Interleukin-3 in hematology and oncology: current state of knowledge and future directions.
Interleukin (IL)-3 is a multipotent hematopoietic growth factor produced by activated T cells, monocytes/macrophages and stroma cells. The human IL-3 gene is located on chromosome 5 near segment 5q31. The high-affinity receptor for human IL-3 is composed of alpha and beta subunits. IL-3 shares a common beta subunit with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-5; this subunit has been mapped to chromosome 22q13.1. The biological effects of IL-3 have been studied in human and murine hematopoietic cell lines and normal human marrow cells. Addition of IL-3 to the culture medium induces proliferation, maturation and probably self-renewal of pluripotent hematopoietic stem cells and cells of myeloid, erythroid and megakaryocytic lineages. Human IL-3 was cloned in 1986, and since then various clinical trials have assessed the in vivo potential of recombinant human (rhIL-3). Initial results of phase I/II studies of IL-3 at a dose of 5-10 microg/kg subcutaneously daily for 5-10 days in patients with relapsed lymphomas, small-cell lung cancer, breast cancer and ovarian cancer showed that post-chemotherapy application of IL-3 reduces chemotherapy delays and induces faster regeneration of granulocytes and platelets. However, these results were not confirmed in phase III studies. The role of IL-3 alone in the treatment of myelodysplastic syndromes (MDS), aplastic anemia (AA) and other bone marrow failure disorders have also been disappointing. However, preliminary studies of IL-3 in combination with chemotherapeutic agents and immunosuppression have demonstrated encouraging results in patients with MDS and AA respectively. The therapeutic potential of IL-3 in peripheral blood stem cell (PBSC) harvesting and priming of stem cells before harvest is beginning to be identified. Initial results of IL-3 combination with GM-CSF or later-acting growth factors such as granulocyte colony-stimulating factor (G-CSF) have yielded larger amounts of PBSC during harvesting. In recent years, the availability of synthetic IL-3 receptor (IL-3R) agonists and similar chimeric molecules with greater in vitro biological activity and fewer inflammatory side-effects has extended our options to employ and compare these molecules and rhIL-3 for the prevention of chemotherapy-induced myelosuppression. The role of IL-3 and IL-3R agonists in ex vivo expansion of stem cells, dendritic cell development and gene transfer requires further evaluation. It appears that future application of IL-3 in combination with other cytokines is an attractive way forward in the prevention of treatment-related mortality and morbidity in oncology patients. It also shows prospects for the development of new therapeutic strategies for dose escalation and immune modulation for cancer patients with relapsed and resistant disease.
Mangi
M H
MH
Department of Haematology, The Royal London Hospital, London, UK. m.h.mangi@mds.qmw.ac.uk
Newland
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AC
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D001853:Bone Marrow / Q000187:drug effects; D001855:Bone Marrow Diseases / Q000188:drug therapy; D002986:Clinical Trials as Topic; D016207:Cytokines / Q000008:administration & dosage; D006410:Hematopoiesis / Q000187:drug effects*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007377:Interleukin-3 / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy*
D000970:Antineoplastic Agents; D016207:Cytokines; D007377:Interleukin-3