IN-VIVO ADENOVIRUS VECTOR-MEDIATED TRANSFER OF THE HUMAN THROMBOPOIETIN CDNA MAINTAINS PLATELET LEVELS DURING RADIATION-INDUCED AND CHEMOTHERAPY-INDUCED BONE-MARROW SUPPRESSION

Thrombopoietin (TPO, c-mpl ligand) has emerged as a major hematopoieti c cytokine stimulating megakaryocyte proliferation, endomitosis, and p latelet production. This study shows that a single administration of a n adenovirus (Ad) vector encoding TPO (AdCMV.TPO) abrogates thrombocyt openia induced in mice by carboplatin and irradiation, Normal Balb/c m ice receiving the vector Rad increased platelet counts peaking at 7 da ys and returning to baseline by day 15. Mice rendered pancytopenic wit h 500 rads and 1.2 mg of carboplatin bad a nadir platelet count of fiv e percent of the baseline, Mice receiving AdCMV.TPO 3 days before rece iving irradiation and chemotherapy achieved a platelet nadir four-fold 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 recove ry. At 30 days after therapy bone marrow and spleen of mice treated wi th AdCMV.TPO were populated with a large number of polyploid megakaryo cytes, but there was no evidence of circulating megakaryocytes in the liver or lungs and no pathologic bone abnormalities such as osteoscler osis or myelofibrosis, These observations suggest that an Ad vector ma y be an excellent delivery system to provide adequate TPO production t o maintain platelet levels in circumstances associated with life-threa tening thrombocytopenia. (C) 1996 by The American Society of Hematolog y.