.

Acute-Phase Proteins↗
PubMedDate not supplied

Monokines: stimulatory and inhibitory regulator molecules of myelopoiesis in vitro.

The conditions for monocytes to secrete molecules that are involved in myelopoiesis, i.e. Colony Stimulating Factors (CSFs), Interleukin-1 (IL-1) and Tumor Necrosis Factor-alpha (TNF-alpha) were investigated. Whereas secretion of these molecules by monocytes is negligible in a quiescent state, activation of monocytes with Interferon-gamma (IFN-gamma) results in mRNA accumulation and subsequent protein secretion of CSF for granulocytes (G-CSF) and for monocytes (M-CSF). Under identical conditions mRNA-transcripts of TNF-alpha, IL-1-alpha and IL-1-beta genes were induced. Whereas IFN-gamma induces secretion of TNF-alpha protein, protein secretion of IL-1 by monocytes failed to occur in response to an IFN-gamma stimulus. However, the presence in culture of IFN-gamma in combination with TNF-alpha induced secretion of IL-1. Although IL-1 regulates the production of CSF for granulocytes and monocytes (GM-CSF) by IL-1 receptive T-lymphocytes, and is therefore involved in upregulatory mechanisms of myeloid growth, it may be able to suppress growth of myelopoietic progenitor cells (MPC) as well, when hematopoietic cultures are depleted of cells, that have the potential to secrete CSFs. Similarly, IFN-gamma, although being a major inducer of CSF secretion by monocytes, was shown to inhibit myeloid colony growth when exposed to purified MPC and allowed to synergize with TNF-alpha.

Biological Factors↗
PubMedDate not supplied

Paracrine stimulation of keratinocytes in vitro and continuous delivery of epidermal growth factor to wounds in vivo by genetically modified fibroblasts transfected with a novel chimeric construct.

BACKGROUND: Growth factors play an important role in tissue repair. While the effectiveness of growth factor therapy in animal wound healing models and limited human clinical trials has been demonstrated, the ideal method for their administration to the wound remains unclear. Experimental data suggest that the continuous presence in the early stages of wound repair is beneficial. MATERIALS AND METHODS: We have constructed a novel chimeric expression plasmid in which the biologically active portion of the human epidermal growth factor (EGF) gene is fused in-frame to the human granulocyte colony-stimulating factor signal sequence. RESULTS: Clonally selected human fibroblasts transfected with this construct secrete biologically active EGF. After the transplantation of irradiated gene-transfected fibroblasts suspended in fibrin glue to murine full-thickness wounds, EGF can be demonstrated for at least seven days in the wounds, slowly decreasing from initially 470 pg/ml to 140 pg/ml on day 7. No EGF was found in the wound at day 14. CONCLUSIONS: A single application of irradiated EGF genetransfected fibroblasts to wounds can thus continuously deliver the transgene in vivo and could be used to administer drugs to the wound bed during the crucial first seven days of wound-healing.

Amino Acid Sequence↗