Immunotherapeutic agents have often been found to provoke opposite effects on
tumor growth--inhibitory or stimulatory--depending on dose, timing or route of administration. The reason for these opposite effects is not yet known.
Levan (
polyfructose), an immunomodulatory
polysaccharide, has been found to exert opposite effects on the growth of the F10 variant of
B16 melanoma. Low doses inhibit and high doses enhance the growth of this
tumor.
Cyclophosphamide (CY) augments the inhibitory effect of the
polysaccharide. In order to elucidate the mechanism of these opposite effects, we tried to determine the changes induced by
levan at inhibitory and stimulatory doses, alone or in conjunction with CY, on the lymphatic and hematopoietic systems of B16-F10
melanoma-bearing mice. In a previous study we reported the effect of these treatments on the morphology of spleen and lymph nodes (Leibovici, Kopel, Siegal & Gal-Mor (1986). Int. J. Immunopharmac., 8, 391). In the present study, we examined the effect of the treatments on bone marrow and peripheral blood composition. The growth of the
tumor itself, as well as the various treatments, induced very marked changes in both bone marrow and blood.
Tumor inoculation produced a sharp
leukopenia and
anemia followed by a restoration of both white and red blood cells. In the bone marrow, the
tumor caused a gradual decrease in lymphocyte number. CY accentuated the severe
leukopenia caused by the
tumor. Lymphocyte depletion was prolonged, while restoration of granulocytes was achieved by day 7. A similar pattern of changes was observed in the bone marrow. With
levan, opposite effects were observed in blood and bone marrow with the two doses in relation to the number of the cells of the lymphoid and myeloid lines: while 0.1 mg (
tumor inhibitory) doses caused a more active restoration of lymphocytes as compared to 10 mg (
tumor stimulatory) doses, an opposite effect was seen on the myeloid series--the high dose induced a more pronounced granulocytosis than the low dose. In the combined treatment, the low
levan dose accelerated lymphocyte restoration in bone marrow compared to CY, while the high dose delayed the recovery of these cells. The results of the present study in conjunction with our previous study may explain the basis of the intriguing
tumor inhibitory-stimulatory effects of some
immunomodulators. Moderate increases in myeloid cell series appear to favor
tumor inhibition and high increases favor
tumor stimulation. In addition, the results of this study suggest that a regulatory relation might exist between the proliferation of the lymphoid and myeloid cell series.