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In vivo adenovirus vector-mediated transfer of the human thrombopoietin
cDNA maintains platelet levels during radiation-and chemotherapy- induced
bone marrow suppression
A Ohwada, S Rafii, MA Moore and RG Crystal
Division of Pulmonary and Critical Care Medicine, New York Hospital-
Cornell Medical Center, New York 10021, USA.
Thrombopoietin (TPO, c-mpl ligand) has emerged as a major hematopoietic
cytokine stimulating megakaryocyte proliferation, endomitosis, and platelet
production. This study shows that a single administration of an adenovirus
(Ad) vector encoding TPO (AdCMV.TPO) abrogates thrombocytopenia induced in
mice by carboplatin and irradiation. Normal Balb/c mice receiving the
vector had increased platelet counts peaking at 7 days and returning to
baseline by day 15. Mice rendered pancytopenic with 500 rads and 1.2 mg of
carboplatin had a nadir platelet count of five percent of the baseline.
Mice receiving AdCMV.TPO 3 days before receiving irradiation and
chemotherapy achieved a platelet nadir fourfold higher, and had significant
reduction in duration of thrombocytopenia, than mice receiving the control
Ad vector. Introduction of AdCMV.TPO the same day of chemotherapy and
irradiation was equally effective in acceleration of platelet recovery, but
administration of AdCMV.TPO 3 days after chemotherapy-radiation had little
effect on platelet recovery. At 30 days after therapy bone marrow and
spleen of mice treated with AdCMV.TPO were populated with a large number of
polyploid megakaryocytes, but there was no evidence of circulating
megakaryocytes in the liver or lungs and no pathologic bone abnormalities
such as osteosclerosis or myelofibrosis. These observations suggest that an
Ad vector may be an excellent delivery system to provide adequate TPO
production to maintain platelet levels in circumstances associated with
life-threatening thrombocytopenia.
Volume 88,
Issue 3,
pp. 778-784,
08/01/1996
Copyright © 1996 by The American Society of Hematology
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