Hemopoietic growth factors

Basic FGF can also stimulate murine hemopoietic progenitors in vitro. It is synergistic with hemopoietic growth factors such as GM-CSF, EPO, and Meg-CSF and has radioprotective activity in vivo, increasing the number of day-9 and day-12 CFU-S from lethaUy irradiated animals (195). Furthermore, b-FGF combiaed with GM-CSF protects against the killing of murine and human CFU-GM exposed to radiation in vitro (195). 

S. H. Bartelmez and E. R. Stanley, Synergism between hemopoietic growth factors (HGFs) detected by their effects on cells bearing receptors for a lineage specific HGF assay of hemopoietin-1, 7.C eT/./ A/sjo/ 122, 370-378 (1985). 

The first experiments describing the clonal growth of hemopoietic progenitor cells immobilized in a soft gel matrix in vitro were reported by Bradley and Metcalf (1966) and Pluznick and Sachs (1965). Clonogenic cells are plated in the presence of various of feeder cells, medium conditioned by the growth of different tissues or cell lines in cultures (for example, 5637 bladder carcinoma conditioned media) and colony stimulating factors such as GM-CSF, G-CSF, M-CSF, Epo, interleukins. 

Outcomes have been reported in a consecutive series of 91 patients hospitalized with non-chemotherapy drug-induced agranulocytosis from 1985-2000 (34). All but two survived. Antithyroid drugs were the cause of agranulocytosis in 20% of cases. Univariate and multivariate analyses failed to reveal a specific effect of antithyroid drugs on the time to neutrophil recovery. In contrast, hemopoietic growth factor treatment was associated with speedier hematological recovery. 

Lang, R.A. (1987) Transgenic mice expressing a hemopoietic growth factor gene (GM-CSF) develop accumulations of macrophages, blindness, and a fatal syndrome of tissue damage. Cell, 20, 675-686. 

N16. Nunez, G., London, L., Hockenbery, D., Alexander, M., McKearn, J. P., and Korsmeyer, S. J., Deregulated Bcl-2 gene expression selectively prolongs survival of growth factor-deprived hemopoietic cell lines. J. Immunol. 144, 3602-3610 (1990). 

Clark-Lewis, I., Aebersold, R. A., Ziltener, H., Schrader, J. W., Hood, L. E., and Kent, S. B. H. (1986) Automated chemical synthesis of a protein growth factor for hemopoietic cells, interleukin-3. Science 231,134-139. 

Stem cell factor, SCF, also called steel factor or mast cell growth factor is a cytokine that stimulates the proliferation of myeloid and lymphoid hemopoietic progenitor cells. SCF is a ligand of the receptor tyrosine kinase, c-KIT, a protoonct ene. The KIT oncogene is the gene of a transforming feline sarcoma virus. 

Balducci L, Lyman GH. Patients aged >70 are at high risk for neutropenic infection and should receive hemopoietic growth factors when treated with moderately toxic chemotherapy. J Clin Oncol 2001 19 1583-5. 

The authors of a study in 101 patients concluded that in addition to the dose of chemotherapy and the administration of hemopoietic growth factors, poor performance status and a high concentration of soluble p75-R-TNF can predict the occurrence of chemotherapy-induced myelosuppression in lymphoma (39). 

Acute febrile interstitial pneumonitis occurred within less than 48 hours after the second to fourth cycles of chemotherapy (doxorubicin, cyclophosphamide, bleomycin, methotrexate, plus methylprednisolone) in five patients with non-Hodgkin s lymphoma who were receiving prophylactic G-CSF n — 3) or GM-CSF (n = 2) (23). Lymphocytic alveolitis was confirmed in four of these patients and all three patients tested had an increased number of CD8+ T cells. Even though all the patients received high-dose methylprednisolone, two died as a result of diffuse and extensive interstitial pulmonary fibrosis, demonstrated at postmortem. Although both G-CSF and GM-CSF can cause acute pneumonitis in patients with cancers, it is still unknown to what extent hemopoietic growth factors are involved in this complication. 

Because the production of cytokines (for example IL-1 or TNF-alfa) involved in the stimulation of cells responsible for graft-versus-host disease can be enhanced by hemopoietic growth factors, the use of growth factors after allogeneic transplantation is theoretically risky. However, in reviews of trials of G-CSF or GM-CSF in allogeneic bone marrow transplantation there were no increases in late engraftment failures, relapse rates, or exacerbation of graft-versus-host disease (54,61). 

Guidelines for the appropriate use of hemopoietic growth factors in children have been proposed by a panel of European experts, who carefully summarized the potential indications and recommendations, and concluded that adult guidelines are apphcable to children in most cases (9). The authors considered that growth factors should be used in children for only a hmited number of circumstances prophylaxis or treatment in low-risk patients treated with chemotherapy, routine use in aplastic anemia, and mobilization of peripheral blood progenitor cells in healthy pediatric donors. 

Stem cell factor amplifies the proliferation and mobilization of myeloid, erythroid, and megakaryocyte colonies when combined with a lineage-specific hemopoietic growth factor (for example G-CSF, IL-3). Stem cell factor, added to other recombinant hemopoietic cytokines, is used to increase the mobilization of peripheral blood progenitor cells. 

Rich I (1986) A role for the macrophage in normal hemopoiesis. II. Effect of varying physiological oxygen tensions on the release of hemopoietic growth factors from bone-marrow-derived macrophages in vitro. Experimental Hematology 14 746-751. 

Nicola, N.A., Metcalf, D., 1992. Subunit promiscuity among hemopoietic growth factor receptors. Cell 67, 1-4. 

I Current Status of Biopharmaceuticals Approved Products and Trends in Approvals Tables Recombinant hemopoietic growth factors approved for general medical use... 

Interleukin-7 (lL-7) plays an important role in stimulating the growth and differentiation of pre-B cells in the bone marrow (H15, S56). The major source of IL-7 in the bone marrow appears to be stromal cells (HIO, K14), upon which B-cell development in the bone marrow appears to be dependent (S56). IL-7 may also play a role in stimulating development of thymocytes (E14,03, S2) and also appears to stimulate proliferation and differentiation of mature T lymphocytes (B33, C18). Receptors for human IL-7 have been identified, cloned, and assigned to the hemopoietic growth factor receptor family (G17). 

Transforming growth factor- 3 (TGFP) inhibits the proliferation of T lymphocytes, B lymphocytes, NK cells, and hemopoietic cells (K9, KIO, L28, R23). TGFp is a potent inhibitor of IL-1 activity and it has been suggested that this effect is mediated by inhibition of IL-1 receptor expression (D28). 

Fig. 4. The role of cytokines in controlling cellular interactions involved in the immune and inflammatory responses. In an immune response, ceils present antigens and release IL-1 to activate appropriate T-helper cells and lL-6, which acts as a B-cell differentiation factor. Activated T-helper cells produce a variety of cytokines, including lymphocyte growth (lL-2 and lL-4) and differentiation (IFNy and IL-10) factors and hemopoietic growth factors (IL-3 and GM-CSF). Macrophages can also be activated by antigen nonspecific mitogens such as LPS. Cytokines released include those with proinflammatoiy activities such as IL-ip, TNFa, and IL-8, as well as the anti-inflammatory IL-6.

Lee, F. Growth factors controlling the development of hemopoietic cells. Prog. Clin. Biol. Res. 352, 385-390 (1990). 

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