A number of cytokines (see p. 280) stimulate the growth, differentiation and functional activity of myeloid progenitor cells. As the name implies the function of these polypeptides was defined by in-vitro colony assays of bone marrow progenitors. They have effects on all myeloid cells including the multipotential stem cells (but probably not the more immature pluripotential cells), intermediate progenitors and circulating mature cells. Those in clinical use are described below.
Granulocyte colony-stimulating factors: G-CSF, an 18 kDa protein encoded by a gene on the long arm of chromosome 17 (17q), stimulates the proliferation of granulocyte progenitors and activates neutrophil function.
Filgrastim is recombinant human granulocyte colony-stimulating factor. A single dose will cause the neutrophil count to rise 4-5-fold within hours and the increased count persists up to 72 h. The drug is rapidly cleared after i.v. injection (t\ 2h) and administration by i.v. infusion or s.c. is necessary to prolong plasma concentration. High concentrations are found in plasma, bone marrow and kidneys. It is degraded to its component amino acids.
G-CSF is widely used to mobilise bone marrow stem cells into the peripheral blood to support both autologous and allogeneic peripheral blood progenitor transplantation. The use of peripheral blood progenitors as opposed to bone marrow progenitors is associated with earlier neutrophil and platelet recovery, fewer red cell transfusions and earlier discharge from hospital.
Another major use of G-CSF is for patients with neutropenia as a result of cytotoxic chemotherapy, to shorten the duration of neutropenia and reduce morbidity due to infection. It is also used for the same purpose after autologous and allogeneic bone marrow transplantation, in aplastic anaemia, AIDS, and congenital, cyclical and idiopathic neutropenia. In combination with epoetin, G-CSF can be effective in the management of some patients with myelodysplasia syndromes. G-CSF not only improves the neutrophil count, but dramatically improves the proportion of patients with a raised haemoglobin in response to epoetin possibly by reduction of erythroid apoptosis (the cause of ineffective erythropoiesis).
Lenograstim is similar.
Granulocyte-monocyte colony-stimulating factor:
GM-CSF, a glycoprotein of 14—35 kDa encoded by a gene on the long arm of chromosome 5 (5q), has a broader spectrum of activity than G-CSF, stimulating both monocyte and granulocyte production with functional effects on the mature cells of both cell lines.
Molgramostim (recombinant human granulocyte-monocyte colony-stimulating factor) has a il/2 of 3 h and administration by i.v. infusion or s.c. is needed to maintain plasma concentration. Molgramostim has also been used to mobilise peripheral blood progenitors and to reduce cytotoxic-induced neutropenia, and in bone marrow transplantation and aplastic anaemia. It is now less widely used than G-CSF. Molgramostim has also been used for neutropenia caused by ganciclovir and for AIDS-related cytomegalovirus retinitis. It appears to be synergistic with amphotericin in the treatment of invasive pulmonary aspergillosis possibly by activation of macrophages to enhance killing of phagocytosed fungi.
Adverse effects. Molgramostim causes medullary bone pain, skin rashes, lethargy and myalgia in 1020% of patients. It may also cause fever, the interpretation of which presents a clinical dilemma in neutropenic patients who are subject to sepsis. Pleural and pericardial effusions occur after high doses.
Thrombopoietin (TPO), a 36 kDa protein encoded by a gene on the long arm of chromosome 3 (3q) stimulates the growth and differentiation of megakaryocyte progenitors, mature megakaryocytes and primes platlets to respond to stimuli. Recombinant human TPO has been examined in a small number of clinical trials and found to produce a dose-dependent increase in bone marrow megakaryocytes and the peripheral blood platelet count. If it proves nontoxic (concerns include the potential for platelet activation leading to thrombosis, and the risk of myelofibrosis), it may have a role in the treatment of chemotherapy-induced thrombocytopenia.
In sickle cell disease, haemoglobin S (HbS) when deoxygenated forms polymers which result in the red cells changing from flexible biconcave discs to unyielding sickle shapes that obstruct blood flow. This gives rise to the clinical features of haemolysis with shortened red cell survival, anaemia and painful bone crises. Haemoglobin F (HbF) interferes with the polymerisation process and is protective against the disease.
Hydroxyurea (hydroxycarbamide) is the first widely available and affordable agent that provides real benefit. It acts by perturbing the maturation of erythrocytes and promoting HbF production. The mode of action may be more complex; reduction in leukocyte counts may reduce vaso-occlusive events; reduced red cell and endothelial adhesiveness may be a direct effect. Beneficial effects have been seen in adults, children and infants. Long-term hydroxyurea (hydroxycarbamide) (at close to myelotoxic doses) raises HbF to 15-20% and reduces the frequency of hospitalisation, pain, acute chest syndrome and blood transfusion. Neurological complications e.g. stroke, may not be reduced. Some 10-20% of patients will fail to respond due to the condition of the bone marrow, or genetic effects (see also p. 607,613).
Adverse effects. The long-term risk of leukaemo-genesis cannot yet be assessed. There appears to be no adverse effects on growth or development.
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