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Biomedical subjects

C G Begley

Publications and source records attributed to C G Begley.

At least 55 records · Page 3Linked to original sources
PubMed1998

Oncostatin M induces the differentiation of breast cancer cells.

We have recently described the action of Oncostatin M (OSM) to inhibit the proliferation of breast cancer cells. In this study we examined the action of OSM on 2 breast cancer cell lines to further characterize the nature of OSM inhibition of cellular proliferation. Treatment with OSM for 6 days resulted in an approximately 2- to 5-fold decrease in cell number, which was independent of estrogen receptor status. Consistent with this, colony formation was reduced to approximately 50% when cells were exposed to OSM in primary agar cultures. Clonogenicity was further inhibited following 7 days treatment with OSM in monolayer cultures: the total number of clonogenic cells was suppressed approximately 10-fold. Analysis of cell cycle status in OSM-treated cells demonstrated a 40% reduction in the proportion of cells in S phase within 12 hr, with an increase in cells in G0/G1. After 6 days, there was a 10-fold reduction in the absolute number of cells in S phase in OSM-treated cultures. These changes were associated with striking changes in cellular morphology, including disruption of intercellular junctions and the production of lipid droplets. There was a 5-fold increase of c-fos and c-myc mRNA within 30 min of commencing treatment with OSM. In addition, in the ER positive cells there was a decrease in ER mRNA (evident within approximately 2 hr) and ER protein expression following treatment with OSM. Conversely, there was a 5-fold increase in epidermal growth factor receptor (EGFR) mRNA within 4 hr, and a 2.5-fold rise in mRNA for transforming growth factor alpha (TGF alpha). Thus, the inhibition of breast cancer cells by OSM was associated with decreased clonogenicity, a decrease in S phase cells and a variety of phenotypic changes, all consistent with the induction of differentiation.

Antineoplastic Agents↗
PubMed1998

The role of IL-II in hematopoiesis as revealed by a targeted mutation of its receptor.

Interleukin 11 (IL-11) is a pleiotropic growth factor with several actions in common with members of the IL-6 family. IL-11 utilizes a specific receptor chain encoded by two genes, IL-11Ra, which is expressed in hematopoietic and other tissues and, IL-11Ra2, which has a restricted pattern of expression. The actions of IL-11 in the hematopoietic compartment include support of multilineage and committed progenitors contributing to myeloid, erythroid, megakaryocyte, and lymphoid lineages. IL-11 demonstrates a prominent thrombopoietic activity which is being evaluated in clinical trials. In contrast to the multiple in vitro and in vivo effects of IL-11, mice with a targeted mutation of the IL-11Ra gene (IL-11Ra-/-) did not exhibit an overt hematological phenotype. Generation of a null phenotype was confirmed by independent assays. The numbers of progenitor cells of various lineages as well as their terminally differentiated progeny were undisturbed in the IL-11Ra-/- mice. In addition, the mutant mice were able to respond appropriately to increased demand in situations of hematopoietic stress. This study has highlighted the growth factor redundancy operative in the hematopoietic compartment, and in addition, has served to identify a critical action of IL-11 in nonhematopoietic organs.

Animals↗
PubMed1998

musculin: a murine basic helix-loop-helix transcription factor gene expressed in embryonic skeletal muscle.

We describe the embryonic expression of musculin, a new murine member of the bHLH family of transcription factors. Musculin protein is closely related to human ABF-1, which is expressed in activated B cells, and to epicardin/capsulin/Pod-1, which is expressed in branchial myoblasts, visceral and urogenital mesoderm and epicardium. In situ hybridisation revealed musculin expression in embryos was largely restricted to the embryonic skeletal muscle lineage. While all skeletal muscles expressed the gene, only a subset of myocytes within each muscle were positive, indicating molecular heterogeneity within fetal muscle.

Amino Acid Sequence↗
PubMed1998

The thrombopoietic factor, Mpl-ligand.

Mpl-ligand (thrombopoietin [TPO] or Megakaryocyte growth and development factor [MGDF]), was identified following the discovery of the oncogene, mpl. This oncogene encodes a truncated receptor belonging to the hemopoietin-receptor superfamily. Mpl-ligand consists of two domains; a carbohydrate-rich domain and an amino-terminal domain which displays homology to erythropoietin and is fully active. Mpl-ligand mRNA is predominantly expressed in liver and kidney and plasma levels are regulated by receptors expressed on megakaryocytes and platelets. Mpl-ligand is the most active single agent capable of promoting proliferation and maturation of cells within the megakaryocyte lineage. In addition to this 'lineage-specific' action, Mpl-ligand also acts on progenitor/stem cells of multiple hemopoietic lineages. Pre-clinical and early clinical studies have demonstrated the ability of Mpl-ligand to increase platelet counts and hasten platelet recovery after chemotherapy. This offers considerable promise for its use in clinical oncology.

Animals↗
PubMed1998

Infertility in female mice lacking the receptor for interleukin 11 is due to a defective uterine response to implantation.

During early pregnancy, in response to the implanting embryo, the surrounding uterine stroma undergoes a dramatic transformation into a specialized tissue known as the decidua. The decidua encapsulates the developing embryo, facilitating nutrient transfer and limiting trophoblast invasion. Here we show that female mice with a null mutation of the interleukin-11 receptor alpha chain are infertile because of defective decidualization. A temporal analysis revealed IL-11 expression is maximal in the normal pregnant uterus at the time of decidualization, and in situ hybridization studies showed expression of the IL-11 and the IL-11 receptor alpha chain in the developing decidual cells. These observations reveal a previously unrecognized critical role for IL-11 signaling in female reproduction.

Animals↗
PubMed1998

Repeatability of refraction and corrected visual acuity in keratoconus. The CLEK Study Group. Collaborative Longitudinal Evaluation of Keratoconus.

PURPOSE: The purpose of the test-retest phase of the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study was to determine the repeatability of the various parts of the CLEK Study protocol. This paper presents the test-retest parameters of the refraction protocol. METHODS: We examined 138 CLEK Study-eligible patients on two occasions (median, 90 days; range, 22 to 268 days). All patients underwent subjective refraction on two occasions, and contact lens over-refractions were performed either over the patient's habitual rigid contact lenses or over a trial rigid contact lens equal in base curve to the steep keratometric reading in nonrigid contact lens wearers. RESULTS: Mean interoccasion differences +/- SD were -0.32 +/- 2.91 D and -0.17 +/- 1.39 D for subjective refraction sphere and cylinder power, respectively, and the mean absolute difference for subjective refraction cylinder axis was 18.1 +/- 20.2 degrees. The mean interoccasion difference +/- SD for high-contrast visual acuity with subjective refraction was 0.38 +/- 10.9 letters correct. Mean interoccasion differences +/- SD were -0.11 +/- 0.81 D and 0.02 +/- 0.67 D for contact lens over-refraction sphere and cylinder power, respectively, and the mean absolute difference for contact lens over-refraction cylinder axis was 11.6 +/- 9.9 degrees. The mean interoccasion difference +/- SD for visual acuity with contact lens over-refraction was 0.50 +/- 5.2 letters correct and 0.71 +/- 6.9 letters correct for high- and low-contrast visual acuity, respectively. CONCLUSIONS: The repeatability of subjective refraction in keratoconus patients is good but somewhat lower than that found in nondiseased eyes. Only 36% of our repeat measures of sphere power from subjective refraction fell within 0.50 D of each other, compared with more than 90% in studies of normal eyes.

Adult↗
PubMed1998

Rapid hematopoietic recovery after multicycle high-dose chemotherapy: enhancement of filgrastim-induced progenitor-cell mobilization by recombinant human stem-cell factor.

PURPOSE: To assess the mobilization potential and safety of recombinant human stem-cell factor (SCF) when coadministered with filgrastim to untreated women with poor-prognosis breast cancer. PATIENTS AND METHODS: Eligible women had breast cancer with 10 or more positive axillary nodes, or estrogen receptor-negative tumor with 4 positive nodes, or stage III disease. Patients were randomized to receive SCF plus filgrastim or filgrastim alone. Filgrastim 12 microg/kg daily was administered for 6 days by continuous subcutaneous infusion. SCF was administered by daily subcutaneous injection at 5, 10, or 15 microg/kg concurrent with filgrastim for 7 days, or 10 microg/kg daily starting 3 days before filgrastim for a total of 10 days (SCF pretreatment). Apheresis was performed on days 5, 6, and 7 of filgrastim administration. Patients then had three cycles of epirubicin 200 mg/m2 and cyclophosphamide 4 g/m2 every 28 days, each supported by one third of the apheresis product. RESULTS: Sixty-two women were treated. Greater yields occurred in patients who received SCF 10 microg/kg daily plus filgastim than those who received filgrastim alone (P=.013 for CD34+ cells; P=.07 for granulocyte-macrophage colony-forming cells [GM-CFCs]). The difference was more marked with SCF-pretreatment than concurrent SCF. Fewer aphereses were required to reach the predetermined target of peripheral-blood progenitor/stem cells (PBPCs) in women who received SCF. SCF was generally well tolerated. Hematologic recovery was rapid after each of the three cycles of chemotherapy. There was no difference in recovery between the different treatment groups. CONCLUSION: Mobilization of PBPCs by filgrastim is significantly enhanced by coadministration of SCF, and commencing SCF before filgrastim can optimize this effect. SCF has the potential to reduce the number of aphereses required to collect a target number of PBPCs.

Adult↗
PubMed1998

Thrombopoietin in vitro and in vivo.

The characterization of the c-Mpl receptor resulted from studies on a murine retrovirus, and proved an important step in the identification of a key hemopoietic regulator. First proposed and named in 1958, the ultimate characterization of the long-awaited 'thrombopoietin' (TPO) came with the molecular cloning and characterization of the in vitro and in vivo properties of the c-Mpl ligand. Gene targeting experiments have demonstrated that the TPO/Mpl receptor signalling pathway is the principal physiological regulator of megakaryocytes and platelets. Analysis of signalling through c-Mpl has provided important insights into the function of this pathway, which, as with other members of the hemopoietin receptor family, involves activation of the JAK/STAT and Ras signalling cascades. Preclinical studies have documented a role for this molecule in overcoming thrombocytopenia following chemo/radiotherapy in several animal models. Clinical studies have demonstrated the safety and efficacy of Mpl ligand in elevating platelet counts. The identification of thrombopoietin has provided an important impetus in understanding megakaryocyte and platelet physiology, and provided a new therapeutic that will find application in a variety of clinical contexts.

Blood Platelets↗
PubMed1998

Repeatability and agreement of two corneal-curvature assessments in keratoconus: keratometry and the first definite apical clearance lens (FDACL). CLEK Study Group. Collaborative Longitudinal Evaluation of Keratoconus.

PURPOSE: This study was conducted to determine the agreement and test-retest repeatability of two methods for measuring corneal curvature in keratoconus: keratometry and the First Definite Apical Clearance Lens (FDACL). Our interest in the FDACL procedure stems from the important contact lens-fitting information and documentation of disease progression provided by the FDACL trial lenses and observation of fluorescein patterns. METHODS: The Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study is an observational study that has enrolled 1,209 keratoconus patients to characterize the progression of keratoconus, to determine factors associated with its progression, and to assess its impact on quality of life. Ten percent of the patients were randomly selected at baseline for a retest examination. The baseline examination, which included keratometry and FDACL, was repeated in this sample. The FDACL is the flattest lens in the standardized CLEK trial lens set that vaults the apex of the cone. FDACL provides an estimate of the sagittal height of the cone. RESULTS: The correlation of FDACL with the steep keratometric reading (r = 0.89; p = 0.0001) and the flat keratometric reading (r = 0.83; p = 0.0001) were high. Test-retest repeatability as measured by the intraclass correlation coefficient (ICC) was high: FDACL ICC, 0.97; steep keratometric reading ICC, 0.96; and flat keratometric reading ICC, 0.95. Test-retest repeatability of FDACL remained high in advanced disease. CONCLUSION: FDACL provides a repeatable new procedure for determining disease severity in keratoconus.

Adult↗
PubMed1997

The CD2-scl transgene alters the phenotype and frequency of T-lymphomas in N-ras transgenic or p53 deficient mice.

Abnormal expression of SCL (TAL-1/TCL5) occurs in the majority of paediatric cases of acute T-cell lymphoblastic leukemia (T-ALL). Unexpectedly however, transgenic mice carrying scl coupled to the human T-cell specific CD2 enhancer (CD2-scl) did not spontaneously develop T-cell lymphomas despite high levels of scl expression in their thymocytes. Analogous to other transgenic models of lymphomagenesis, it is likely that additional genetic abnormalities are required to cooperate with scl to trigger lymphomagenesis. Two possible candidates are the p53 and N-ras genes which are mutated in some cases of T-ALL, particularly in relapsed disease. Therefore, we examined lymphomagenesis in the progeny of CD2-scl mice crossed with N-ras transgenic mice or p53 deficient. Surprisingly, the frequency of lymphomas in the p53 nullizygous or N-ras transgenic mice was not enhanced by expression of the scl transgene. In fact, expression of scl in both genetic backgrounds paradoxically reduced the frequency of thymic lymphomas and, at least in the p53 nullizygous mice, shifted the pattern of organ involvement to the peripheral lymphoid organs. In contrast, CD2-scl transgene expression accelerated lymphomagenesis in p53 heterozygous mice. These data suggest that the collaborative effects of scl with N-ras or p53 vary according to the developmental stage of the T-cell.

Alleles↗
PubMed1997

Recombinant soluble interleukin-11 (IL-11) receptor alpha-chain can act as an IL-11 antagonist.

We have expressed a soluble N-glycosylated form of the murine interleukin-11 (IL-11) receptor alpha-chain (sIL-11R) and examined signaling in cells expressing the gp130 molecule. In the presence of gp130 but not the transmembrane IL-11R, the sIL-11R mediated IL-11-dependent differentiation of M1 leukemic cells and proliferation in Ba/F3 cells. Early intracellular events stimulated by the sIL-11R including phosphorylation of gp130, STAT 3, and SHP-2 were similar to signaling through the transmembrane IL-11R. IL-11 bound to sIL-11R with low affinity (kd 10 to 50 nmol/L). Binding of sIL-11R to gp130 was IL-11 dependent with intermediate affinity (kd 1.5 to 3.0 nmol/L). However, the concentration of IL-11 required for signaling through the sIL-11R was 10- to 20-fold greater than that required for cells expressing the transmembrane IL-11R and gp130 in the absence of sIL-11R. Furthermore, the sIL-11R was capable of antagonizing the activity of IL-11 when tested on cells expressing the transmembrane IL-11R and gp130. We propose that the observed IL-11 antagonism by the sIL-11R may depend on limiting numbers of gp130 molecules on cells already expressing the transmembrane IL-11R.

Amino Acid Sequence↗
PubMed1997

Transcription of the SCL gene in erythroid and CD34 positive primitive myeloid cells is controlled by a complex network of lineage-restricted chromatin-dependent and chromatin-independent regulatory elements.

The SCL gene (also known as TAL-1) encodes a basic helix-loop-helix transcription factor that is essential for the development of all haematopoietic lineages, and ectopic expression of which results in T cell leukaemia. SCL is expressed in normal pluripotent haematopoietic stem cells and its expression is maintained during differentiation along erythroid, mast and megakaryocytic lineages, but is extinguished following commitment to other cell types. The mechanisms responsible for this pattern of expression are poorly understood, but are likely to illuminate the molecular basis for stem cell development and lineage commitment. We have identified multiple lineage-restricted DNase I hypersensitive sites in a 45 kb region spanning the murine SCL locus. Committed erythroid cells and CD34 positive primitive myeloid cells exhibited both shared and unique DNase I hypersensitive sites whereas none were found in T cells. The function of each hypersensitive site was studied using both transient and stable reporter assays in erythroid, primitive myeloid and T cells. Multiple positive and negative regulatory elements were characterised and found to display lineage-specificity, promoter-specificity and/or chromatin-dependence. These results represent the first description of key components of a complex network of regulatory elements controlling SCL expression during haematopoiesis.

Animals↗
PubMed1997

Enhanced levels and enhanced clonogenic capacity of blood progenitor cells following administration of stem cell factor plus granulocyte colony-stimulating factor to humans.

Administration of hematopoietic growth factors is being used increasingly to obtain populations of blood progenitor/stem cells (PBPC) for clinical transplantation. Here we examined the effect of combining stem cell factor (SCF ) and granulocyte colony-stimulating factor (G-CSF ) versus G-CSF alone in a randomized clinical study involving 62 women with early-stage breast cancer. In the first patient cohorts, escalating doses of SCF were administered for 7 days with concurrent G-CSF administration. At baseline, levels of progenitor cells in the bone marrow or blood were comparable in the different patient groups. As with administration of G-CSF alone, the combination of SCF plus G-CSF did not alter the wide variation in levels of PBPC observed between individuals and did not alter the selective nature of PBPC release, with preferential release of day-14 granulocyte-macrophage colony-stimulating factor (GM-CFC) versus day-7 GM-CFC. However, SCF acted to sustain the levels of PBPC after cessation of growth factor treatment; levels of PBPC were elevated 100-fold at later timepoints compared with G-CSF alone. In addition, the maximum levels of PBPC observed were increased approximately fivefold at day 5 of growth-factor administration. The increased levels of PBPC resulted in significantly increased levels of PBPC obtained by leukapheresis. In a subsequent patient cohort, 3-days pretreatment with SCF was introduced and followed by 7 days concurrent SCF plus G-CSF. The 3-days pretreatment with SCF resulted in an earlier wave of PBPC release in response to commencement of G-CSF. In addition, maximum PBPC levels in blood and PBPC yield in leukapheresis products were further increased. Unexpectedly however, SCF pretreatment resulted in progenitor cells with enhanced self-generation potential. Recloning assays documented the ability of approximately 30% of primary granulocyte-macrophage (GM) colonies from control cell populations to generate secondary GM colonies (n = 1,106 primary colonies examined). In contrast approximately 90% of GM colonies from PBPC after SCF pretreatment generated secondary clones and 65% generated secondary colonies. The action of SCF was not explicable in terms of altered SCF, GM-CSF, or G-CSF responsiveness, but SCF pretreatment was associated with maximum serum SCF levels at the time G-CSF was commenced. These results show that PBPC populations mobilized by different growth factor regimens can differ in their functional properties and caution against solely considering number of harvested progenitor cells without regard to their function.

Administration, Cutaneous↗
PubMed1997

Adult mice with targeted mutation of the interleukin-11 receptor (IL11Ra) display normal hematopoiesis.

Interleukin-11 (IL-11) is a pleiotropic growth factor with a prominent effect on megakaryopoiesis and thrombopoiesis. The receptor for IL-11 is a heterodimer of the signal transduction unit gp130 and a specific receptor component, the alpha-chain (IL-11R alpha). Two genes potentially encode the IL-11R alpha: the IL11Ra and IL11Ra2 genes. The IL11Ra gene is widely expressed in hematopoietic and other organs, whereas the IL11Ra2 gene is restricted to only some strains of mice and its expression is confined to testis, lymph node, and thymus. To investigate the essential actions mediated by the IL-11R alpha, we have generated mice with a null mutation of IL11Ra (IL11Ra-/-) by gene targeting. Analysis of IL11Ra expression by Northern blot and reverse transcriptase-polymerase chain reaction, as well as the absence of response of IL11Ra-/- bone marrow cells to IL-11 in hematopoietic assays, further confirmed the null mutation. Compensatory expression of the IL11Ra2 in bone marrow cells was not detected. IL11Ra-/- mice were healthy with normal numbers of peripheral blood white blood cells, hematocrit, and platelets. Bone marrow and spleen contained normal numbers of cells of all hematopoietic lineages, including megakaryocytes. Clonal cultures did not identify any perturbation of granulocyte-macrophage (GM), erythroid, or megakaryocyte progenitors. The number of day-12 colony-forming unit-spleen progenitors were similar in wild-type and IL11Ra-/- mice. The kinetics of recovery of peripheral blood white blood cells, platelets, and bone marrow GM progenitors after treatment with 5-flurouracil were the same in IL11Ra-/- and wild-type mice. Acute hemolytic stress was induced by phenylhydrazine and resulted in a 50% decrease in hematocrit. The recovery of hematocrit was comparable in IL11Ra-/ - and wild-type mice. These observations indicate that IL-11 receptor signalling is dispensable for adult hematopoiesis.

Animals↗
PubMed1997

Expression of SCL is normal in transfusion-dependent Diamond-Blackfan anemia but other bHLH proteins are deficient.

Basic helix-loop-helix proteins, which are tissue specific (SCL) or broadly expressed (E proteins), interact positively to regulate erythroid specific genes. Here, expression of SCL and two broadly expressed E proteins, E47 and HEB, was high early in erythroid differentiation and declined during maturation. Stimulation of erythroid progenitors/precursors with stem cell factor (SCF) enhanced SCL and E protein levels, one mechanism by which SCF may increase erythroid proliferation. Interactions between SCL and E proteins are competed by Id2, which binds and sequesters E proteins. Upregulation of Id2, demonstrated here late in erythroid differentiation, may downregulate genes involved in erythroid proliferation/differentiation. We examined expression of bHLH proteins in transfusion-dependent patients with Diamond-Blackfan anemia (DBA) to determine if these interactions are disrupted. In erythroblasts from patients, expression of SCL protein and mRNA was normal and SCL increased in response to SCF. However, E47 and HEB protein levels were significantly decreased. Id2 was strongly expressed in patients. Through reduction of SCL/E protein heterodimer formation, abnormal levels of bHLH transcription factors may affect expression of erythroid specific genes, such as beta globin. Stimulation of Diamond-Blackfan cells with SCF partially compensated for this defect, enhancing expression of E47, HEB, and SCL. SCF may function to increase SCL/E protein heterodimer formation, which may be one of the mechanisms through which SCF stimulates erythroid proliferation/differentiation in DBA.

Basic Helix-Loop-Helix Proteins↗
PubMed1997

Hematopoietic-specific genes are not induced during in vitro differentiation of scl-null embryonic stem cells.

The helix-loop-helix transcription factor, scl, plays an essential role in hematopoietic development. Embryos in which the gene has been disrupted fail to develop yolk sac erythropoiesis, and scl-null embryonic stem cells do not contribute to hematopoiesis in chimeric mice. To analyze the molecular consequences of scl deficiency, we compared the gene expression profiles of control (wild-type and scl-heterozygous) and scl-null embryonic stem cells differentiated in vitro for up to 12 days. In control and scl-null embryoid bodies the temporal expression pattern of genes associated with the formation of ventral mesoderm, such as Brachyury, bone morphogenetic protein-4, and flk-1, was identical. Similarly, GATA-2, CD34, and c-kit, which are coexpressed in endothelial and hematopoietic lineages, were expressed normally in scl-null embryonic stem cell lines. However, hematopoietic-restricted genes, including the transcription factors GATA-1, EKLF, and PU.1 as well as globin genes and myeloperoxidase, were only expressed in wild-type and scl-heterozygous embryonic stem cells. Indirect immunofluorescence was used to confirm the observations that GATA-1 and globins were only present in control embryoid bodies but that CD34 was found on both control and scl-null embryoid bodies. These data extend the previous gene ablation studies and support a model whereby scl is absolutely required for commitment of a putative hemangioblast to the hematopoietic lineage but that it is dispensable for endothelial differentiation.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Randomized, blinded, placebo-controlled phase I trial of pegylated recombinant human megakaryocyte growth and development factor with filgrastim after dose-intensive chemotherapy in patients with advanced cancer.

Thrombocytopenia caused by chemotherapy is an important cause of morbidity and mortality in the treatment of malignant disease. Recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) is a potent stimulator of megakaryocytopoiesis and prevents chemotherapy-induced thrombocytopenia in preclinical studies. We administered PEG-rHuMGDF with filgrastim after dose-intensive chemotherapy to 41 patients with advanced cancers to determine its safety and effects on hematologic recovery. Carboplatin 600 mg/m2 and cyclophosphamide 1,200 mg/m2 were administered to patients with advanced cancer. Patients were randomly assigned to receive blinded study drug, either PEG-rHuMGDF or placebo (3-to-1 ratio), commencing the day after chemotherapy. PEG-rHuMGDF was given at doses of 0.03, 0.1, 0.3, 1.0, 3.0, and 5.0 microg per kilogram body weight by daily subcutaneous injection for between 7 and 20 days. All patients received concurrent filgrastim 5 microg per kilogram body weight per day until neutrophil recovery. Fifteen patients had received PEG-rHuMGDF alone in a previous phase I study. Platelet function and peripheral blood progenitor cells (PBPC) were assessed. PEG-rHuMGDF enhanced platelet recovery in a dose-related manner when compared with placebo. The platelet nadir occurred earlier in patients given PEG-rHuMGDF (P = .002) but there was no difference in the depth of the nadir. Recovery to baseline platelet count was achieved significantly earlier following PEG-rHuMGDF administration compared with placebo (median, 17 days for PEG-rHuMGDF 0.3 to 5.0 microg/kg versus 22 days for placebo, P = .014). In addition, platelet recovery was faster in patients who had previously received PEG-rHuMGDF, suggesting that pretreatment might be beneficial. Platelet function did not change during or after administration of PEG-rHuMGDF. Levels of PBPC on day 15 after chemotherapy were significantly greater in patients administered PEG-rHuMGDF 0.3 to 5.0 microg/kg and filgrastim compared with those given placebo plus filgrastim. PEG-rHuMGDF was well tolerated at all doses. Two patients given PEG-rHuMGDF had a thrombotic episode. PEG-rHuMGDF accelerates platelet recovery after moderately dose-intensive carboplatin and cyclophosphamide, and is likely to be clinically useful in treatment of chemotherapy-induced thrombocytopenia. Because it enhances mobilization of PBPC by filgrastim, PEG-rHuMGDF might also allow more efficient collection of stem cells for autologous or allogeneic transplantation.

Adult↗