Publications by authors named "Lionel Wightman"

2 Publications

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Reactivation of the mitosis-promoting factor in postmitotic cardiomyocytes.

Cells Tissues Organs 2003 ;175(2):61-71

Institute of Cell Biology, Swiss Federal Institute of Technology, Zürich, Switzerland.

Cardiomyocytes cease to divide shortly after birth and an irreversible cell cycle arrest is evident accompanied by the downregulation of cyclin-dependent kinase activities. To get a better understanding of the cardiac cell cycle and its regulation, the effect of functional recovery of the mitosis-promoting factor (MPF) consisting of cyclin B1 and the cyclin-dependent kinase Cdc2 was assessed in primary cultures of postmitotic ventricular adult rat cardiomyocytes (ARC). Gene transfer into ARC was achieved using the adenovirus-enhanced transferrinfection system that was characterized by the absence of cytotoxic events. Simultaneous ectopic expression of wild-type versions of cyclin B1 and Cdc2 was sufficient to induce MPF activity. Reestablished MPF resulted in a mitotic phenotype, marked by an abnormal condensation of the nuclei, histone H3 phosphorylation and variable degree of decay of the contractile apparatus. Although a complete cell division was not observed, the results provided conclusive evidence that cell cycle-related events in postmitotic cardiomyocytes could be triggered by genetic intervention downstream of the G1/S checkpoint. This will be of importance to design novel strategies to overcome the proliferation arrest in adult cardiomyocytes.
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http://dx.doi.org/10.1159/000073750DOI Listing
July 2004

Tumor-targeted gene delivery of tumor necrosis factor-alpha induces tumor necrosis and tumor regression without systemic toxicity.

Cancer Gene Ther 2002 Aug;9(8):673-80

Boehringer Ingelheim Austria, Vienna, Austria.

We have recently developed surface-shielded transferrin-polyethylenimine (Tf-PEI)/DNA delivery systems that target reporter gene expression to distant tumors after systemic application. In the present study, we used surface-shielded Tf-PEI/DNA complexes for delivering the gene for a highly potent cytokine, tumor necrosis factor-alpha (TNFalpha). TNFalpha is known for its ability to induce hemorrhagic tumor necrosis and tumor regression. However, the therapeutic application of TNFalpha is hampered by its high systemic toxicity dictating the need to target TNFalpha activity to the tumor. Systemic application of surface-shielded Tf-PEI complexes with the TNFalpha gene resulted in preferential expression of TNFalpha in the tumor without detectable TNFalpha serum levels, in contrast to the application of nontargeted complexes. Tumor-targeted TNFalpha gene delivery induced pronounced hemorrhagic tumor necrosis and inhibition of tumor growth in three murine tumor models of different tissue origins, Neuro2a neuroblastoma, MethA fibrosarcoma, and M-3 melanoma, with complete tumor regressions observed in the MethA model. No systemic TNF-related toxicity was observed due to the localization of the TNFalpha activity to the tumor. Targeted gene therapy may be an attractive strategy applicable to highly active, yet toxic, molecules such as TNFalpha.
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http://dx.doi.org/10.1038/sj.cgt.7700487DOI Listing
August 2002