Enhanced inhibition of experimental metastasis by the combination chemotherapy of Cu-ZnSOD and adriamycin

We previously reported that reactive oxygen species (ROS) enhance tumor cel l metastasis, and by administration of recombinant human superoxide dismuta se (rh SOD), an enzyme which scavenges O-2(-) successfully reduced lung met astasis of mouse MethA sarcoma and Lewis lung carcinoma. These observations suggested that rh SOD suppressed tumor cell invasion by eliminating O-2(-) , the primary source of ROS. However, for the clinical application of the d rug as an anti metastatic agent, rh SOD needs to be administered in combina tion with other cytotoxic agents, since SOD by itself has no cytotoxic acti vity. In this paper, we investigated the effectiveness of the combination c hemotherapy of rh SOD and adriamycin (ADR), an anti-cancer agent against th e experimental metastasis of highly metastatic clone, MH-02, which was deri ved from murine Meth A sarcoma. The present metastasis experiment clearly i ndicates that the administration of rh SOD enhances the anti-metastatic eff ect of ADR. On the other hand, we found that the inhibition rate of metasta sis exhibited by the combination chemotherapy of rh SOD and a certain dose (5 mg/ml) of ADR was inferior to that of rh SOD. This apparent paradoxical phenomenon was presumably explained by our finding that tumor cells themsel ves augment their invasive capacity and platelet aggregation, both of which are causative factors for metastasis formation, by generation of O-2(-) wh en they were treated with ADR. Nevertheless, the combination chemotherapy o f SOD with anticancer drugs such as ADR can be a practical anti-metastasis strategy.