INDUCTION OF TUMOR-NECROSIS-FACTOR BY A CAMPTOTHECIN DERIVATIVE, IRINOTECAN, IN MICE AND HUMAN MONONUCLEAR-CELLS

Irinotecan (CPT-11) has been reported to be cytotoxic to tumor cells t hrough its inhibitory activity on type I DNA topoisomerase. CPT-11 has also been shown to have several unique biological activities apart fr om direct cytotoxicity. We investigated the ability of CPT-11 to induc e tumor necrosis factor (TNF) production. Human peripheral blood monon uclear cells (MNCs) were incubated with LPS, CPT-11, or with vinblasti n sulfate as a control. The priming effect of CPT-11 on endogenous pro duction of TNF was examined by injecting the drug intravenously into m ice, followed 3 hours by the injection of OK432. At a dose of 200-400 mu g/kg, CPT-11 showed a significant priming effect A significant amou nt of TNF was released when MNCs were incubated with 100-300 mu M of C PT-11 for more than 4 hours, but not with vinblastin sulfate, indicati ng a triggering effect of TNF production on MNCs in vitro. These effec ts may be advantageous in cancer therapy.