Combination chemo-immunotherapy of murine solid tumor with OK-432, G-CSF, IL-2, and chemotherapeutics

An experimental tumor model was previously established in which BALB/c mice could survive the otherwise fatal intraperitoneal (i.p.) inoculation of BAMC-1 fibrosarcoma cells if the mice were treated with five sequential i.p. injections of OK-432 (a potent BRM) starting 2 days after tumor inoculation. In the present study, although a single i.p. injection of OK-432 alone on day 2 was not enough to cure the tumor-bearing mice, a combination therapy, an injection of OK-432 (5 mg/kg) on day 2 followed by injection of G-CSF (50 micrograms/kg) on day 3, could eradicate the tumor cells in more than 80% of the mice. In contrast to this ascites tumor model, solid tumors induced by intradermal transplantation of BAMC-1 tumor cells were resistant to the combined treatments with OK-432 and G-CSF, dying within 60 days. However, when these mice received a combined chemoimmunotherapy with cisplatin, OK-432, G-CSF and IL-2, starting on day 4, the tumors had regressed, and were completely eradicated. When the same treatment was started as late as day 8, no significant therapeutic effect was observed. Even at this advanced stage, however, it was found that a similar chemo-immunotherapy protocol using CAP-D (cyclophosphamide, epirubicin and DWA2114R) in lieu of cisplatin was extremely effective, achieving the eradication of tumors in more than 70% of the mice. These results indicated that the combination therapy with OK-432, G-CSF, IL-2, and chemotherapeutics could achieve a potent anti-tumor effect against the solid tumor, even at the advanced stage. Subsequent experiments using athymic nude mice transplanted with the tumor cells revealed that the same combination therapy showed weak tumor-regressing effects without achieving a complete cure. These results suggest that T-cells are key effectors in this type of chemo-immunotherapy of malignant tumors.