Thrombopoietic growth factors

Bibliography

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• ••This paper was one of the first reports describing the purification of Mpl ligand fromthrombocytopenic plasma and its subsequent cloning and expression.
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• ••This paper was one of the first reports describing the purification of Mpl ligand fromthrombocytopenic plasma and its subsequent cloning and expression.
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• •This was the first report of the isolation of TPO by conventional chromatography without the use of Mpl. The eluted protein was then sequenced.
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• •This was one of the earliest reports describing the purification of ovine TPO directly from thrombocytopenic plasma by conventional chromatography.
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• ••This was the first report of murine TPO, which was cloned using direct-expression cloningtechniques.
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• •Both c-Mpl- and TPO-deficient mice have decreased bone marrow precursor cells, as would be expected, but also have decreased precursor cells for the other lineages. However, leukocyte and erythrocyte counts are normal in these mice. This study demonstrated the multilineage effect of TPO, as administration of rTPO to the TPO-deficient mice (but not to the c-Mpl-deficient mice) corrected the precursor cell defect.
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• •The thrombopoietin gene was knocked out to generate TPO-deficient mice. Homozygous TPO-deficient mice had platelet counts 20% of normal while heterozygous TPO-deficient mice had counts 60% of normal. This gene-dosage effect is strong evidence that the level of TPO gene expression is not regulated by the platelet count.
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• •This study was a comprehensive examination of the effects of PEG-rHuMGDF on platelet number and function in non-human primates (baboons). A log-linear relationship of dose to response was demonstrated for megakaryocyte number, ploidy, and platelet concentration for doses ranging from 0.05-2.5 pg/kg/day. Platelet function was analysed by fibrin deposition to Dacron® vascular grafts.
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• ••This was the first study to demonstrate that PEG-rHuMGDF could reduce the severity of thrombocytopenia in patients receiving cancer chemotherapy. Patients were given PEG-rHuMGDF or placebo in a randomised, double-blind, placebo-controlled, dose-escalation study. Patients receiving PEG-rHuMGDF had higher nadir platelet counts (188 x 109/1) than did patients receiving placebo (111 x 109/1) and earlier return to baseline platelet counts (14 days vs. > 21 days).
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• ••Patients with cancer who were being treated with carboplatin and cyclophosphamide plus
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• ••This was the first publication of the effects of the full-length form of Mpl ligand (rHuTP0) inhumans. A single intravenous injection of rHuTPO (0.3-1.2 pg/kg) to 12 patients being treated for sarcoma produced a dose-related increase in platelet count and increases in megakaryocytes.
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• •This was the first report of the use of MGDF (non-pegylated version) in non-human primates. Rhesus monkeys given MGDF responded with a 5- to 7-fold increase above normal platelet levels with no adverse effects.
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