Effect of tumor inhibitory and stimulatory doses of levan, alone and in combination with cyclophosphamide, on spleen and lymph nodes.

Immunotherapeutic agents are often reported to induce opposite effects -- inhibitory and stimulatory -- on tumor growth, depending on the dose, timing or route of administration of the drug. The reason underlying these opposite effects is not yet known. The immunomodulatory polysaccharide levan (polyfructose) has been found to exert such opposite effects on the growth of the F10 variant of B16 melanoma. Low doses inhibit and high doses enhance tumor growth. Cyclophosphamide (CY) augment the inhibitory effect of levan. In order to clarify the mechanism of this switch, we tried in the present study to determine the changes induced by levan at inhibitory and stimulatory treatments, alone or with CY, on the morphology of spleens and lymph nodes of the melanoma-bearing mice. The growth of the tumor in non-treated mice was found to induce a moderate splenomegaly. Microscopically, two main changes were observed: a mild extramedullary hematopoiesis and a sharp increase in the number of germinal centers. A parallel increase in germinal center number was found in the lymph nodes. The data presented suggest that the immune system plays a role in both the inhibition and stimulation of tumor growth by levan. Levan induced a dose dependent splenomegaly, even more pronounced in combination with CY, due to an extramedullary hematopoiesis. Levan reduced the B cell activity caused by the tumor, proportionally to its dose. In combination with CY, levan accelerated the recovery of the B cell activity at the low dose, while the high dose prevented it. A similar trend was found in the lymph nodes. The changes involved in the switch inhibition-stimulation could be either the degree of reduction in B cell activity or the degree of extramedullary hematopoiesis or some interplay between the myelocytic and lymphocytic series, which was found to change in an opposite fashion under the influence of various treatments. Since the immune system is a finely equilibrated system, it is possible that immunomodulation rather than immunostimulation should be aimed at in cancer immunotherapy. However, the conditions required for achieving this equilibrium have to be defined.