Antiangiogenic gene therapy of myeloproliferative disease developed in transgenic mice expressing P230 bcr/abl.
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.
Miyake
K
K
Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan.
Inokuchi
K
K
Miyake
N
N
Dan
K
K
Shimada
T
T
D000256:Adenoviridae / Q000235:genetics*; D020533:Angiogenesis Inhibitors / Q000235:genetics*; D000818:Animals; D043169:Endostatins / Q000235:genetics*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D007273:Injections, Intramuscular; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D010455:Peptides / Q000235:genetics; D011993:Recombinant Fusion Proteins
D020533:Angiogenesis Inhibitors; D043169:Endostatins; D010455:Peptides; D011993:Recombinant Fusion Proteins; C042459:p 230; D016044:Fusion Proteins, bcr-abl