Isabelle de Waziers Molecular basis of response to xenobiotics

Course and current status

Qualifications

1998         Habilitation to manage  researches (University Paris V, France)

1994   PhD: Molecular Pharmacology, Experimental Pharmacology and Metabolism

1981         PhD: Physiology of Nutrition (University Paris VI, France)

1978         Masters Degree in Nutrition (university Paris VI, France)

 Positions

 From 2006       INSERM U775, 45 rue des Saints Pères, 75270 Paris Cedex O6, France

1997-2005           INSERM U490, Laboratory of Molecular Toxicology, 45 rue des Saints Pères, 75270 Paris Cedex 06. France

1987-1997     INSERM U75, CHU-Necker, 156 rue de Vaugirard, 75015 Paris, France

1983-1987     Laboratory of Industrial and Agro-alimentary Biology

CNAM, 292, rue Saint Martin, 75131 Paris Cedex 03, France.

1981-1983     Institute of Scientific Research in Cancer

Laboratory of Cellular Toxicology

7 rue Guy Moquet, 94802 Villejuif, France

1977-1981     INSERM U177, Laboratory of Physiopathology of Nutrition

15-21 rue de Médecine, 75270 Paris Cedex 06

Scientific summary

The overall purpose of our research consists to study the function, expression and regulation of enzymes involved in the metabolism of xenobiotics. Therefore, we developed relevant tools, methods of producing pure and active proteins, probes, antibodies, expression system, promoters, substrates and specific inhibitors and we have put in place collaborations with platforms allowing global transcriptomic and metabonomic studies. Thanks to these tools and collaborations, we investigated the molecular mechanisms of the responses to numerous xenobiotics in different organs in humans.

Furthermore, we developed a new method of suicide gene therapy against cancer. Our approach consists of expressing in lung and head and neck tumors, the cytochrome P4502B6/NADPH cytochrome P450 reductase fusion gene (CYP2B6/RED) able to activate, in situ, a prodrug, the cyclophosphamide (CPA), into cytotoxic metabolites. This fusion protein has been successfully expressed in several human pulmonary and head and neck cancer cell lines inducing CPA cytotoxicity whereas no cytotoxicity was observed in uninfected cells. Moreover, we built a mutated CYP2B6TM/RED gene able to metabolize CPA 10-fold more efficiently than CYP2B6wt (patent PCT/EP2012/058219). Expression of CYP2B6TM/RED gene by recombinant lentivirus, sensibilized human pulmonary and head and neck cancer cell lines to weaker doses of CPA than cells expressing CYPB6wt and RED. Animal models are now in progress to evaluate in vivo our strategy before its potential use in human cancer therapy.