Interleukin-4 enhances the survival of severe combined immunodeficient mice engrafted with human B-cell precursor leukemia.
Human interleukin-4 (huIL-4) has been shown to inhibit the growth in vitro of cells from patients with acute lymphoblastic leukemia (ALL). With the aim of determining whether this cytokine might be useful in the treatment of patients with ALL, the effects of huIL-4 on human B-cell precursor ALL engrafted in severe combined immunodeficient (SCID) mice were examined. The inhibition of [3H] thymidine uptake of primary ALL cells by huIL-4 was maintained following engraftment and passage of leukemia in SCID mice. Five of seven xenograft leukemias showed significant inhibition in vitro by huIL-4 at concentrations as low as 0.5 ng/mL; furthermore, huIL-4 counteracted the proliferative effects of IL-7. When used to treat two human leukemias engrafted in SCID mice, huIL-4 200 microgram/kg/d, as a continuous 14-day subcutaneous infusion, suppressed the appearance of circulating lymphoblasts and extended survival of mice by 39% and 108%, respectively, the first demonstration of IL-4 activity against human leukemia in vivo. The mean steady-state huIL-4 level in mouse plasma during the infusion was 1.46 ng/mL (SEM +/- 0.14 ng/mL), which was similar to concentrations found to be effective in vitro. ALL cells obtained from mice relapsing after huIL-4 treatment continued to show inhibition by the cytokine in vitro. These data suggest that IL-4 may be useful in the treatment of patients with ALL.
Mitchell
P L
PL
Academic Department of Haematology and Cytogenetics, Institute of Cancer Research, Sutton, UK.
Clutterbuck
R D
RD
Powles
R L
RL
De Lord
C
C
Morilla
R
R
Hiorns
L R
LR
Titley
J
J
Catovsky
D
D
Millar
J L
JL
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use*; D015847:Interleukin-4 / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology / Q000628:therapy*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology / Q000628:therapy; D011828:Radiation Chimera; D016511:Severe Combined Immunodeficiency / Q000150:complications; D014183:Transplantation, Heterologous
D007155:Immunologic Factors; D015847:Interleukin-4