Treatment of normal or MBL-2
tumor-bearing mice with
cyclophosphamide (CY) caused severe suppression of myelopoiesis and macrophage (M phi) functions, both of which may limit further use of
chemotherapy. Additional treatment with the chemically defined
biological response modifier maleic anhydride divinyl ether copolymer (MVE-2) was able to ameliorate the myelosuppressive effects of CY and to restore normal bone marrow cellularity. The stimulatory effects on myelopoiesis, however, could only be obtained by administering
MVE-2 at greater than or equal to 3 days after CY, which correlated with an MVE-2-induced simultaneous increase in granulocyte and/or
macrophage colony-stimulating factor secretion by bone marrow cells or M phi. Injection of MBL-2
tumor-bearing mice with
MVE-2, at 3 days after Cy treatment, caused a decrease in
tumor burden and a significant increase in median survival time as compared to treatment with CY alone. At the same time,
MVE-2 induced an increase in the number of cytotoxic M phi and a complete restoration within the myelopoietic lineage, which might prevent delayed side effects of CY, such as
secondary infections, and might permit more intensive chemotherapeutic treatment. Treatment of MBL-2
tumor-bearing mice with
MVE-2, at 6 days after CY, induced a significant increase in M phi cytotoxicity but did not prolong median survival time, probably due to a rapid regrowth of
tumor after treatment with CY. Our studies thus show that successful combined
therapy with the primary
cytotoxic agent CY and the
biological response modifier MVE-2 depends on precise timing of the
drug regimen and is influenced by the extent and reversibility of CY-induced immunosuppression, as well as by the kinetics of recruitment of new effector cells from bone marrow and by the
tumor burden present at the time of treatment.