Haemopoietic progenitor and myeloid cell kinetics in humans treated with interleukin-3 and granulocyte/macrophage colony-stimulating factor in combination.
Patients with advanced adenocarcinoma of the colon, rectum or pancreas were entered into trials for evaluation of treatment with sequential doses of IL-3 and GM-CSF. They received 0.25 to 5 micrograms IL-3/kg/d for up to 7 days, followed by 1 microgram GM-CSF/kg/day for a maximum of 10 further days. We assessed the kinetics of bone-marrow cell proliferation and of blood production using tritiated thymidine labelling in vitro and in vivo. Megakaryocytic-CFC were unaffected but proliferation rates of GM-CFC and BFU-E were increased. Progenitor cells were mobilized (12-fold over baseline) into the peripheral blood. The proliferative activity of maturing cells in the marrow was increased (cell-cycle times were reduced by at least 30%). This translated into amplified blood cell production (WCC approximately 30 x 10(9)/l), a 2.2-fold increase in platelet counts and significant eosinophilia. Newly generated neutrophils appeared in the circulation at the normal time and their peripheral half-life was also normal. The calculated 3.2-fold amplification in neutrophil production required nearly 2 extra divisions in the marrow, shared between the progenitors and the proliferating granulocytic cells. The results were compared with those of a previous trial using GM-CSF only, although at a 10-fold higher dose level. Comparable levels of peripheral neutrophils were obtained in both trials but significant ineffective granulopoiesis developed in the earlier study. This was overcome in the present study, the priming dose of IL-3 apparently giving the latitude to utilize lower doses of GM-CSF with less risk of complications.
Lord
B I
BI
Department of Experimental Haematology, PICR, Manchester, UK.
Testa
N G
NG
Bretti
S
S
Chang
J
J
Demuynck
H
H
Coutinho
L
L
de Campos
E
E
Fitzsimmons
L
L
Scarffe
J H
JH
D000230:Adenocarcinoma / Q000188:drug therapy; D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy; D003114:Colony-Forming Units Assay; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006098:Granulocytes / Q000187:drug effects*; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D007377:Interleukin-3 / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D007958:Leukocyte Count; D009504:Neutrophils / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000188:drug therapy; D012004:Rectal Neoplasms / Q000188:drug therapy
D007377:Interleukin-3; D016178:Granulocyte-Macrophage Colony-Stimulating Factor