摘要:

AbstractGranulocyte‐macrophage colony stimulating factor (GM‐CSF) and interleukin 3 (IL‐3) are multilineage acting hematopoietic growth factors which have overlapping but distinct biological properties. Cellular sources of IL‐3 are confined to activated T cells, natural killer (NK) cells, mast cells and possibly megakaryocytes, while these cells and activated macrophages, fibroblasts and endothelial cells are important sources of GM‐CSF. In vitro studies have implicated both cytokines in the autocrine growth of human myeloid or murine mast cell leukemias. The human GM‐CSF and IL‐3 genes map to the long arm of chromosome 5, show similar genomic structures, and share several conserved elements in their 5′ and 3′ flanking regions. The promoters of these genes contain a variety of positive and negative regulatory regions, and the level of expression of these genes is controlled by both transcriptional and post‐transcr

ISSN:1066-5099    

DOI:10.1002/stem.5530130402

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractThe pros and cons of purging of either bone marrow or peripheral blood stem cell preparations for autologous transplantation for cancer has been debated strongly over the past decade. Recent data implicating the role of minimal residual disease in autografted marrow in cancer relapse have renewed interest in this question. There is a considerable body of literature supporting the possibility that photosensitizer molecules in combination with light might provide a therapeutic window permitting selective elimination of malignant stem cells while sparing those of normal lineage. Molecules of this class are known to be taken up more actively by most malignant cells, and intracellular concentrations are critical in their cytotoxic effect when they are activated by light at an appropriate wavelength. The present paper reviews the observations made over the past decade on a variety of photosensitizers and their effects on hemopoietic progenitors.

ISSN:1066-5099    

DOI:10.1002/stem.5530130403

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractThree hematopoietic growth factors, recombinant human granulocyte‐macrophage colony‐stimulating factor, recombinant human granulocyte colony‐stimulating factor and erythropoietin, which are commonly used in other clinical situations are being increasingly studied in the setting of allogeneic marrow transplantation. Major questions being addressed are: 1) can administration of growth factors post‐transplant accelerate hematopoietic recovery, 2) are growth factors of use in the treatment of patients with poor graft function or graft failure, 3) can growth factor mobilized peripheral blood stem cells be used as a substitute for allogeneic marrow and 4) is there a role for the use of growth factors in the treatment of patients with specific types of infection post‐transplant? This review will discuss where we are in answering these four

ISSN:1066-5099    

DOI:10.1002/stem.5530130404

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractBone marrow damage caused by mye‐loablative radiation therapy and/or chemotherapy can be repaired by intravenously infusing viable stem/progenitor cells collected from either blood or bone marrow. The hematopoietic graft product contains both stem/progenitor cells and populations of hematopoietic and nonhematopoietic (accessory) cells. The frequency of accessory cell types varies with the source of the graft product; marrow or blood. Reinfusion of these accessory cells causes effects other than the hematopoietic restoration provided by the stem/progenitor cells such as graft versus host disease and graft versus leukemia effect after allogeneic transplants. Effects of infused accessory cells in the autologous setting are less well studied and could provide ancillary advantages and/or disadvantages to the patient. Do these additional effects actually occur, and, if they do, are they more likely to appear following peripheral blood cell transplants (PBCT) or after autologous bone marrow transplants (ABMT)? Preliminary data are beginning to accumulate which suggest that reinfusion of occult tumor cells is less likely with PBCT, that immune reconstitution is different depending on the source of the autograft and that, for certain diseases, patient event‐free survival following PBCT rather than ABMT may be better. However, infusion of occult tumor cells may result in re‐establishment of the malignancy. If the accessory cells (including potential occult tumor cells) are eliminated from the product before transplant, will the patient have a better clinical outcome, or would benefits provided by infused accessory cells outweigh the risks of infused occult tumor cells? These controversial issues are in the very early stages of investig

ISSN:1066-5099    

DOI:10.1002/stem.5530130405

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractThe relationships among thrombocytosis, abnormal platelet aggregation and altered hemostasis in primary thrombocythemia remain poorly understood. Consequently, the appropriate management of asymptomatic patients is controversial and needs to be individualized. For symptomatic patients, conventional therapy, usually hydroxyurea, is directed primarily at lowering the platelet count by suppression of megakaryocyte activity. Recombinant interferon alpha can selectively lower platelet counts and may offer a reasonable alternative. Recent experience with anagrelide is also most promising in both symptomatic and asymptomatic patients. Current thoughts on the pathogenesis and management guidelines are presented here.

ISSN:1066-5099    

DOI:10.1002/stem.5530130406

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractActivation of tyrosine kinase‐containing receptors and intracellular tyrosine kinases by ligand stimulation is known to be crucial for mediating initial and subsequent events involved in mitogenic signal transduction. Receptors for insulin and insulin‐like growth factor 1 (IGF‐1) contain cytoplasmic tyrosine kinase domains that undergo autophosphorylation upon ligand stimulation. Activation of these receptors also leads to pronounced and rapid tyrosine phosphorylation of insulin receptor substrate 1 (IRS‐1) in cells of connective tissue origin. A related substrate, designated 4PS, is similarly phosphorylated by insulin and IGF‐1 stimulation in many hematopoietic cell types. IRS‐1 and 4PS possess a number of tyrosine phosphorylation sites that are within motifs that bind specific SH2‐containing molecules known to be involved in mitogenic signaling such as PI‐3 kinase, SHPTP‐2 (Syp) and Grb‐2. Thus, they appear to act as docking substrates for a variety of signaling molecules.The majority of hematopoietic cytokines bind to receptors that do not possess intrinsic kinase activity, and these receptors have been collectively termed as members of the hematopoietin receptor superfamily. Despite their lack of tyrosine kinase domains, stimulation of these receptors has been demonstrated to activate intracellular kinases leading to tyrosine phosphorylation of multiple substrates. Recent evidence has demonstrated that activation of different members of the Janus family of tyrosine kinases is involved in mediating tyrosine phosphorylation events by specific cytokines. Stimulation of the interleukin 4 (IL‐4) receptor, a member of the hematopoietin receptor superfamily, is thought to result in activation of Jak1, Jak3, and/or Fes tyrosine kinases. Unlike several other hematopoietins, IL‐4 stimulation has been shown to mediate tyrosine phosphorylation of the substrates, IRS‐1 and 4PS. In this review, the signal transduction cascade evoked by IL‐4 will be analyzed and compared with those utilized by other cytokines as well as by insulin and IGF‐1. The role of 4PS/IRS‐1 expression in mediating mitogenesis by IL‐4, insulin

ISSN:1066-5099    

DOI:10.1002/stem.5530130407

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractDNA topoisomerases are enzymes that regulate DNA topology and are essential for the integrity of the genetic material during transcription, replication and recombination processes. Inhibitors of the mammalian enzymes are widely used antitumor drugs. They stabilize topoisomerase‐DNA cleavable complexes by hindering the DNA relegating step of the catalytic reaction, thus resulting in DNA cleavage stimulation. Investigations on the sequence selectivity of DNA cleavage stimulated by chemically unrelated compounds established that specific nucleotides flanking strand cuts are required for drug action. Moreover, structure‐activity relationship studies have identified structural determinants of drug sequence specificities, thus eventually allowing the design of new agents targeted at selected genomic regions. The initial cellular lesion, i.e., the drug‐stabilized cleavable complex, is a reversible molecular event; however, how it may lead to cell death remains to be fully clarified. Several laboratories focused in past years on molecular and genetic aspects of drug‐activated apoptosis. Irreversible double‐stranded DNA breaks, generated from collisions between cleavable complexes and advancing replication forks, were suggested to increase p53 protein levels, thus triggering the cell death program. Other genes were also shown to cooperate in modulating the cell response to drug treatments. Recently, several groups have evaluated the possible prognostic value of topoisomerase II levels in solid tumors and hematopoietic neoplasms. Topoisomerase II inhibitors may also have genotoxic effects. Secondary leukemias, characterized by a translocation between chromosomes 11 and 9, have been reported in disease‐free patients after treatments with drug regimens that included antitopoisomerase II agents. It has been proposed that an impairment of topoisomerase activity may be involved in the molecular pathogenesis of secondar

ISSN:1066-5099    

DOI:10.1002/stem.5530130408

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractProtein‐tyrosine kinases (PTKs) are of vital importance in a variety of cell functions. Recent studies have provided considerable insight into the binding of growth factors to tyrosine kinase receptors and the consequent induction of signal pathways that lead to a biologic response. Future studies will further delineate the signals that result in a proliferative response and those that induce a differentiation response. Current studies, reviewed here, indicate an important biologic role for PTKs in the regulation of megakaryocyte development and maturation. Whether PTKs function in megakaryocytes in signaling pathways that are similar to pathways in other cells will need to be examined in future studie

ISSN:1066-5099    

DOI:10.1002/stem.5530130409

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractIt has been known for many years that cytolytic T lymphocytes that specifically recognize the tumor cells of the same patient can be derived from the blood of melanoma patients. Several of the antigens recognized by these antitumor T lymphocytes have now been completely identified. Some of them are sufficiently tumor‐specific to envision their use as antitumor vaccines in selected cancer patient

ISSN:1066-5099    

DOI:10.1002/stem.5530130410

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractThe synergistic effects of stem cell factor (SCF) in combination with other growth factors including interleukin (IL)‐6, IL‐11, IL‐3, GM‐CSF, G‐CSF, IL‐1α and interferon‐γ (IFN‐γ) on the expansion of murine hematopoietic progenitors were studied in a short‐term liquid suspension culture system. Bone marrow (BM) cells obtained 2 days after 5‐fluorouracil (5‐FU) injection were cultured for up to 18 days in serum‐containing and serum‐free cultures in the presence of combinations of various cytokines. The numbers of nucleated cells, total colony‐forming cells (CFC), mixed‐colony forming units (CFU‐Mix) and high‐proliferative potential colony‐forming cells (HPP‐CFC) before and after liquid suspension cultures were measured in the presence of different combinations of cytokines. Combinations of SCF with IL‐11, IL‐6 or IL‐1α markedly increased the numbers of total CFC, CFU‐Mix and HPP‐CFC. A combination of SCF and IL‐3 also expanded the number of total CFC; however, the fold increase was smaller than those of SCF plus IL‐11, IL‐6 or IL‐1α. Three or four factor combinations including SCF with IL‐3, IL‐6 and IL‐11 did not yield increased numbers of total CFC over that supported by SCF plus either IL‐6 or IL‐11. The addition of IFN‐γ to the culture containing SCF plus IL‐11 resulted in a decrease of the expansion efficiency. However, this difference is not statistically significant. In contrast, the addition of IFN‐γ to the cultures containing SCF plus IL‐6 did not affect the expansion efficiency. Interestingly, the addition of IL‐1α in the culture containing SCF plus IL‐3 significantly increased the number of HPP‐CFC over that supported by SCF plus IL‐3 (p<0.01). In contrast, IL‐1α did not significantly affect the expansion efficiency in the presence of SCF plus IL‐6 or IL‐11. These results suggest that combinations of SCF plus either IL‐6 or IL‐11 or a combination of SCF, IL‐3 and IL‐1α ca

ISSN:1066-5099    

DOI:10.1002/stem.5530130411

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY