Hematopoietic Growth Factors

Over the preceding decades, a variety of hematopoietic growth factors—glycoproteins by their chemical structure—have been identified. Following purification, cloning, and manufacturing of recombinant forms of these glycoproteins, their potential use in clinical practice has been tested extensively. Native growth factors and their recombinant derivatives target cytokine type receptors and facilitate growth and differentiation of multilineage and late-stage cell types.

Two groups of myeloid growth factors currently available for clinical use are recombinant human granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). These factors differ in their specific roles as well as in their hematopoietic targets. G-CSF stimulates cells of multilineage potential and enhances late-stage differentiation of neutrophils. GM-CSF also effects multilineage proliferation and acts synergisti-cally with G-CSF in its effect on neutrophils. In addition, it supports development of mixed neutrophil, eosinophil, and macrophage colonies.12 Two recombinant G-CSF products are currently in the market: lenograstim—expressed in yeast—is available outside the United States, while filgrastim—expressed in Escherichia coli—is in use within the United States. Recently, a pegylated version of filgrastim, characterized by a much-prolonged half-life, has been successfully tested and approved as a potential alternative to filgrastim. Out of the two GM-CSF preparations in use, sargramostim is expressed in yeast, while molgramostim is bacteria-derived. Sargramostim is in clinical use in the United States.

Recombinant human erythropoietin is the primary regulatory growth factor of erythropoiesis. Erythropoi-etin is responsible for the differentiating and maturation process in later phases of red cell development. Epoetin alpha and its glycosylated modified form darbepoetin alpha (with a resulting longer half-life) are clinically used in the United States, while epoetin beta is used elsewhere.3-5

The primary regulator of thrombopoiesis is throm-bopoietin. While this glycoprotein does have an effect on multilineage progenitors, there is substantial homology between this growth factor and erythropoietin, e.g., it is unique by its functional ability in stimulating megakaryocyte progenitor colony growth and differentiation. Lack of expression of the receptor for this growth factor will result in substantially reduced thrombocyte counts, but, albeit in reduced number, functional platelets will still be present, suggesting that other factors might play a role in the growth, differentiation, and maturation of the megakaryocyte lineage. Recombinant thrombopoietin will lead to an increase in megakaryocyte and platelet counts, but, due to its relatively late onset of effects (10-14 days), and pending further evaluation of safety of specific recombinant thrombopoietin products following administration, identification of its potential clinical benefits await validation in future clinical trials.67

Platelet release is also facilitated by interleukin-11 (IL-11), possibly through a synergistic effect with other cytokines, including thrombopoietin. IL-11 is associated with a number of side effects, and its role as well as the appropriate dosing in hematologic malignancies has yet to be established adequately.89

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