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Valérie Lallemand-Breitenbach^*, Marie-Claude Guillemin^*, Anne Janin, Marie-Thérèse Daniel, Laurent Degos^||, Scott C. Kogan^¶, J. Michael Bishop^¶, and Hugues de Thé^*

From the ^* Centre National de la Recherche Scientifique, UPR 9051, Laboratoire Associé au Comité de Paris de la Ligue contre le Cancer, Institut d'Hématologie de l'Université de Paris VII; Service d'Anatomie Pathologique, Service d'Hématologie Biologique, ^|| Service des Maladies du Sang, Hôpital St. Louis, 75475 Paris, Cedex 10 France; and ^¶ The Hooper Foundation, Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California 94143-0552

In acute promyelocytic leukemia (APL) patients, retinoic acid (RA) triggers differentiation while arsenic trioxide (arsenic) induces both a partial differentiation and apoptosis. Although their mechanisms of action are believed to be distinct, these two drugs both induce the catabolism of the oncogenic promyelocytic leukemia (PML)/RAR fusion protein. While APL cell lines resistant to one agent are sensitive to the other, the benefit of combining RA and arsenic in cell culture is controversial, and thus far, no data are available in patients. Using syngenic grafts of leukemic blasts from PML/RAR transgenic mice as a model for APL, we demonstrate that arsenic induces apoptosis and modest differentiation, and prolongs mouse survival. Furthermore, combining arsenic with RA accelerates tumor regression through enhanced differentiation and apoptosis. Although RA or arsenic alone only prolongs survival two- to threefold, associating the two drugs leads to tumor clearance after a 9-mo relapse-free period. These studies establishing RA/arsenic synergy in vivo prompt the use of combined arsenic/RA treatments in APL patients and exemplify how mouse models of human leukemia can be used to design or optimize therapies.

Key Words: differentiation • apoptosis • cancer • clinical trials • transgenics

We warmly thank all members of the PML group for suggestions during the course of this work and for critical reading of the manuscript. We thank Prof. Zhu Chen (Shanghai Institute of Hematology, Rui-Jin Hospital, China) for sharing unpublished results and constructive discussions at various stages of this work. We are grateful to M. Pla and her team, as well as to J. Valla for help in the animal facilities. We thank B. Cassina and C. Chomienne for PCR analysis, and S. Chevret for statistical analysis. Laboratoire Photo Hematologie is acknowledged for the artwork, and the Department of Pathology and Electron Microscopy for their efficient cooperation.

This project was supported by grants from Ligue contre le Cancer (Nationale and Comité de Paris), Association pour la Recherche contre le Cancer (ARC), European Economic Community (EEC; BIOMED II), Fondation St. Louis, and the University of Paris VII.

Abbreviations used: APL, acute promyelocytic leukemia; arsenic, arsenic trioxide; NB, nuclear body; PML, promyelocytic leukemia; RA, retinoic acid; TUNEL, terminal deoxynucleotidyltransferase– mediated dUTP nick end labeling.

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