Profile of cytokines produced in tumor tissue after administration of cyclophosphamide in a combination therapy with tumor necrosis factor.

BACKGROUND Recent studies have shown that locoregional administration of tumor necrosis factor (TNF) or production of endogenous TNF in tumor tissue with a chemotherapeutic agent showed considerable antitumor effect without severe toxicities. To analyze the immunological role of chemotherapeutic agents in locoregional TNF therapy, the effect of cyclophosphamide (CY) on cytokine production after ONO-4007 treatment was examined. MATERIALS AND METHODS Seven days after inoculation of Meth A fibrosarcoma in BALB/c mice, CY (100-150 mg/kg) was injected intraperitoneally and, after another 7 days, ONO-4007 (30 mg/kg) was injected intravenously. A competitive PCR quantitative analysis of the induced cytokine messenger RNA (mRNA) was performed for IL-12 (p40), TGF-beta, TNF-alpha, IL-1beta, IL-10 and IL-6. RESULTS The antitumor effect of ONO-4007 was enhanced by preadministration of CY. CY significantly enhanced IL-12 (p40) mRNA compared to that by ONO-4007 alone. No increase in TGF-beta mRNA was observed in either treatment. CONCLUSION The preadministration of CY enhances IL-12 production in tumor tissues and shifts the cytokine profile to the dominant Th1 type.