title: Impact of in vivo administration of interleukin 3 on proliferation, differentiation, and chemosensitivity of acute myeloid leukemia.
abstract: Early clinical trials of growth factor augmentation of induction chemotherapy for acute myeloid leukemia have yielded variable results. To test the hypothesis that this heterogeneity is a consequence of the pleiotropic effects of growth factors on leukemic cell biology, we measured the effects of in vivo interleukin 3 (IL-3) administration on leukemic cell proliferation and drug sensitivity. Thirty-four patients with acute myeloid leukemia with high-risk features or advanced myelodysplasia received IL-3 as a continuous infusion beginning 3 days prior to chemotherapy and continuing for the duration of intensive induction therapy. Bone marrow cells were studied prior to and after 3 days of IL-3 administration to assess changes in overall and leukemic progenitor cell [leukemia colony-forming unit (CFU-L)] proliferation, and progenitor cell sensitivity to 1-betad-arabinofuranosylcytosine. The median fold increase in overall leukemic cell proliferation in response to IL-3, assessed as expression of the nuclear antigen Ki67 in 28 patients, was 1.2. The median fold increase in percentage of cells in S phase (assessed in 29 patients) was 1.3. Despite the increase in overall cell proliferation in 70% of cases, CFU-L number increased in only 4 of 20 patients successfully studied (median day 4:day 1 ratio of CFU-L number, 0.6). While this suggests possible terminal differentiation of leukemic progenitor cells, expression of CD34, HLA-DR, c-kit, CD15, and CD14 were not consistently affected by the cytokine. 1-betad-Arabinofuranosylcytosine sensitivity of CFU-L increased significantly in 30% of cases, decreased in 30%, and was unchanged in 40%. Changes in overall cell proliferation (Ki67 expression) and CFU-L were independent predictors of change in 1-beta-d-arabinofuranosylcytosine sensitivity; increase in percentage of cells in S phase in response to IL-3 was correlated with attainment of complete remission. While these findings support the concept of cell cycle recruitment, IL-3 has marked pleiotropic effects on proliferation, differentiation, and survival of leukemic progenitors which make the clinical impact of in vivo cytokine administration for individual patients difficult to predict.
authors.affiliation: The Johns Hopkins Oncology Center, Oncology 2-109, Baltimore, Maryland 21287-8963, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Gore
authors.forename: L J
authors.initials: LJ
authors.lastname: Weng
authors.forename: R J
authors.initials: RJ
authors.lastname: Jones
authors.forename: K
authors.initials: K
authors.lastname: Cowan
authors.forename: M
authors.initials: M
authors.lastname: Zilcha
authors.forename: S
authors.initials: S
authors.lastname: Piantadosi
authors.forename: P J
authors.initials: PJ
authors.lastname: Burke
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D003114:Colony-Forming Units Assay; D003561:Cytarabine / Q000008:administration & dosage; D003630:Daunorubicin / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000473:pathology; D006801:Humans; D016130:Immunophenotyping; D007262:Infusions, Intravenous; D007377:Interleukin-3 / Q000627:therapeutic use*; D019394:Ki-67 Antigen / Q000032:analysis; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D017978:Receptors, Growth Factor / Q000032:analysis / Q000235:genetics; D012074:Remission Induction
chemical_list: D000970:Antineoplastic Agents; D007377:Interleukin-3; D019394:Ki-67 Antigen; D017978:Receptors, Growth Factor; D003561:Cytarabine; D005047:Etoposide; D003630:Daunorubicin