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The Oncologist, Vol. 2, No. 5, 311–318, October 1997
© 1997 AlphaMed Press

Megakaryocyte Growth and Development Factor: A Review of Early Clinical Studies

Rick Abraham, Russell L. Basser

Center for Development of Cancer Therapeutics, Parkville, Victoria, Australia

Correspondence: Dr. Russell L. Basser, Center for Development of Cancer Therapeutics, c/o P.O. Royal Melbourne Hospital, Parkville, Victoria 3050, Australia. Telephone: 61-3-9342-8792; Fax: 61-3-9347-7508; e-mail: basser{at}licre.ludwig.edu.au


   ABSTRACT
Top
 Abstract
Introduction
 Preclinical Studies
 Clinical Studies with MGDF
 Conclusion
 References
 
Megakaryocyte growth and development factor (MGDF), a Mpl ligand, recently entered clinical trials worldwide and has been demonstrated to have potent biological activity. MGDF administration causes a dose-dependent increase in platelet count but no effect on white cell count or hematocrit. These platelets are morphologically and functionally normal. When administered following moderately myelosuppressive chemotherapy, MGDF significantly enhances platelet recovery, although scheduling in relation to chemotherapy may be important in optimizing the full effects. MGDF mobilizes progenitor cells of multiple hematopoietic lineages, and may enhance the effects of filgrastim on peripheral blood progenitor cell levels after chemotherapy. MGDF is well tolerated and does not cause toxicity similar to that observed with other thrombopoietic cytokines. Numerous studies are under way to help determine the precise role of MGDF in clinical practice.

Key Words. Thrombopoietin • Megakaryocyte growth and development factor • Platelets • Chemotherapy • Progenitor cell mobilization • Toxicity • Thrombocytopenia • Mpl ligand • c-mpl • Clinical • Human • Phase 1 • Aggregation • Platelet function • Safety


   INTRODUCTION
Top
 Abstract
 Introduction
Preclinical Studies
 Clinical Studies with MGDF
 Conclusion
 References
 
The term thrombopoietin (TPO) was first coined in 1958 by Keleman to describe a humoral substance which appeared to regulate platelet production [1]. Keleman found that the urine, serum and plasma of animals and patients with severe thrombocytopenia could increase platelet numbers when injected into normal animals [2]. The successful cloning of TPO followed a long and fruitless attempt to purify the molecule from plasma, serum, urine and conditioned culture media with various cell lines [3–6].

The initial breakthrough in the search for TPO came with the discovery of a murine myeloproliferative oncogene, v-mpl [7]. That this was a finding of great serendipity was realized with the recognition that the cellular homologue of v-mpl, termed c-mpl, encoded the cytoplasmic portion of a membrane protein expressed on hematopoietic cells, predominantly those of megakaryocytic lineage [8,9]. A critical observation was that the addition of c-mpl antisense oligonucleotides to cultured CD34+ cells selectively prevented the generation of megakaryocyte colonies [9]. The flurry of activity searching for the ligand to c-mpl came to a climax in 1994, with the publication of the sequence of the cDNA [10–15]. Mpl ligand has subsequently been shown to be the central physiological regulator of megakaryocytopoiesis and platelet production, and is now referred to in its natural form as thrombopoietin [16].

Human TPO is a 60-70 kDa, glycosylated protein which is primarily produced in the liver and kidneys [10,17]. It consists of 332 amino acids, is highly conserved between species, and has 23% homology with human erythropoietin (EPO) [18]. Megakaryocyte growth and development factor (MGDF) is a truncated protein, with homology with the EPO-like amino-terminus of human TPO [10,19]. It has identical biological properties to TPO in vitro [19–21] and in vivo [22,23], suggesting that the EPO-like domain contains all the required elements to bind and activate c-mpl. However, MGDF has a short circulatory half-life, which can be markedly increased when coupled to polyethylene glycol [24]. The pegylated form (PEG-rHuMGDF) is approximately ten times more potent in vivo than the unconjugated polypeptide [24]. Clinical trials with PEG-rHuMGDF commenced in Australia and the United States in May 1995.


   PRECLINICAL STUDIES
Top
 Abstract
 Introduction
 Preclinical Studies
Clinical Studies with MGDF
 Conclusion
 References
 
Mpl ligand acts as a megakaryocyte growth and differentiation/maturation factor [20,25–30]. The pivotal role of the cytokine in platelet production is demonstrated by the marked reduction in platelet levels in c-mpl- [31,32] and TPO- [33] deficient mice to 5% to 15% of littermate controls. Because platelet counts in the deficient animals are detectable, it is obvious that other thrombopoietic cytokines, such as interleukin 3 (IL-3), IL-6, IL-11 and stem cell factor, play a minor role in platelet production.

Further evidence of the regulatory role of Mpl ligand in thrombopoiesis is demonstrated by the finding of an inverse relationship between platelet count and serum Mpl ligand in animals and humans [20,34–37]. As platelet counts recover, TPO levels decrease in parallel. Interestingly, production of TPO appears to be regulated by platelet mass, rather than at the transcriptional level [38–40], and it is unlikely that the rate of TPO gene expression is altered in response to physiological stimuli [16]. Platelet c-mpl has a high affinity for the ligand [41,42], and once bound, the ligand is internalized and degraded [43].

Mpl ligand increases platelet sensitivity to a number of agonists in vitro [44–49], but no alteration in platelet function is detectable following in vivo administration [23].

The in vivo physiological effects of Mpl ligand have been studied in a number of animal models. In mice, daily administration of MGDF produced a profound increase in marrow and splenic megakaryocyte progenitors (CFU-Mk) and a three- to fourfold increase in platelet numbers [22,24,50–52]. This effect was lineage-specific, with no noticeable effect on red or white cell counts. Similarly, in nonhuman primates platelet levels up to 10 times baseline were observed after 10 days of daily administration of MGDF [23,50,53,54]. In baboons, PEG-rHuMGDF produced dose-dependent increases in the circulating platelet count over a dose range from 0.05 to 2.5 µg/kg/day [23,53]. Log-dose dependent increases in bone marrow megakaryocyte numbers, volume and ploidy were recorded [53]. Toxicity in these animal studies was minimal, and few side effects could be ascribed to the cytokine.

The ability of Mpl ligand to alleviate thrombocytopenia has been studied in detail. In mice given ablative doses of chemotherapy either alone or with radiation, daily injections of MGDF resulted in abrogation of severe thrombocytopenia and a significant reduction in mortality [22,24]. No effect was observed on other cell lineages. However, when MGDF or TPO were combined with G-CSF, neutrophil recovery was also markedly enhanced [55–57]. In murine models of progenitor cell transplantation, the period of severe thrombocytopenia after transplant was substantially reduced by MGDF [58–60]. In primates, treatment-induced thrombocytopenia was prevented with administration of MGDF [54,55,61,62] or TPO [63]. In these studies, both the platelet nadir and duration of thrombocytopenia were abrogated.


   CLINICAL STUDIES WITH MGDF
Top
 Abstract
 Introduction
 Preclinical Studies
 Clinical Studies with MGDF
Conclusion
 References
 
Methods
We assessed the safety and biological activities of PEG-rHuMGDF in a series of phase 1 studies. The initial trials were randomized, double-blinded and placebo controlled. In the first study [64–66], 17 patients with advanced cancer received either PEG-rHuMGDF (13 patients) or placebo (4 patients) alone prior to chemotherapy. PEG-rHuMGDF was administered by daily s.c. injection in sequential cohorts of 0.03 (n = 3), 0.1 (n = 3), 0.3 (n = 4) and 1.0 (n = 3) µg/kg/day. The placebo and lower three dose schedules were given for 10 days, whereas the highest dose was given for six, seven, and nine days because of early thrombocytosis.

In the second study [67], PEG-rHuMGDF or placebo (3:1 ratio) was given with filgrastim after carboplatin 600 mg/m2 and cyclophosphamide 1,200 mg/m2 to 41 patients (Table 1Go, Table 2Go). Fifteen patients who had participated in the pre-chemotherapy trial received the same study drug and dose after chemotherapy. Study drug was given daily for up to 21 days at doses of 0.03, 0.1, 0.3 and 1.0 µg/kg/day commencing on the day after chemotherapy. In the cohorts receiving 1, 3 or 5 µg/kg/day, the duration of PEG-rHuMGDF administration was shortened to seven days because of asymptomatic thrombocytosis in the previous dose levels. Filgrastim 5 µg/kg/day was given until neutrophil recovery. In the absence of intolerable toxicity or disease progression, patients were able to receive the chemotherapy in 28-day intervals. After the second and subsequent cycles of chemotherapy, PEG-rHuMGDF was not given. The functional characteristics of PEG-rHuMGDF produced platelets, and the mobilization of peripheral blood progenitor cells was assessed in detail in both studies.


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  		Table 1. Baseline characteristics of 41 patients with advanced cancer administered placebo plus filgrastim or PEG-rHuMGDF plus filgrastim after chemotherapy
 

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  		Table 2. Non-hematological adverse events in 41 patients who received study drug
 
Platelet Counts

Pre-chemotherapy
A dose-dependent increase in platelet counts was observed following the administration of PEG-rHuMGDF (Fig. 1Go), although considerable individual variation in response was seen. Patients receiving 0.3 and 1 µg/kg PEG-rHuMGDF had increases in platelet counts ranging from 51% to 584%. However, an increase in bone marrow megakaryocytes by up to 1.8-fold was observed in all PEG-rHuMGDF cohorts. The platelet numbers began to increase from day 6 and continued to rise despite cessation of PEG-rHuMGDF. The peak count was reached between days 12 and 18, and platelets returned to normal between days 22 and 30. The rise in platelet counts in the lower dose cohorts was considerably less pronounced. No effects were observed on absolute neutrophil count or hematocrit.



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  		Figure 1. The effects of PEG-rHuMGDF (daily administration indicated by the bar) on platelet counts in patients receiving placebo, and 0.03, 0.1, 0.3 and 1.0 µg/kg/day of PEG-rHuMGDF. Reprinted with permission [64].

 
These observations are similar to those of Vadhan-Raj et al. [68], who gave a single dose of glycosylated TPO alone prior to chemotherapy. They reported elevated platelet counts of up to 212% and the kinetics of thrombocytosis were consistent with the findings in our study.

Post-chemotherapy
The doses of chemotherapy delivered in our study were moderately myelosuppressive. Administration of PEG-rHuMGDF significantly enhanced platelet recovery when given in "effective" doses (0.3 to 5 µg/kg/day). In these patients (n = 25), the platelet nadir occurred significantly earlier than in the placebo group (Fig. 2AGo), analogous to the effect of G-CSF on neutrophil recovery following chemotherapy [69]. PEG-rHuMGDF did not influence the depth of the platelet nadir, but rather shortened the time to recovery of pre-treatment platelet count (median 17 days versus 22 days for the placebo group) (Fig. 2BGo). PEG-rHuMGDF did not influence neutrophil recovery or red cell toxicity. Antibodies to PEG-MGDF were not detected in any patients.



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  		Figure 2. Platelet recovery in patients receiving PEG-rHuMGDF 0.3 to 5.0 µg/kg (n = 25) versus those given placebo (n = 10). Panel A shows platelet counts, while Panel B demonstrates the time of recovery to baseline (pre-chemotherapy) platelet levels. {blacksquare}=PEGrHuMGDF, {triangleup}=placebo. Reprinted with permission [67].

 
A hint to the importance of scheduling of PEG-rHuMGDF was given by the observation that faster platelet recovery occurred in five patients who received PEG-rHuMGDF 0.3 or 1.0 µg/kg/day both before and after chemotherapy, compared with that of nine patients given 1.0 µg/kg/day only after chemotherapy. In addition, recovery of platelet count to normal following the second cycle of chemotherapy was significantly reduced in those patients who had received PEG-rHuMGDF after the first cycle compared to the placebo group (21 versus 24 days; p = 0.013). This difference was greater in patients who experienced a shorter interval between cessation of PEG-rHuMGDF and commencement of the second cycle of chemotherapy. These observations have led to further studies investigating the potential benefit in administering PEG-rHuMGDF prior to chemotherapy.

The results from our studies contrast to those of Fanucchi et al., who administered PEG-rHuMGDF alone after mildly myelosuppressive chemotherapy (paclitaxel and carboplatin) [70]. Fifty-three patients with non-small cell lung cancer were treated. At all dose levels of PEG-rHuMGDF, the nadir of the platelet count was higher and the time to recovery of baseline platelet count shorter than that observed with placebo. No dose response to PEG-rHuMGDF was observed.

Platelet Function
We assessed platelet function during PEG-rHuMGDF administration by measures of platelet aggregation and release of adenosine triphosphate (ATP) in vitro in response to a variety of standard agonists, and analyzed platelet surface activation markers, as described elsewhere [65].

The previously reported observations that recombinant forms of Mpl ligand increase sensitivity of platelets to aggregating agents were not borne out by our study. There were no significant changes in aggregation response or ATP release between baseline measurements and repeated testing during and after PEG-rHuMGDF administration when given alone [65], or when given with filgrastim after chemotherapy [67]. Furthermore, there were no changes in coagulation parameters. The platelets produced by PEG-rHuMGDF were morphologically normal by light- and electron-microscopy, and platelet activation markers did not change over the duration of the study. In addition, in a patient given aspirin because of asymptomatic thrombocytosis (platelet peaking at 1,876 x 109/l), platelets responded with the expected inhibition of aggregation response and ATP release.

Peripheral Blood Progenitor Cell (PBPC) Mobilization
Given the expression of the c-mpl on a number CD34+ cells, the observations of progenitor cell mobilization in preclinical models [71], and the unexpected observations during phase 1 studies of G-CSF [72], we assessed the levels of PBPC, when given alone and when used in combination with filgrastim after chemotherapy.

Pre-chemotherapy
In contrast to the lineage-dominant effect of PEG-rHuMGDF on mature cell populations, multilineage mobilization of PBPC occurred in patients given MGDF. However, there was a preferential increase in blood levels of megakaryocyte progenitors (Meg-CFC) compared to myeloid (GM-CFC) and erythroid (BFU-E) progenitor cells. Mobilization of Meg-CFC was observed in patients given >=0.1 µg/kg of PEG-rHuMGDF, but GM-CFC and BFU-E increased only at doses >=0.3 µg/kg. Furthermore, the degree of mobilization appeared to be related to the dose of PEG-rHuMGDF [66].

An interesting observation was that the kinetics of progenitor cell release from the marrow were unlike that of other lineage-dominant cytokines, such as G-CSF. Following administration of the latter, PBPC levels rise almost immediately, peak at day 5 or 6, and fall when G-CSF is ceased. However, PEG-rHuMGDF resulted in a late and sustained rise in progenitor cells, so that increased levels were first detected only on day 8, and were generally greater on day 12, despite discontinuation of the cytokine several days earlier.

Post-chemotherapy
Administration of PEG-rHuMGDF in doses of 0.3 to 5.0 µg/kg combined with filgrastim after chemotherapy significantly enhanced mobilization of PBPC compared to placebo plus filgrastim. Furthermore, higher peak levels of PBPC were observed with increasing dose of PEG-rHuMGDF. In the 5 µg/kg cohort, levels of GM-CFC were up to 1,000-fold greater than in the placebo group (Fig. 3Go).



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  		Figure 3: Fold-increase in PBPC levels on day 15 after chemotherapy compared with baseline (pre-chemotherapy) in placebo (n = 10) and PEG-rHuMGDF (n = 25). The PEG-rHuMGDF group includes only patients given 0.3 to 5.0 µg/kg.

 
Safety

Pre-chemotherapy
Importantly, PEG-rHuMGDF was associated with minimal toxicity. One episode of mild superficial thrombophlebitis which resolved spontaneously was seen in a patient with a platelet count of 694 x 109/l. There were no changes in performance status, vital signs or body weight during the study, and there were no changes in biochemical, renal or liver function tests. Unlike other, less potent thrombopoietic cytokines, there was no evidence of induction of an acute phase response.

Post-chemotherapy
Two patients developed thrombo-embolic events after treatment with PEG-rHuMGDF, although in both instances the platelet counts at the time were low and no abnormalities in platelet function or surface marker expression were present. Eleven patients developed a platelet count of greater than 1,000 x 109/l in the recovery phase post-chemotherapy without clinical sequelae. There were no significant differences in non-hematological toxicity between the groups who received PEG-rHuMGDF compared to placebo.

The low incidence of adverse effects due to PEG-rHuMGDF was consistent with the report from Fanucchi [70]. Glycosylated TPO was also associated with minimal toxicity in the study of Vadhan-Raj et al. [68].


   CONCLUSION
Top
 Abstract
 Introduction
 Preclinical Studies
 Clinical Studies with MGDF
 Conclusion
References
 
MGDF is an important new hematopoietic cytokine which potently stimulates the production of functionally and morphologically normal platelets in a lineage-specific manner. It significantly reduces the time to platelet recovery following myelosuppressive chemotherapy and is able to mobilize large numbers of multilineage peripheral blood progenitor cells, both as a single agent and also when given following chemotherapy in concert with filgrastim. Importantly, MGDF is well tolerated and associated with very little significant toxicity.

The potential uses of MGDF include the treatment of disease- and therapy-related severe thrombocytopenia. The most apparent clinical states in which this might apply are acute leukemia and bone marrow or peripheral blood progenitor cell transplantation. MGDF may also permit the maintenance of dose intensity in multicycle chemotherapy regimens. The lack of toxicity and potent biological activity of MGDF suggest it will be safe in healthy volunteers to enhance the efficiency of platelet or progenitor cell donation. MGDF also has potential for use in other causes of thrombocytopenia, such as HIV infection, liver disorders, surgery, myelodysplasia and auto-immune platelet destruction.

However, before these clinical directions can be explored, there remain questions with regard to the optimum dose and schedule of MGDF. For example, we are currently investigating the effects of different dose and schedules of PEG-rHuMGDF when administered prior to chemotherapy [73]. Given the rapid introduction of MGDF into clinical trials following its discovery, the results of further studies that help to define the role of MGDF are eagerly awaited.


   REFERENCES
Top
 Abstract
 Introduction
 Preclinical Studies
 Clinical Studies with MGDF
 Conclusion
 References
 

  1. Kelemen E, Csehati I, Tanos B. Demonstration and some properties of human thrombopoietin in thrombocythemic sera. Acta Haematol 1958;20:350–355.[Medline]
  2. McDonald TP. Thrombopoietin: its biology, purification, and characterization. Exp Hematol 1988;16:201–205.[Medline]
  3. Hill RJ, Leven RM, Levin FC et al. The effect of partially purified thrombopoietin on guinea pig megakaryocyte ploidy in vitro. Exp Hematol 1989;17:903–907.[Medline]
  4. Vannucchi AM, Grossi A, Rafanelli D et al. Partial purification and biochemical characterization of human plasma thrombopoietin. Leukemia 1988;2:236–240.[Medline]
  5. Miyake T, Kawakita M, Enomoto K et al. Partial purification and biological properties of thrombopoietin extracted from the urine of aplastic anemia patients. STEM CELLS 1982;2:129–144.
  6. McDonald TP, Cottrell M, Clift R et al. Studies on the purification of thrombopoietin from kidney cell culture medium. J Lab Clin Med 1985;106:162–174.[Medline]
  7. Wendling F, Varlet P, Charon M et al. MPLV: a retrovirus complex inducing an acute myeloproliferative leukemia disorder in adult mice. Virology 1986;149:242–246.[Medline]
  8. Souyri M, Vigon I, Penciolelli JF et al. A putative truncated cytokine receptor gene transduced by the myeloproliferative leukemia virus immortalizes hematopoietic progenitors. Cell 1990;63:1137–1147.[Medline]
  9. Methia N, Louache F, Vainchenker W et al. Oligodeoxynucleotides antisense to the proto-oncogene c-mpl specifically inhibit in vitro megakaryocytopoiesis. Blood 1993;82:1395–1401.[Abstract/Free Full Text]
  10. Bartley TD, Bogenberger J, Hunt P et al. Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor mpl. Cell 1994;77:1117–1124.[Medline]
  11. de Sauvage FJ, Hass PE, Spencer SD et al. Stimulation of megakaryopoiesis and thrombopoiesis by the c-mpl ligand. Nature 1994;369:533–538.[Medline]
  12. Lok S, Kaushansky K, Holly RD et al. Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production in vivo. Nature 1994;369:565–568.[Medline]
  13. Kato T, Ogami K, Shimada Y et al. Purification and characterization of thrombopoietin. J Biochem (Tokyo) 1995;118:229–236.[Abstract/Free Full Text]
  14. Kuter DJ, Beeler DL, Rosenberg RD. The purification of megapoietin: a physiological regulator of megakaryocyte growth and platelet production. Proc Natl Acad Sci USA 1994;91:11104–11108.[Abstract/Free Full Text]
  15. Wendling F, Maraskovsky E, Debili N et al. c-mpl ligand is a humoral regulator of megakaryopoiesis. Nature 1994;369:571–574.[Medline]
  16. Kaushansky K. Thrombopoietin: the primary regulator of platelet production. Blood 1995;86:419–431.[Free Full Text]
  17. Klein B, Zhang X-G, Lu Z-Y et al. Interleukin-6 in human multiple myeloma. Blood 1995;85:863–872.[Free Full Text]
  18. Gurney AL, Kuang W-J, Xie M-H et al. Genomic structure, chromosomal localization, and conserved alternative splice forms of thrombopoietin. Blood 1995;85:981–988.[Abstract/Free Full Text]
  19. Hunt P, Li Y-S, Nichol JL et al. Purification and biologic characterization of plasma-derived megakaryocyte growth and development factor. Blood 1995;86:540–547.[Abstract/Free Full Text]
  20. Nichol JL, Hokom MM, Hornkohl A et al. Megakaryocyte growth and development factor. Analyses of in vitro effects on human megakaryopoiesis and endogenous serum levels during chemotherapy-induced thrombocytopenia. J Clin Invest 1995;95:2973–2978.
  21. Debili N, Wendling F, Katz A et al. The Mpl-ligand or thrombopoietin or megakaryocyte growth and differentiative factor has both direct proliferative and differentiative activities on human megakaryocyte progenitors. Blood 1995;86:2516–2525.[Abstract/Free Full Text]
  22. Ulich TR, Del Castillo J, Yin S et al. Megakaryocyte growth and development factor ameliorates carboplatin-induced thrombocytopenia in mice. Blood 1995;86:971–976.[Abstract/Free Full Text]
  23. Harker LA, Hunt P, Marzec UM et al. Regulation of platelet production and function by megakaryocyte growth and development factor (MGDF) in nonhuman primates. Blood 1996;87:1833–1844.[Abstract/Free Full Text]
  24. Hokom MM, Lacey D, Kinstler OB et al. Pegylated megakaryocyte growth and development factor abrogates the lethal thrombocytopenia associated with carboplatin and irradiation in mice. Blood 1995;86:4486–4492.[Abstract/Free Full Text]
  25. Kaushansky K, Lok S, Holly RD et al. Promotion of megakaryocyte progenitor expansion and differentiation by the c-mpl ligand thrombopoietin. Nature 1994;369:568–571.[Medline]
  26. Zeigler FC, de Sauvage F, Widmer HR et al. In vitro megakaryocytopoietic and thrombopoietic activity of c-mpl ligand (TPO) on purified murine hematopoietic stem cells. Blood 1994;84:4045–4052.[Abstract/Free Full Text]
  27. Broudy VC, Lin NL, Kaushansky K. Thrombopoietin (c-mpl ligand) acts synergistically with erythropoietin, stem cell factor, and interleukin-11 to enhance murine megakaryocyte colony growth and increases megakaryocyte ploidy in vitro. Blood 1995;85:1719–1726.[Abstract/Free Full Text]
  28. Banu N, Wang J, Deng B et al. Modulation of megakaryocytopoiesis by thrombopoietin: the c-Mpl ligand. Blood 1995;86:1331–1338.[Abstract/Free Full Text]
  29. Choi ES, Nichol JL, Hokom MM et al. Platelets generated in vitro from proplatelet-displaying human megakaryocytes are functional. Blood 1995;85:402–413.[Abstract/Free Full Text]
  30. Angchaisuksiri P, Carlson PL, Dessypris EN. Effects of recombinant human thrombopoietin on megakaryocyte colony formation and megakaryocyte ploidy by human CD34+ cells in a serum-free system. Br J Haematol 1996;93:13–17.[Medline]
  31. Gurney AL, Carver-Moore K, de Sauvage FJ et al. Thrombocytopenia in c-mpl-deficient mice. Science 1994;265:1445–1447.[Abstract/Free Full Text]
  32. Alexander WS, Roberts AW, Nicola NA et al. Deficiencies in progenitor cells of multiple hemopoietic lineages and defective megakaryopoiesis in mice lacking the thrombopoietin receptor c-mpl. Blood 1996;87:2162–2170.[Abstract/Free Full Text]
  33. de Sauvage FJ, Carver-Moore K, Luoh S-M et al. Physiological regulation of early and late stages of megakaryocytopoiesis by thrombopoietin. J Exp Med 1996;183:651–656.[Abstract/Free Full Text]
  34. McCarty JM, Sprugel KH, Fox NE et al. Murine thrombopoietin mRNA levels are modulated by platelet count. Blood 1995;86:3668–3675.[Abstract/Free Full Text]
  35. Kuter DJ, Rosenberg RD. The reciprocal relationship of thrombopoietin (c-Mpl ligand) to changes in the platelet mass during busulfan-induced thrombocytopenia in the rabbit. Blood 1995;85:2720–2730.[Abstract/Free Full Text]
  36. Meng YG, Martin TG, Peterson ML et al. Circulating thrombopoietin concentrations in thrombocytopenic patients, including cancer patients following chemotherapy, with or without peripheral blood progenitor cell transplantation. Br J Haematol 1996;95:535–541.[Medline]
  37. Emmons RVB, Reid DM, Cohen RL et al. Human thrombopoietin levels are high when thrombocytopenia is due to megakaryocyte deficiency and low when due to increased platelet destruction. Blood 1996;87:4068–4071.[Abstract/Free Full Text]
  38. Stoffel R, Wiestner A, Skoda RC. Thrombopoietin in thrombocytopenic mice: evidence against regulation at the mRNA level and for a direct regulatory role of platelets. Blood 1996;87:567–573.[Abstract/Free Full Text]
  39. Eaton DL, de Sauvage FJ. Thrombopoietin: the primary regulator of megakaryocytopoiesis and thrombopoiesis. Exp Hematol 1997;25:1–7.[Medline]
  40. Nagata Y, Shozaki Y, Nagahisa H et al. Serum thrombopoietin level is not regulated by transcription but by the total counts of both megakaryocytes and platelets during thrombocytopenia and thrombocytosis. Thromb Haemost 1997;77:808–814.[Medline]
  41. Fielder PJ, Gurney AL, Stefanich E et al. Regulation of thrombopoietin levels by c-mpl-mediated binding to platelets. Blood 1996;87:2154–2161.[Abstract/Free Full Text]
  42. Broudy VC, Lin NL, Sabath DF. Human platelets display high-affinity receptors for thrombopoietin. Blood 1997;89:1896–1904.[Abstract/Free Full Text]
  43. Fielder PJ, Hass P, Nagel M et al. Human platelets as a model for the binding and degradation of thrombopoietin. Blood 1997;89:2782–2788.[Abstract/Free Full Text]
  44. Toombs CF, Young CH, Glaspy JA et al. Megakaryocyte growth and development factor (MGDF) moderately enhances in-vitro platelet aggregation. Thromb Res 1995;80:23–33.[Medline]
  45. Kojima H, Hamazaki Y, Nagata Y et al. Modulation of platelet activation in vitro by thrombopoietin. Thromb Haemost 1995;74:1541–1545.[Medline]
  46. Chen JC, Herceg-Harjacek L, Groopman JE et al. Regulation of platelet activation in vitro by the c-Mpl ligand, thrombopoietin. Blood 1995;86:4054–4062.[Abstract/Free Full Text]
  47. Peng JP, Friese P, Wolf RF et al. Relative reactivity of platelets from thrombopoietin- and interleukin-6 treated dogs. Blood 1996;87:4158–4163.[Abstract/Free Full Text]
  48. Oda A, Miyakawa Y, Druker BJ et al. Thrombopoietin primes human platelet aggregation induced by shear stress and by multiple agonists. Blood 1996;87:4664–4670.[Abstract/Free Full Text]
  49. Wun T, Paglieroni T, Hammond WP et al. Thrombopoietin is synergistic with other hematopoietic growth factors and physiologic platelet agonists for platelet activation in vitro. Am J Hematol 1997;54:225–232.[Medline]
  50. Farese AM, Hunt P, Boone T et al. Recombinant human megakaryocyte growth and development factor stimulates thrombocytopoiesis in normal nonhuman primates. Blood 1995;86:54–59.[Abstract/Free Full Text]
  51. Ulich TR, del Castillo JC, Senaldi G et al. Systemic hematological effects of PEG-rHuMGDF-induced megakaryocyte hyperplasia in mice. Blood 1996;87:5005–5015.
  52. Arnold JT, Daw NC, Stenberg PE et al. A single injection of pegylated murine megakaryocyte growth and development factor (MGDF) into mice is sufficient to produce a profound stimulation of megakaryocyte frequency, size, and ploidization. Blood 1997;89:823–833.[Abstract/Free Full Text]
  53. Harker LA, Marzec UM, Hunt P et al. Dose-response effects of pegylated human megakaryocyte growth and development factor on platelet production and function in nonhuman primates. Blood 1996;88:511–521.[Abstract/Free Full Text]
  54. Andrews RG, Winkler A, Myerson D et al. Recombinant human ligand for MPL, megakaryocyte growth and development factor (MGDF), stimulates thrombopoiesis in vivo in normal and myelosuppressed baboons. STEM CELLS 1996;14:661–677.[Medline]
  55. Farese AM, Hunt P, Grab LB et al. Combined administration of recombinant human megakaryocyte growth and development factor and granulocyte colony-stimulating factor enhances multilineage hematopoietic reconstitution in nonhuman primates after radiation-induced marrow aplasia. J Clin Invest 1996;97:2145–2151.[Medline]
  56. Grossmann A, Lenox J, Ren HP et al. Thrombopoietin accelerates platelet, red blood cell, and neutrophil recovery in myelosuppressed mice. Exp Hematol 1996;24:1238–1246.[Medline]
  57. Grossmann A, Lenox J, Deisher TA et al. Synergistic effects of thrombopoietin and granulocyte colony-stimulating factor on neutrophil recovery in myelosuppressed mice. Blood 1996;88:3363–3370.[Abstract/Free Full Text]
  58. Molineux G, Hartley C, McElroy P et al. Megakaryocyte growth and development factor accelerates platelet recovery in peripheral blood progenitor cell transplant recipients. Blood 1996;88:366–376.[Abstract/Free Full Text]
  59. Molineux G, Hartley CA, McElroy P et al. Megakaryocyte growth and development factor stimulates enhanced platelet recovery in mice after bone marrow transplantation. Blood 1996;88:1509–1514.[Abstract/Free Full Text]
  60. Molineux G, Hartley C, McElroy P et al. An analysis of the effects of combined treatment with rmGM-CSF and PEG-rHuMGDF in murine bone marrow transplant recipients. STEM CELLS 1997;15:43–49.[Medline]
  61. Fibbe WE, Heemskerk DPM, Laterveer L et al. Accelerated reconstitution of platelets and erythrocytes after syngeneic transplantation of bone marrow cells derived from thrombopoietin pretreated donor mice. Blood 1995;86:3308–3313.[Abstract/Free Full Text]
  62. Harker LA, Marzec UM, Kelly AB et al. Prevention of thrombocytopenia and neutropenia in a nonhuman primate model of marrow suppressive chemotherapy by combining pegylated recombinant human megakaryocyte growth and development factor and recombinant human granulocyte colony-stimulating factor. Blood 1997;89:155–165.[Abstract/Free Full Text]
  63. Akahori H, Shibuya K, Obuchi M et al. Effect of recombinant human thrombopoietin in nonhuman primates with chemotherapy-induced thrombocytopenia. Br J Haematol 1996;94:722–728.[Medline]
  64. Basser RL, Rasko JEJ, Clarke K et al. Thrombopoietic effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) in patients with advanced cancer. Lancet 1996;348:1279–1281.[Medline]
  65. O’Malley CJ, Rasko JEJ, Basser RL et al. Administration of pegylated recombinant human megakaryocyte growth and development factor to humans stimulates the production of functional platelets that show no evidence of in vivo activation. Blood 1996;88:3288–3298.[Abstract/Free Full Text]
  66. Rasko JEJ, Basser RL, Boyd J et al. Multilineage mobilization of peripheral blood progenitor cells in humans following administration of PEG-rHuMGDF. Br J Haematol 1997;97:871–880.[Medline]
  67. Basser RL, Rasko JEJ, Clarke K et al. Randomized, blinded, placebo-controlled phase I trial of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) with filgrastim after dose-intensive chemotherapy in patients with advanced cancer. Blood 1997;89:3118–3128.[Abstract/Free Full Text]
  68. Vadhan-Raj S, Murray LJ, Bueso-Ramos C et al. Stimulation of megakaryocyte and platelet production by a single dose of recombinant human thrombopoietin in patients with cancer. Ann Intern Med 1997;126:673–681.[Abstract/Free Full Text]
  69. Crawford J, Ozer H, Stoller R et al. Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med 1991;325:164–170.[Abstract]
  70. Fanucchi M, Glaspy J, Crawford J et al. Effects of polyethylene glycol-conjugated recombinant human megakaryocyte growth and development factor on platelet counts after chemotherapy for lung cancer. N Engl J Med 1997;336:404–409.[Abstract/Free Full Text]
  71. Kaushansky K, Lin N, Grossmann A et al. Thrombopoietin expands erythroid, granulocyte-macrophage, and megakaryocytic progenitor cells in normal and myelosuppressed mice. Exp Hematol 1996;24:265–269.[Medline]
  72. Duhrsen U, Villeval JL, Boyd J et al. Effects of recombinant granulocyte colony-stimulating factor on hematopoietic progenitor cells in cancer patients. Blood 1988;72:2074–2081.[Abstract/Free Full Text]
  73. Basser R, DeBoer R, Mitchell P et al. Randomized study of megakaryocyte growth and development factor (PEG-rHuMGDF) before and after chemotherapy. Influence of schedule on clinical effect: early results. Proc Am Soc Clin Oncol 1997;16:120a.
accepted for publication September 8, 1997.




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