Murray L J, Luens K M, Estrada M F, Bruno E, Hoffman R, Cohen R L, Ashby M A, Vadhan-Raj S
SyStemix, Palo Alto, California 94304, USA.
Exp Hematol. 1998 Mar;26(3):207-16.
Thrombopoietin (TPO), the primary regulator of megakaryocytopoiesis, also mediates biologic effects in vitro on hematopoietic cells more primitive than those committed to the megakaryocyte (MK) lineage. To assess the spectrum of hematopoietic effects of recombinant human (rh)TPO in vivo, we evaluated its proliferative effect on bone marrow (BM) progenitor cells, its maturation effect on BM MKs, and its mobilizing effect on peripheral blood (PB) progenitor cells during a phase I clinical laboratory investigation in which rhTPO was administered to cancer patients with normal hematopoiesis. Twelve patients received a single dose of rhTPO (0.3, 0.6, 1.2, or 2.4 microg/kg of body weight) prior to chemotherapy. BM and PB samples from these patients were analyzed 1 to 2 days before (baseline) and 7 days after rhTPO administration. At higher doses (1.2-2.4 microg/kg), rhTPO produced increased concentrations of primitive CD34+Thy-1+Lin-cells (mean 2.1-fold), CD34+mpl+ cells (mean 5.2-fold), CD34+CD41+CD14- promegakaryoblasts (mean 2.9-fold), and myeloerythroid colony-forming cells (mean threefold) in BM. No significant increases in the frequency of BM colony-forming unit (CFU)-MK were observed. Elevated numbers of both immature (2N-8N) and more mature (64N and 128N) CD41+ MKs were detected in BM, with modal ploidy remaining at 16N. Higher doses of rhTPO (1.2-2.4 microg/kg) also induced increased concentrations of CD34+ cell subsets in PB, including both primitive CD34+Thy-1+Lin- (mean 8.8-fold) and MK lineage-committed CD34+CD41+CD14- cells (mean 14.6-fold) as well as various myeloerythroid colony-forming cells (mean 3.6- to 5.5-fold). These results demonstrate that rhTPO given as a single dose not only promotes proliferation and maturation of cells of the MK lineage, but also expands the pool of BM primitive hematopoietic cells. In addition, rhTPO induces mobilization of hematopoietic progenitors into peripheral circulation. The extent to which such multilineage effects on human progenitor cells will contribute to clinical efficacy remains to be determined.
血小板生成素（TPO）是巨核细胞生成的主要调节因子，它在体外对造血细胞也具有生物学效应，这些造血细胞比那些定向于巨核细胞（MK）谱系的细胞更为原始。为了评估重组人（rh）TPO在体内的造血效应谱，我们在一项I期临床实验室研究中评估了其对骨髓（BM）祖细胞的增殖作用、对BM MKs的成熟作用以及对外周血（PB）祖细胞的动员作用，该研究中rhTPO被给予造血功能正常的癌症患者。12名患者在化疗前接受了单剂量的rhTPO（0.3、0.6、1.2或2.4μg/kg体重）。在给予rhTPO前1至2天（基线）和给药后7天对这些患者的BM和PB样本进行分析。在较高剂量（1.2 - 2.4μg/kg）时，rhTPO使BM中原始的CD34 + Thy-1 + Lin-细胞（平均2.1倍）、CD34 + mpl +细胞（平均5.2倍）、CD34 + CD41 + CD14-前巨核母细胞（平均2.9倍）和髓系红系集落形成细胞（平均3倍）的浓度增加。未观察到BM集落形成单位（CFU）-MK频率的显著增加。在BM中检测到未成熟（2N - 8N）和更成熟（64N和128N）的CD41 + MKs数量增加，众数倍性保持在16N。较高剂量的rhTPO（1.2 - 2.4μg/kg）还诱导PB中CD34 +细胞亚群浓度增加，包括原始的CD34 + Thy-1 + Lin-（平均8.8倍）和MK谱系定向的CD34 + CD41 + CD14-细胞（平均14.6倍）以及各种髓系红系集落形成细胞（平均3.6至5.5倍）。这些结果表明，单剂量给予rhTPO不仅促进MK谱系细胞的增殖和成熟，还扩大了BM原始造血细胞池。此外，rhTPO诱导造血祖细胞动员到外周循环中。这种对人类祖细胞的多谱系效应在多大程度上有助于临床疗效仍有待确定。
