Application of Granulocyte-Macrophage Colony-Stimulating Factor in Patients with Malignant Hematological Diseases

Ganser, Arnold; Völkers, B.; Greher, J.; Walther, Frank; Hoelzer, Dieter

doi:10.1007/978-3-642-73721-3_11

Cited by 5 publications

(2 citation statements)

References 13 publications

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“…Apart from mild bone pain, skin rash, and weakness no severe adverse effects were observed. These results have been confirmed by other investigators [49,50].…”

Section: Gm-csfsupporting

confidence: 90%

The role of cytokines in oncology

Lange¹,

Brugger²,

Rosenthal³

et al. 1991

The International Journal of Cell Cloning

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The availability of sufficient quantities of recombinant human cytokines and promising preclinical data have led to their introduction into clinical trials. Cytokines have potential as new therapeutic agents in a variety of hematological disorders as well as in solid tumors. Only a few of the still increasing number of these glycoprotein hormones have been studied in humans so far, either as single agents or in combination with chemotherapy and other cytokines. Their clinical effects, beneficial role in supportive care, and use in the treatment of certain cancer patients are reviewed.

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“…Apart from mild bone pain, skin rash, and weakness no severe adverse effects were observed. These results have been confirmed by other investigators [49,50].…”

Section: Gm-csfsupporting

confidence: 90%

The role of cytokines in oncology

Lange¹,

Brugger²,

Rosenthal³

et al. 1991

The International Journal of Cell Cloning

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“…Some of the hematopoietic growth factors produced by endothelial cells have already been reported to enhance endothelial cell proliferation and migration (26). Nonetheless, a great number of studies spanning more than three decades have not shaken the belief that the only well-documented action of Epo is on the proliferation and differentiation of erythroid cells, notwithstanding observations that suggest an effect on thrombopoiesis (27) and possibly on early hematopoietic stem cells (28 (21,29,30) or of both low-and high-affinity types (31,32). A low number of receptors per cell is common in studies of factors whose main action is differentiation 4 etic cells (17 …”

Section: Discussionmentioning

confidence: 99%

Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells.

Anagnostou

Lee

Kessimian

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

549

328

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Erythropoietin is known to be a hematopoietic growth factor with a sinulrly specific action on the proliferation and differentiation of erythroid progenitor cells. We have observed a dose-dependent proliferative action of human recombinant erythropoletin on human umbilical vein endothelial cells and bovine adrenal capillary endothelial cells. Binding studies with radioiodinated recombinant human erythropoietin revealed a large number (s27,000) of an apparent single class of receptors with an affinity in the 10-9 M range.Linkage of the radiolabeled ligand to its receptor via a bifunctional crosslinking agent allowed us to identify an endothelial cell protein of 45 kDa as the principal receptor associated with this mitogenic effect of erythropoietin. Recombinant human erythropoietin also enhanced the migration ofendothelial cells.Human umbilical vein endothelial cells (HUVECs) have been reported to produce a variety of colony-stimulating factors and lymphokines, although not erythropoietin (Epo) (1-5). Epo has been considered unique among the other hematopoietic stimulators because its only generally accepted action has been the proliferation and differentiation of cells of erythroid lineage (6). Colony-stimulating factors, on the other hand, are known to affect a variety of hematopoietic cells, and even cells of nonhematopoietic origin (6)(7)(8). Recombinant human Epo (rHuEpo) has been used therapeutically in thousands of uremic, anemic patients, with the only side effects arising from the vascular system (hypertension and thrombosis) (9).In experiments designed originally to study additional mechanisms of the vascular manifestations (thrombosis and hypertension) of Epo treatment (aside from the ones ascribed to increased blood viscosity), we serendipitously noticed significant cell proliferation when rHuEpo from Integrated Genetics (Framingham, MA) was added to HUVEC cultures. We pursued this observation with a series of new experiments, verifying that rHuEpo from various manufacturers has indeed a mitogenic effect on both HUVECs and bovine adrenal capillary endothelial cells (BACECs). We further analyzed the number and molecular weight of the putative receptor through which this action may be exerted. Since many agents with a mitogenic effect on endothelial cells have also an effect on endothelial cell migration, we investigated this aspect, finding again that the rHuEpo preparations enhanced the chemotaxis of both HUVECs and BACECs. MATERIALS AND METHODSCell Culture. Cesarian section-derived HUVECs were cultured at 37°C and in 5% C02/95% air by standard methodologies (10) in T 25-cm2, 50 ml capacity, tissue culture flasks (Falcon, Becton Dickinson Labware) in the presence of heparin and endothelial cell growth supplement (Sigma). They were characterized by the homogeneous and typical cobblestone morphology, factor VIII antigen positivity, and the presence of Weibel-Palade bodies on electron microscopy. In general, HUVECs were used for our experiments after two to four passages. rHuEpo, initially from I...

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