Human hematopoietic growth factors: Old lessons and new perspectives

Erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF) and gra nulocyte-macrophage stimulating factor (GM-CSF) are currently licensed for use in cancer patients and play a significant role in the management of ane mia and neutropenia following myeloablative chemotherapy. EPO was the first recombinant hematopoietic growth factor to be used clinically after a numb er of clinical trials which demonstrated ifs effectiveness in treating mild to moderate cancel-associated anemia with or without concomitant chemother apy (particulary cisplatin). An extensive research has been made for the im provement of the quality of life with EPO therapy, however; when formally a ssessed, variable effects of this important treatment have been observed. R ecently, EPO has been shown to significantly accelerate hematopoietic recon stitution after peripheral blood stem cell transplantation (PBSCT) resultin g in reduced infection rates. Both, G-CSF and GM-CSF have been shown, in nu merous trials, to shorten the period of chemotherapy-induced neutropenia, w ith reduction in attendant morbidity and to mobilize PBSC. In addition, adm inistration of both cytokines after PBSCT significantly reduced the use of antibiotics and duration of hospitalization suggesting an economic benefict . The narrower therapeutic window of GM-CSF at higher doses accounts for th e fact that it is used much less frequently than G-CSF. To date, none of th e growth factors used clinically has been shown to stimulate thrombopoiesis . Although thrombspoietin (TPO) has been found to induce megakaryocyte diff erentiation in vitro, it is unlikely to enter. routine clinical use for tre atment of post-chemotherapy thrombocytopenia, since results of clinical tri als are not very encouraging, mainly because TPO is difficult to schedule a nd platelet aggregation may occur. Recently, innovative chimeric growth fac tor receptor agonists have been synthesized. Synthokine (SC-55494) (a high- affinity human IL-3 receptor ligand analog), myelopoietin (MPO) (activates human IL-3 and G-CSF receptors) and promegapoietin (PMP) (stimulates the hu man IL-3 and c-mpl receptors) were found to be multilineage hematopoietic g rowth factors and are currently undergoing clinical trials. Preliminary res ults suggest that these compounds may have a major impact on the management of myeloablative chemotherapy because of their ability to enhance platelet recovery in addition to their neutrophil restorative activity.