Depressed cytolytic activity of peripheral blood mononuclear cells in unusually high paclitaxel concentrations: Reversal by IL-2 and IL-12

Background. Human lymphocyte function was inhibited by high concentrations of paclitaxel and the effect was reversed by interleukin (IL)- 2. However, there was no parallel study determining the relationship between paclitaxel concentrations in the lymphocyte cultures and pharmacokinetic analysis in human patients, nor was there any study on the reversal by cytokines, other than IL-2, of the paclitaxel-induced suppression of lymphocyte cytotoxicity. Methods. We tested the effect of different doses of paclitaxel with various incubation times on the cytolytic activity of peripheral blood mononuclear cells (PBMNCs) against K-562 target cells. Results. Our results showed that using a schedule similar to that for treating patients with tolerable doses of paclitaxel, no inhibition of cytolytic activity of PBMNCs was seen. When the paclitaxel concentration was increased 10-fold, the cytolytic activity of PBMNCs was significantly reduced. This suppression was reversed by the simultaneous addition of a low dose (10 U/ml] of IL-2 or IL-12. Addition of granulocyte macrophage-colony stimulating factor (10 U/ml] did not affect the cytolytic activity of PBMNCs, whereas addition of IL-4 reduced it. Time kinetic studies revealed that, with the addition of IL-2 or IL-12, most of the mononuclear cellular cytolytic activity recovered within 48 to 72 hours. Conclusions. These findings suggested that, to reduce the toxicity on mononuclear cellular function when high-dose paclitaxel treatment is elected in clinical practice, paclitaxel should be infused over a longer duration of time, or the treatment should be combined with the administration of a low dose of IL-2 or IL-12.