Therapeutic implications of serum factors inhibiting proliferation and inducing differentiation of myeloid leukemic cells.
Murine post-endotoxin sera contain high levels of myeloid colony-stimulating factor(s) (GM-CSF) and factors capable of inducing terminal granulocyte and macrophage differentiation of the murine myelomonocytic leukemic cell line WEHI-3. The combination of C. parvum and endotoxin induced a serum activity capable of inducing tumor necrosis and inhibiting leukemic colony formation in vitro. This factor (TNF) could be separated from the differentiation-inducing factor (GM-DF) and from CSF. In conjunction with a Phase I trial of highly purified endotoxin in patients with advanced malignancy, we monitored human post-endotoxin sera for CSF and GM-DF. Induction of GM-DF occurred maximally at 2-6 h and was associated with increased serum levels of CSF active against the patient's own bone marrow. Following repeated injections of escalating doses of endotoxin, persistent levels of GM-DF were detected both pre-endotoxin and 24 h post-endotoxin treatment. The ability to induce repeatedly a serum protein with potent capacity to promote terminal differentiation of myelomonocytic leukemic cells suggests a possible therapeutic role in human myeloid leukemias.
D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D003115:Colony-Stimulating Factors / Q000037:antagonists & inhibitors / Q000097:blood; D004731:Endotoxins / Q000008:administration & dosage; D005293:Ferritins; D006023:Glycoproteins / Q000097:blood*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha
D003115:Colony-Stimulating Factors; D004731:Endotoxins; D006023:Glycoproteins; D014409:Tumor Necrosis Factor-alpha; C020391:acidic isoferritin; D005293:Ferritins