1. ¹Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan
2. ²Division of Gene Therapy Research, Center for Advanced Medical Technology, Nippon Medical School, Tokyo, Japan
3. ³Department of Internal Medicine, Division of Hematology/Oncology, Nippon Medical School, Tokyo, Japan

Correspondence: Professor T Shimada, Department of Biochemistry and Molecular Biology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan

⁴These authors contributed equally to this work

Received 26 May 2004; Accepted 27 October 2004; Published online 23 December 2004.

Abstract

Antiangiogenic gene therapy offers an attractive approach to the treatment of a variety of malignancies, including those of the hematological system. However, evaluation of this approach has been hampered by the lack of appropriate animal models. We have recently produced transgenic mice expressing P230 bcr/abl that develop myeloproliferative disease (MPD) closely resembling human chronic myelogenous leukemia. Using this MPD murine model, we examined the feasibility of systemic antiangiogenic gene therapy for hematological malignancy. An adenoviral vector containing the secretable endostatin gene was injected into the right quadriceps muscle of the MPD mice. The increased endostatin level was detected for at least 6 months. Hematological parameters including platelet counts, granulocyte counts, and the hemoglobin concentration were improved by this gene therapy. Infiltration of megakaryocytes was also significantly inhibited in treated MPD mice. Reduction of the microvessel density was confirmed by histological examination. These results demonstrated, for the first time, that antiangiogenic gene therapy is effective to inhibit leukemogenesis caused by expression of the chimeric bcr/abl gene.