Chemotherapy amplifies production of tumor necrosis factor

Several chemotherapeutic agents exert cytotoxicity through the generation of reactive oxygen species (ROS), and our laboratory has shown that ROS increase tumor necrosis factor (TNF) production. Therefore, we hypothesized that cis-dichlorodiammine platinum (CDDP), mitomycin-C, and doxorubicin hydrochloride (Adriamycin), by the release of ROS, would increase macrophage TNF production. Murine macrophages were incubated for 20 hours with varying doses of the chemotherapeutic drugs and 2.5 micrograms/ml endotoxin. Both CDDP and mitomycin-C increased TNF production compared to nondrug-exposed cells. Peak TNF values occurred at 10 micrograms/ml CDDP and 62.5 micrograms/ml mitomycin-C with 377 +/- 38 and 427 +/- 54 units/ml TNF produced, respectively. These increases were significant (p2 less than 0.05) compared to the nonchemotherapy; but endotoxin-exposed macrophages (CDDP 11 +/- 3 units/ml; mitomycin-C 10 +/- 3 units/ml). Only CDDP-increased production of TNF from non-endotoxin-primed macrophages (0 microgram/ml CDDP - 0 +/- 0 unit/ml TNF; 50 micrograms/ml CDDP - 13 +/- 5 units/ml TNF; p2 less than 0.038). 5-Fluorouracil, a non-ROS-generating chemotherapeutic, and Adriamycin failed to amplify TNF production. By Northern blot analysis, CDDP induced transcription of the TNF gene in non-endotoxin-primed macrophages as early as 3 hours after exposure to 50 micrograms/ml CDDP, and this preceded the increase in TNF protein in kinetic studies. Because CDDP, mitomycin-C, and Adriamycin all produce ROS, the mechanism for this selective chemotherapy-induced cytokine amplification remains unclear. This finding may explain both indirect toxic and tumoricidal properties of CDDP and mitomycin-C.