Search PubMed⌕ Search

Biomedical subjects

J U Gutterman

Publications and source records attributed to J U Gutterman.

At least 73 records · Page 4Linked to original sources
PubMed1991

LIF: not just a leukemia inhibitory factor.

Increasingly it seems that many cytokines are pleiotropic, and individual molecules may have critical roles in several different organ systems. LIF exemplifies this phenomenon: it influences embryogenesis, bone and lipid metabolism, and hematopoietic and nervous system function. Many of LIF's effects are reminiscent of those of IL-1, TNF, and TGF-beta. Further, even within a single system, LIF can display totally different effects, i.e. induction of differentiation of one leukemic cell line vs. stimulation of proliferation of another. The corollary to these observations is that there appears to be many parallels in developmental systems. For instance, in the case of neuronal "lineage commitment," the events that relate to migration of neural crest cells along various pathways and their ultimate arrest in different locales demonstrate sufficient analogies to hematopoietic lineage commitment phenomena that, in a provocative review, Anderson coined the term "neuropoiesis". This type of analogy becomes even more intriguing when one realizes that some of the same molecules are regulating neuronal and hematopoietic "lineage" proliferation and differentiation. In this respect, several interleukins in addition to LIF are important in neuronal development, and nerve growth factor turns out to also be a hematopoietic regulatory molecule. Similar parallels are enacted in other organ systems as well. The mediation of identical effects by distinct cytokines bound to unique receptors could conceivably be explained by receptor transmodulation or by overlapping signaling sequences. It is nevertheless also unclear how a single cytokine attached to a single receptor can accomplish varied and opposing effects, although divergent intracellular signaling mechanisms could account for some of these phenomena. Yet another enigma relates to how cells from one system can be properly influenced by a pleiotropic molecule such as LIF without significant "cross-effects" on other potentially responsive systems. Cytokine production that is restricted to certain developmental stages, or very localized distribution and spheres of influence within a microenvironment, could be explanatory. The findings of Rathjan and colleagues, i.e. that LIF exists as both a diffusible molecule and as a molecule incorporated into the extracellular matrix, is of special interest in relation to the above questions. Indeed, the distinctions between the roles of diffusible and immobilized signaling molecules could be crucial to the multiplicity of LIF's actions. Diffusible regulatory factors allow communication between spatially separated cells. Cellular responsiveness to such factors is dictated by the presence of appropriate receptors and postreceptor machinery.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Constitutive expression of leukemia inhibitory factor RNA by human bone marrow stromal cells and modulation by IL-1, TNF-alpha, and TGF-beta.

Recent in vitro studies indicate that bone marrow mesenchymal elements, residing in close proximity to hematopoietic cell populations, elaborate a network of cytokines that are, at least partially, responsible for modulating the growth and maturation of the latter compartment. Leukemia inhibitory factor (LIF), a molecule with both positive and negative regulatory activities, has been implicated in murine embryogenesis and hematopoiesis. We demonstrate that cultured normal human bone marrow stromal cells constitutively express LIF message. Further, exposure of these cells to other hematopoietic modulators including interleukin 1 alpha (IL-1 alpha), interleukin 1 beta (IL-1 beta), transforming growth factor-beta (TGF-beta), and tumor necrosis factor-alpha (TNF-alpha) (but not interferon-alpha [IFN alpha]) increases the level of LIF RNA. Interestingly, cultured stromal cells derived from three of four patients with chronic myelogenous leukemia showed enhanced LIF expression. These observations suggest that LIF may participate, either alone or through interaction with other cytokines, in the bone marrow microenvironment-mediated influence on both normal and malignant hematopoietic processes.

Bone Marrow↗
PubMed1991

Erythropoietin treatment in patients with myelodysplastic syndrome and anemia.

Hematological disorders are commonly complicated by anemia, and the symptoms of red cell deficiency adversely affect the quality of life. Erythropoietin is a glycoprotein which controls red blood cell production. Recombinant human erythropoietin, 50 U/kg/day, was given subcutaneously to 16 patients with myelodysplastic syndrome and anemia. All but one patient was transfusion dependent. Diverse pretreatment endogenous serum erythropoietin levels were noted and ranged from 17 to 3616 IU/l. Two patients (12.5%) demonstrated an improvement in hemoglobin levels obviating the need for transfusions. Their responses lasted 5+ and 7 months with maintenance erythropoietin treatment. The responders had endogenous serum erythropoietin levels of 44 and 170, respectively. Treatment was generally tolerated without constitutional side-effects. However, three patients developed thrombocytopenia and one developed joint pain and leukocytosis on treatment. Overall, six patients showed changes in non-erythroid cells: two patients had an increase in platelet counts; three patients, a decrease in platelet counts; and one patient, an increase in white blood cell counts. Most of these changes reversed rapidly once erythropoietin was stopped. It is concluded that (a) serum erythropoietin levels are extremely variable in anemia patients with myelodysplastic syndrome, (b) only a minority of patients benefit from treatment with recombinant human erythropoietin, and (c) erythropoietin can affect cells of the myeloid and megakaryocytic lineage in a small proportion of patients.

Aged↗
PubMed1991

Appearance of acute leukemia-associated P190BCR-ABL in chronic myelogenous leukemia may correlate with disease progression.

The Philadelphia translocation in chronic myelogenous leukemia (CML) results in the production of a 210 kD BCR-ABL protein. In contrast, in 50% of Philadelphia-positive acute leukemias, the translocation results in the production of a 190 kD BCR-ABL protein. To investigate the hypothesis that the production of P190 may be associated with the progression from chronic phase to blast crisis in CML, we used polymerase chain reaction to analyze blood from 37 patients with accelerated phase/blast crisis CML for the transcripts coding for the P210BCR-ABL and P190BCR-ABL. The mRNA encoding for P210 was detected in all patients. In three patients, mRNA encoding both P210 and P190 was present. In two of these three patients, samples were available from the time of initial diagnosis. Analysis of these samples did not reveal any transcripts for P190. We conclude that in some patients the appearance of P190BCR-ABL may correlate with transformation to a more aggressive, terminal phase of CML.

Adolescent↗
PubMed1991

Synergistic antiproliferative effect of interferon alpha and azidothymidine in chronic myelogenous leukemia.

The possible synergistic interaction between azidothymidine (AZT) and interferon alpha (rIFN-alpha 2a) in the treatment of chronic myelogenous leukemia (CML) was studied in vitro using marrow or peripheral blood hematopoietic progenitors from 10 patients with CML in the mixed (CFU-GEMM) colony culture assay. Used singly, either agent inhibited erythroid (BFU-E) and granulocyte-macrophage (CFU-GM) CML hematopoietic progenitor proliferation in a dose-dependent fashion, with the inhibitory effect being more pronounced on BFU-E than on CFU-GM colony-forming cells. The combination of both drugs in therapeutic concentrations exerted a significant synergistic inhibition on CML stem cells as assessed by the median-effect principle and isobologram equation analysis. A suboptimal dose of AZT (0.5 mumol/l) synergistically augmented the effect of rIFN-alpha 2a whereas an inactive dose of 10 U/ml rIFN-alpha 2a similarly enhanced the CML stem cell growth inhibition exerted by AZT. Our data indicate that AZT may augment the already established therapeutic benefits of IFN-alpha in CML.

Adult↗
PubMed1991

Cytokines in tumor therapy. Interleukin-3.

IL-3 is a T-cell-derived hematopoietin. This cytokine stimulates the growth of multipotential progenitor cells and is therefore of clinical interest for the therapy of pancytopenic processes. Both in vitro and animal studies suggest that the development and maturation of multiple lineages of blood cells can best be achieved by combining IL-3 with other growth factors. IL-3 may therefore act to expand a primitive pool of precursor cells, and the presence of additional factors may aid in the differentiation of these cells to functional status. Studies of IL-3 in human beings are in early phase I stages. These trials indicate that this molecule has a short half-life, and hence should be given by routes that permit prolonged serum levels. IL-3 is generally well tolerated, and stimulation of progression to acute leukemia was not observed in our subjects with preleukemic states. This agent increased neutrophil, eosinophil, platelet, and reticulocyte counts in individual patients. However, responses varied from patient to patient, and the IL-3-induced changes in neutrophil counts were modest as opposed to those previously described after GM-CSF therapy. Comparison of the in vitro effects of IL-3 in the colony/culture assay to subsequent in vivo effects in a small number of patients indicates that increases in CFU-G, CFU-M, and CFU-GM can, at times, predict for changes in granulocyte and monocyte counts. A synthesis of currently available data indicates that future trials should be designed to treat additional patients with IL-3 alone and to combine IL-3 with GM-CSF, G-CSF, erythropoietin, and other growth factors.

Animals↗
PubMed1990

Constitutive and induced expression of growth factors in normal and chronic phase chronic myelogenous leukemia Ph1 bone marrow stroma.

Study of growth factor RNA levels in the stromal cells derived from the adherent layer of long-term bone marrow culture demonstrated constitutive expression of transforming growth factor beta 1 (TGF-beta 1) and macrophage colony-stimulating factor. These cells did not express granulocyte colony-stimulating factor, granulocyte-monocyte colony-stimulating factor, interleukin (IL) 1 alpha, IL-1 beta, IL-3, and IL-6. However, granulocyte colony-stimulating factor expression could be induced by recombinant human IL-1 beta; while IL-6 could be induced by both IL-1 beta and tumor necrosis factor-alpha. No differences could be detected between adherent layers established from normal and benign phase Ph1 chronic myelogenous leukemia bone marrow. The uninduced expression of TGF-beta 1, a potent hematopoietic cell growth inhibitor, suggests that stromal cells play an inherent role in regulating the proliferation of adjacent bone marrow hematopoietic progenitor cells. However, a defect in stromal TGF-beta 1 production cannot account for the profoundly expanded myeloid compartment in chronic phase chronic myelogenous leukemia. In contrast to the constitutive expression of TGF-beta 1 and macrophage colony-stimulating factor, hematopoietic growth factors are only expressed following a proper stimulation.

Biological Factors↗
PubMed1990

Effect of recombinant human interleukin 4 on human monocyte activity.

Recombinant human interleukin 4 (rhuIL-4), a lymphokine that reportedly stimulates tumoricidal activity in mouse macrophages, is currently undergoing clinical studies to determine its efficacy in the treatment of cancer. IL-4 is known to participate with other cytokines to regulate growth and differentiation of various hematopoietic cells as well as modulate the immune response. Little is known about the effect of rhuIL-4 on human monocyte tumoricidal activity. The purpose of these studies was to examine the effect of rhuIL-4 on human peripheral blood monocytes. Peripheral blood monocytes isolated from normal donors failed to demonstrate tumoricidal activity or interleukin 1 secretion after treatment with rhuIL-4 in vitro. Furthermore, monocyte-mediated cytotoxicity induced by recombinant human gamma-interferon plus muramyl dipeptide was suppressed in a dose-dependent manner by rhuIL-4. This reduction in cytotoxicity corresponded to a reduction in IL-1 production and secretion. Further investigation of rhuIL-4 and its role in the cytokine network is necessary for the development of effective immunotherapy in cancer patients.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1990

Escalated therapy for refractory urothelial tumors: methotrexate-vinblastine-doxorubicin-cisplatin plus unglycosylated recombinant human granulocyte-macrophage colony-stimulating factor.

Thirty-two assessable patients with metastatic urothelial tumors refractory to standard chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) were treated with escalated doses of MVAC plus unglycosylated recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF). Results of this phase I trial revealed that escalated MVAC (30 mg of methotrexate/m2, 4 mg of vinblastine/m2, 60 mg of doxorubicin/m2, and 100 mg of cisplatin/m2) can be tolerated by heavily pretreated patients. The side effects of rhGM-CSF are dose- and schedule-dependent. The maximum tolerated dose is 250 micrograms/m2 per day as a single dose administered subcutaneously (SC) for 10 consecutive days. This dose is well tolerated in outpatients, resulting in only modest fever and few side effects. The same dose delivered as a continuous infusion or a higher dose delivered either as a continuous infusion or SC caused significant side effects. For phase II trials, the starting dose of rhGM-CSF when combined with escalated MVAC is 120 micrograms/m2 per day SC for 10 consecutive days. forty percent of the treated patients responded, seven (23%) with complete remission and five (17%) with partial remission. This response rate is higher than anticipated from such a modest dosage escalation in chemotherapy-refractory patients.

Agranulocytosis↗
PubMed1990

Increased incidence of hypersensitivity to iodine-containing radiographic contrast media after interleukin-2 administration.

Eight of 28 (28%) cancer patients with liver metastases treated by either splenic (four) or hepatic (four) arterial infusion of recombinant interleukin-2 (rIL-2) developed hypersensitivity reactions to iodine-containing radiographic contrast media. These reactions consisted of fever, chills, malaise, nausea and vomiting, skin rash, diarrhea, and occasionally, hypotension. Reactions usually occurred 1 month after the initial arteriographic procedure and rIL-2 infusion, with 1-hour to 4-hour intervals between procedure and reexposure of the patient to the iodine-containing contrast medium (used in conjunction with computerized tomography or repeated arteriography for subsequent courses of rIL-2 infusions) and the onset of symptoms. Prompt administration of corticosteroids during the reaction and premedication of patients who were known to have had a reaction in the past were very effective in stopping reactions or preventing them from reoccurring. The high incidence (28%) of hypersensitivity reactions, the temporal relationship (4 hours) between the arteriographic procedure (utilizing iodine-containing contrast medium) and the initial infusion of rIL-2 (while some of the contrast medium was still present), and the absence of such hypersensitivity reactions among patients receiving systemic (intravenous) rIL-2 (not requiring the use of concomitant iodine-containing contrast medium) provide additional evidence that in the presence of a potentially immunogenic moiety, rIL-2, a potent stimulant of the human immune system, can produce an initial sensitization followed by subsequent anamnestic reaction upon reexposure of the patient to the immunogen (even without the additional rIL-2).

Adult↗
PubMed1990

Stimulation of myelopoiesis in a patient with congenital neutropenia: biology and nature of response to recombinant human granulocyte-macrophage colony-stimulating factor.

To stimulate granulopoiesis, we gave recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF; 120 microgram/m2/d) to a patient with congenital neutropenia. The treatment resulted in marked increases in white blood cell counts (maximum, 17,400/microL), consisting mainly of eosinophils (maximum, 13,050/microL) and monocytes (maximum, 1305/microL), rather than neutrophils (maximum, 798/microL). Circulating phagocytes (97% eosinophils) derived after GM-CSF treatment were less effective in chemotaxis, slower but equally effective in phagocytosis, and more effective in H2O2 production compared with normal control neutrophils, but comparable in chemotaxis and H2O2 production to control eosinophils. Before GM-CSF treatment, the bone marrow showed a maturation defect in the neutrophilic series that persisted after treatment despite marked increases in mature cells of other lineages. In vitro agar culture of bone marrow cells before GM-CSF treatment showed a normal number of granulocyte colonies; however, maturation was limited to the metamyelocyte stage. Although the absolute number and cycling rates of myeloid colony forming cells (predominantly eosinophils) increased after treatment, the maturation defect in the neutrophilic series persisted. The finding that GM-CSF induced stimulation of proliferation, which was coupled with maturation in the eosinophilic and monocytic but not the neutrophilic components, suggests that this patient had an intrinsic cellular or humoral defect in neutrophil maturation.

Adolescent↗
PubMed1990

Philadelphia chromosome-negative chronic myelogenous leukemia without breakpoint cluster region rearrangement: a chronic myeloid leukemia with a distinct clinical course.

The hallmarks of chronic myelogenous leukemia (CML) include the Philadelphia chromosome (Ph) translocation [t (9;22)(q34;q11)] and consistent molecular genetic aberrations: a break within a restricted 5.8 kb DNA segment, bcr, on chromosome 22q11; transposition of the c-abl protooncogene from chromosome 9q34 to 22q11; and formation of a hybrid bar-abl gene encoding an abnormal 210 Kd bcr-abl protein with augmented tyrosine kinase enzymatic activity. These molecular phenomena may occur even in the absence of cytogenetic evidence of the Ph translocation. They are highly specific and sensitive markers for CML, and are presumed to play a significant role in the pathogenesis of this malignancy. Surprisingly, we have encountered 11 patients who lacked the Ph translocation, bcr rearrangement, and (in the four patients with available mRNA) a bcr-abl message, and yet had a disease phenotype at diagnosis that was a morphologic facsimile of classic chronic phase CML. These patients presented with high white blood cell counts, neutrophilia, occasional basophilia, splenomegaly, and a hypercellular bone marrow with granulocytic hyperplasia and a left shift in myeloid maturation. Despite the striking resemblance between the early stages of bcr-negative and bcr-positive CML, disease progression manifests distinctly in these two disorders. In contrast to the blastic transformation that inevitably complicates bcr-positive CML, the natural history of our 11 Ph-negative, bcr-negative CML patients was characterized by increasing leukemia burden with leukocytosis, pronounced organomegaly, extramedullary infiltrates, and eventual bone marrow failure (anemia and thrombocytopenia) without marked increases in blast cells. Our current observations suggest that a chronic myeloid leukemia process can develop without associated changes in the bcr or c-abl genes. Although the initial phase of this disease is indistinguishable from CML, the presence or absence of molecular markers may aid in the prediction of the clinical course of Ph-negative CML.

Aged↗
PubMed1990

Stimulation of myelopoiesis in chronic lymphocytic leukemia and in other lymphoproliferative disorders by recombinant human granulocyte-macrophage colony-stimulating factor.

In an attempt to stimulate granulopoiesis, we administered recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) to 11 patients with lymphoproliferative disorders. Ten patients had neutropenia, six of whom had severe neutropenia (less than 500 neutrophils), including two with agranulocytosis. GM-CSF (60-250 micrograms/m2/day) was administered by continuous intravenous infusion daily for 14 days at 2-week intervals. Significant increases in white blood cell counts (1.3-to 11.7-fold) and neutrophils (1.7- to more than 29-fold) were seen in 10 of 11 patients, including one patient with agranulocytosis. Eosinophils (3.9- to greater than 65-fold) and monocytes (1.3- to 5-fold) increased as well. In contrast, no significant increases were seen in total lymphocytes or in different phenotypic subsets of lymphocytes during treatment. The overall proportion of myeloid and lymphoid elements in bone marrow remained stable. These results indicate that GM-CSF is effective in stimulating myelopoiesis in neutropenic states associated with lymphoproliferative disorders. Further studies will be necessary to determine whether the correction of neutropenia ultimately translates into clinical benefit.

Bone Marrow↗
PubMed1990

Treatment of poor-prognosis, newly diagnosed acute myelogenous leukemia with high-dose cytosine arabinoside (Ara-C) and rHUGM-CSF.

We gave 4 days of high-dose Ara-C followed 2 days later by rHUGM-CSF (which continued until the neutrophil count was greater than 1000/microliters) to 12 patients with newly diagnosed AML and a relatively poor prognosis. Six CRs occurred, there were four deaths during induction, and in only one case was there an rHUGM-CSF-associated growth of leukemia. The pattern of hematologic recovery was variable but in some patients rHUGM-CSF seemed to accelerate normal myelopoiesis following chemotherapy. Continued investigation of rHUGM-CSF and chemotherapy in AML is warranted.

Aged↗
PubMed1990

Alpha interferon dose-dependent suppression of secondary clones in a patient with Philadelphia-positive chronic myelogenous leukemia.

A patient whose chronic myelogenous leukemia (CML) was treated with interferon alpha (IFN-alpha) is described. The disease showed karyotypic evolution during the chronic phase and the later myeloid acceleration. Both of these secondary clonal phenomena responded to IFN-alpha dose escalation. The case illustrates the dose dependence of CML responses to IFN-alpha. The phenomenon of clonal evolution is discussed in the context of this patient's disease.

Clone Cells↗