Colonystimulating factors


The pharmacology of colony-stimulating factors is discussed by Lieschke.┬žnd lyroess..(1n992}. Four colony-stimulating factors promote growth and differentiation of myeloid hemopoietic cells: macrophage colony-stimulating factor, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and IL-3. Recombinant human forms of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor are available for clinical use.

The effects of intravenous recombinant human granulocyte colony-stimulating factor administration include an immediate transient leukopenia (nadir 5 to 15 min), a sustained dose-dependent increase in circulating neutrophils (plateau at 1 week), a leftward shift towards more immature forms, and enhanced neutrophil function (chemotaxis, superoxide generation, phagocytic activity). Neutrophil counts return to baseline 4 to 7 days after therapy ceases. Administration of granulocyte-macrophage colony-stimulating factor is associated with a lesser neutrophil response, but the circulating neutrophil half-life is increased from 8 to 48 h. Prolonged high-dose courses of both factors (2 weeks) is associated with a transient platelet reduction.

Therapeutic use

To date, the principal clinical application has been the treatment of acute neutropenia after myelotoxic chemotherapy. Prophylactic granulocyte colony-stimulating factor reduces the incidence of febrile neutropenic events, infections, hospital admission, and antibiotic use. Neutropenia is not prevented during myeloablative therapy for bone marrow transplantation, but the time to recovery is reduced.

Early studies suggest that augmentation of neutrophil number and function with granulocyte colony-stimulating factor may also be beneficial in non-neutropenic patients with severe pneumonia and sepsis. Clinically, neutrophil counts and free-radical production are increased and L-selectin is downregulated in surgical and trauma patients at risk of sepsis. Increased levels of IL-1 receptor antagonist and soluble tumor necrosis factor-a are also observed. However, preliminary trials in patients with pneumonia do not show a convincing improvement in outcome, and a role for granulocyte colony-stimulating factor in critically ill patients with infection has yet to be established.


The recommended dose of granulocyte colony-stimulating factor in hematological patients is 5 pg/kg/day subcutaneously, but higher doses (30-60 pg/kg) have been used. To prevent a rebound leukocytosis, therapy is ceased when the neutrophil count rises to 5000 to 7000/mm 3 The dose of granulocyte-macrophage colony-stimulating factor generally administered is 0.3 to 10 pg/kg/day subcutaneously. Both colony-stimulating factors can also be administered intravenously.


Granulocyte colony-stimulating factor is generally well tolerated. Dose-dependent side-effects include bone pain, rash, increased lactate dehydrogenase and alkaline phosphatase, and, infrequently, vasculitis and anaphylaxis. A large number of adverse effects have limited the clinical use of granulocyte-macrophage colony-stimulating factor. The first dose may be associated with flushing, nausea, vomiting, hypotension, dyspnea, and hypoxia, particularly with intravenous doses of 1 pg/kg or more. With daily doses of 0.3 to 10 pg/kg it causes bone pain, lethargy, anorexia, weight loss, rash, fever and chills (> 3 pg/kg), increased liver enzymes, and decreased albumin. These effects are probably mediated by enhanced cytokine production.

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