picibanil and Leukemia-P388

The synergistic effects of combined chemotherapy with adriamycin (ADR) and cyclophosphamide (CY) on L1210 tumors in mice were potentiated by use of a streptococcal preparation, OK-432, in a time- and dose-dependent way. Some mice were cured by treatment with the three agents, and resisted a later challenge by L1210 but not P388 leukemia cells. This immunity was blocked by administration of antimacrophage agents or CY. The effects of OK-432 were also studied with mice sensitized by L1210 cells attenuated with mitomycin C. OK-432 potentiated syngeneic and semi-syngeneic transplantation resistance in vivo and augmented primary and secondary cytotoxicity mediated by spleen cells in vitro. In vivo administration of ADR and CY together enhanced in vivo tumor transplantation resistance and in vitro cytotoxicity was blocked, but this inhibition was reversed by injection of OK-432. The results suggested that OK-432 acted by increasing the activity of cytotoxic spleen cells against L1210 cells, which are fast-growing and poorly immunogenic, and that this cytotoxicity killed tumor cells that survived the chemotherapy.

Topics: Animals; Biological Products; Carrageenan; Cyclophosphamide; Cytotoxicity, Immunologic; Dose-Response Relationship, Drug; Doxorubicin; Immune Tolerance; Immunotherapy; Leukemia L1210; Leukemia P388; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Neoplasm Transplantation; Picibanil; Spleen; Time Factors; Trypan Blue

Sensitization with mitomycin C-treated L1210 or EL-4 tumor cells followed by intraperitoneal injection of a streptococcal preparation OK-432 rendered histocompatible or syngeneic mice immune to the corresponding tumor cells. The antitumor immunity, which was more potent than that induced by attenuated tumor cells alone, was manifested by transplantation resistance to challenge tumor cells, and by cytotoxic activity of spleen cells from the primed mice. The former activity was closely related to the latter, which was found to be mainly due to tumor-specific cytotoxic T lymphocytes. The in vivo immunoaugmentation by OK-432 was susceptible to macrophage toxins such as trypan blue and carragheenins, and was partly dependent on the activity of noncytotoxic Ia-positive peritoneal macrophages. OK-432-mediated enhancement of Ia-positive macrophage functions was confirmed by concanavalin A-blastogenesis and T cell-dependent antibody formation. Allo-reactive cytotoxicity induced in allogeneic or semiallogeneic mice, which had been primed with clonogenic or attenuated tumor cells, was also augmented by concomitant administration of OK-432. These results suggest that OK-432 augments induction of antitumor immunity and alloreactive cytotoxicity, associated with stimulation of noncytotoxic Ia-positive accessory macrophage activity.

Topics: Animals; Biological Products; Graft Rejection; Histocompatibility Antigens Class II; Leukemia L1210; Leukemia P388; Leukemia, Experimental; Lymphocyte Activation; Macrophages; Male; Mice; Mice, Inbred Strains; Neoplasm Transplantation; Picibanil; T-Lymphocytes, Cytotoxic; Thymoma; Thymus Neoplasms; Transplantation, Homologous