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Augmentation of Murine Natural Killer Cell Activity by Swainsonine, a New Antimetastatic Immunomodulator¹

Departments of Oncology [M. J. H., K. M., S. L. W., K. O.] and Microbiology [S. L. W.], Howard University Cancer Center, Washington, DC 20060, and Western Regional Research Center, Agricultural Research Service, USDA, Albany, California 94710 [R. J. M.]

Swainsonine, an indolizidine alkaloid, has been found to inhibit the experimental metastasis of B16-F10 melanoma cells when administered systemically to syngeneic C57BL/6 mice. The inhibition was both potent and dose dependent with 80% reduction in pulmonary colonization being observed after only 24-h exposure to 3 µg/ml of swainsonine in drinking water. In contrast, the inhibitory activity of swainsonine was completely abrogated when assays were performed in mice depleted of their natural killer (NK) cell activity either experimentally (anti-asialo-GM₁ antibody- or cyclophosphamide-treated C57BL/6 mice) or as a result of genetic mutation (homozygous C57BL/6^bg/bg beige mice). Swainsonine elicited a 32.0% increase in spleen cell number 2 days after administration and induced a concomitant 2- to 3-fold increase in splenic NK cell activity. These results indicate (a) an absolute requirement for a functional NK cell population in order for swainsonine to exert its inhibitory effects on experimental metastasis, and (b) that the antimetastatic activity of swainsonine is mediated primarily through the ability of the drug to augment NK cell reactivity. On the basis of these findings, swainsonine can be classified as a new immunomodulator that has the ability, at least in a prophylactic setting, to block tumor metastasis.

¹ This work was supported in part by NIH Grants CA-14718 and CA-45290, and ACS Grant PDT-312 to K. O., and the Howard University Faculty Research Support Grant.

² Supported by a Cancer Research Institute fellowship.

Received 8/12/87. Revised 12/ 9/87. Accepted 12/11/87.