In vivo induction of terminal differentiation of malignant myelopoietic progenitor cells by CSF-inducing biological response modifiers

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.