In vivo induction of terminal differentiation of malignant myelopoietic
progenitor cells by CSF-inducing biological response modifiers
E Schlick and FW Ruscetti
We have investigated the mechanisms by which colony-stimulating factor
(CSF)-inducing biological response modifiers (BRM) may have beneficial
effects on tumor-bearing hosts undergoing anti-tumor therapy. First, we
have documented that treatment of mice with the chemically defined BRM
maleic anhydride divinyl ether copolymer (MVE-2), which induces CSF
secretion by macrophages (M phi) and bone marrow cells (BMC), significantly
increased growth and differentiation of normal myelopoietic cells and
counteracted the myelosuppressive effects of cyclophosphamide (CY). Second,
we established that MVE-2 may exert CSF- mediated antitumor effects on
certain leukemic tumor cells. Serum from mice pretreated in vivo with
MVE-2, which contained CSF, induced terminal differentiation of cloned
tumor cells from the CSF responsive WEHI-3B D+ subline in vitro, but not
from the WEHI-3B D- subline, which is unresponsive to CSF. In vivo
experiments showed that treatment of mice bearing the WEHI-3B D+ tumor
first with CY and three days later with the CSF inducer MVE-2,
significantly increased their survival time and rendered 20% to 50% of the
tumor-bearing mice disease free. No such effects were obtained in mice
bearing the WEHI-3B D- tumor. Thus, the induction of CSF or other
differentiation factors by some BRMs may result in therapeutic effects
against certain leukemias based on at least two distinct mechanisms: In
addition to their restorative effects on normal bone marrow functions,
CSF-inducing BRMs may also prevent further leukemogenesis by induction of
terminal differentiation of leukemic cells.
Volume 67,
Issue 4,
pp. 980-987,
04/01/1986
Copyright © 1986 by The American Society of Hematology
