J. Exp. Med., Volume 189, Number 7, April 5, 1999 1043-1052

Retinoic Acid and Arsenic Synergize to Eradicate Leukemic Cells in a Mouse Model of Acute Promyelocytic Leukemia

By 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.

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