THE EFFICACY OF RECOMBINANT THROMBOPOIETIN IN MURINE AND NONHUMAN PRIMATE MODELS FOR RADIATION-INDUCED MYELOSUPPRESSION AND STEM-CELL TRANSPLANTATION

Radiation-induced pancytopenia proved to be a suitable model system in mice and rhesus monkeys for studying thrombopoietin (TPO) target cell range and efficacy. TPO was highly effective in rhesus monkeys expose d to the mid-lethal dose of 5 Gy (300 kV x-rays) TBI, a model in which it alleviated thrombocytopenia, promoted red cell reconstitution, acc elerated reconstitution of immature CD34(+) bone marrow cells, and pot entiated the response to growth factors such as GM-CSF and G-CSF. In c ontrast to the results in the 5 Gy TBI model, TPO was ineffective foll owing transplantation of limited numbers of autologous bone marrow or highly purified stem cells in monkeys conditioned with 8 Gy TBI. In th e 5 Gy model, a single dose of TPO augmented by GM-CSF 24 h after TBI was effective in preventing thrombocytopenia. The strong erythropoieti c stimulation may result in iron depletion, and TPO treatment should b e accompanied by monitoring of iron status. This preclinical evaluatio n thus identified TPO as a potential major therapeutic agent for count eracting radiation-induced pancytopenia and demonstrated pronounced st imulatory effects on the reconstitution of immature CD34(+) hemopoieti c cells with multilineage potential. The latter observation explains t he potentiation of the hematopoietic responses to G-CSF and GM-CSF whe n administered concomitantly. It also predicts the effective use of TP O to accelerate reconstitution of immature hematopoietic cells as well as possible synergistic effects in vivo with various other growth fac tors acting on immature stem cells and their direct lineage-committed progeny. The finding that a single dose of TPO might be sufficient for a clinically significant response emphasizes its potency and is of pr actical relevance. The heterogeneity of the TPO response encountered i n the various models used for evaluation points to multiple mechanisms operating on the TPO response and heterogeneity of its target cells. Mechanistic mouse studies made apparent that the response of multiline age cells shortly after TBI to a single administration of TPO is quant itatively more important for optimal efficacy than the lineage-restric ted response obtained at later intervals after TBI and emphasized the importance of a relatively high dose of TPO to overcome initial c-mpl- mediated clearance. Further elucidation of mechanisms determining effi cacy might very well result in a further improvement, e.g., following transplantation of limited numbers of stem cells. Adverse effects of T PO administration to myelosuppressed or stem cell transplanted experim ental animals were not observed.