BACKGROUND: Previously, we showed that retroviral vectors pseudotyped with the envelope of the amphotropic murine leukemia virus 10A1 (MLV-10A1) more efficiently transduce primary human CD8+ T lymphocytes when compared with other A-MLV, gibbon ape leukemia virus (GaLV) and feline endogenous retrovirus (RD114) vector pseudotypes. For the success of several gene therapeutic approaches (ADA, HIV) it is important to effectively transduce primary human CD4+ T lymphocytes. METHODS: We have used retroviral vectors encoding the enhanced green fluorescent protein (EGFP) as a marker gene and carrying envelopes of MLV-10A1, A-MLV and GaLV and have analyzed the transduction efficiency of both human CD4+ T cell lines (CEM, H9, HUT78, J16) and primary human CD4+ T lymphocytes using a RetroNectin-assisted transduction protocol and virus-containing supernatant. RESULTS: In CD4+ T cell lines the MLV-10A1 vector pseudotype was most effective and infected up to 85% of cells which then stably expressed GFP over time. MLV-10A1 was also superior and infected approximately 32% of primary human CD4+ T lymphocytes in comparison to GaLV (18%) and A-MLV (12%). The superior efficiency of MLV-10A1 for the transduction of CD4+ T cells correlates with the longer half-life of this pseudotype in comparison to A-MLV and, as previously shown by interference analysis, with the usage of both the A-MLV (Pit2) and the GaLV receptor (Pitl) for cell entry. CONCLUSIONS: MLV-10A1 is a suitable vector for transferring genes with high efficacy into primary human CD4+ T lymphocytes. The use of MLV-10A1 pseudotyped vectors should make it easier to obtain a sufficient number of gene-modified T lymphocytes for an adoptive transfer.

Animals↗

PubMedDate not supplied

CIRSE '96 summary report. Proceedings of the Annual Meeting of CIRSE. Madeira, Funchal, September 8-12, 1996.

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Humans↗

PubMedDate not supplied

Therapy of metastatic breast cancer with humanized antibodies against the HER2 receptor protein.

The HER2 protein, a member of the epidermal growth factor family, is encoded by the protooncogene c-erbB-2. Its overexpression, occurring in approximately one-third of all breast carcinomas, is associated with a poor prognosis. A humanized mouse antibody against HER2 has been developed by genetic engineering. Here an unspecific human IgG was connected to the recognizing mouse IgG fragment. The allergization typical for allogeneic antibodies does not take place in this context. The effectiveness of this antibody has been confirmed by two international prospective phase III trials that tested it alone and combined with chemotherapy. Both modes of application increased the response rates and the time to progression. Side-effects were rare except for a high rate of cardiac dysfunction when the antibody was combined with anthracyclines. The effectiveness and negligible side-effects of the chimeric antibody against HER2 (Herceptin) render it a valuable tool in the treatment of breast cancer.

Antibodies, Monoclonal↗

PubMedDate not supplied

Pharmacokinetics of nimodipine in multimorbid elderly patients with chronic brain failure.

Twenty-one elderly patients with chronic brain failure received a single 30 mg oral dose of the calcium channel blocker nimodipine followed by two weeks of 30 mg three times a day (t.i.d.) administration. The aim of this study was to assess if drug accumulation occurred in our frail elderly subjects under this dose regimen. Plasma concentrations of nimodipine and three main metabolites were determined by gas chromatography. During the 2-week period we did not find significant changes in peak plasma concentrations and corresponding areas under the plasma concentration-time curves. Trough nimodipine plasma concentrations before administration of the morning dose were similar on days 7 and 14. Therefore, no evidence of drug accumulation was found. Blood pressure and heart rate remained stable throughout the study period and no adverse effects were observed. During the study period, there was a decline in the proportion of patients who complained about dizziness and insomnia. Overall, our data suggest that there is no need to alter the usual adult dose of nimodipine if this drug is administered to multimorbid frail elderly patients suffering from chronic brain failure.

Journal Article↗

PubMedDate not supplied

Transcoronary sinus administration of autologous bone marrow in patients with chronic refractory stable angina Phase 1.

PURPOSE: Based on our preclinic studies with autologous unfractionated bone marrow (AUBM) via coronary sinus with transitory occlusion, a clinic study in patients with chronic stable angina was designed. The objectives were to evaluate safety, tolerance and feasibility. METHODS AND MATERIALS: A multicenter prospective study with inclusion and exclusion criteria defined by an Independent Clinical Committee was carried out. Fourteen patients underwent transcoronary sinus administration of freshly aspirated and filtered AUBM (60-120 ml). Safety and tolerance were evaluated. Feasibility was evaluated with Seattle Angina Questionnaire (SAQ), Canadian Cardiovascular Society (CCS) angina classification (baseline-Day 180), myocardial perfusion (baseline-Day 90) with independent core laboratory and coronary angiography (baseline and Day 30). RESULTS: There were no changes in the safety and tolerance parameters. Preliminary clinical efficacy at Day 180 disclosed a significant improvement of 38%, evaluated by the SAQ. The CCS angina classification shows that the mean angina class was 3.0+/-0.55 at baseline and improved to 2.0+/-0.00 at Day 180 (P <.001). Semiquantitative radionuclide perfusion imaging (core lab) showed a significant improvement at Day 90 in 13/14 patients, with a mean improvement of 24% at rest (P <.01) and 33% at stress (P <.05). Coronary angiography showed more collateral vessels in 9/14 patients. CONCLUSIONS: We can conclude that AUBM via coronary sinus with transitory occlusion is tolerable and safe. Significant improvement in the myocardial perfusion at Day 90 and in the quality of life at Day 180 was observed.

Angina Pectoris↗