Synergistic Antimetastatic Effects of Lentinan and Interleukin 2 with Pre‐ and Post‐operative Treatments

The antimetastatic activity of a combination of lentinan and interleukin 2 (IL‐2) was evaluated against spontaneously metastatic 3‐methylcholanthrene‐induced DBA/2.MC.CS.T fibrosarcoma. Although pre‐operative treatment with either IL‐2 or lentinan alone exerted little effect on the reduction of lung metastasis colony numbers (7.1% or 28.4% reduction, respectively), the combination exhibited a synergistic effect (85% reduction). Furthermore, 3 of 13 mice given the pre‐operative combination treatment achieved complete cure, while no mice given saline did. Although the post‐operative combination treatment also reduced the colony number (71% reduction), it caused little prolongation of survival and no mouse achieved complete cure. Synergistic effects were observed between pre‐ and post‐operative treatments with lentinan and IL‐2: 8 of 12 mice were completely cured. The anti‐metastatic activity was abolished in mice treated simultaneously with antibodies to CD4 and CDS antigens, whereas either CD4, CDS, or NK1.1 antibody alone was ineffective. Analysis of the cellular mechanism involved in the antimetastatic activity revealed the involvement of a tumor‐associated antigen‐specific delayed‐type hypersensitivity response. These data suggest that the life‐prolonging effect of the combination of lentinan and IL‐2 is mediated by antigen‐specific T cells and that the combination of pre‐ and post‐operative therapy with lentinan and IL‐2 may be effective to prevent cancer recurrence and metastasis after surgical resection.