We studied the effect of the anticancer drug taxol on the cytotoxic mechanism of major histocompatibility complex nonrestricted lymphocytes and their activation with interleukin 2. Unseparated lymphocytes or highly enriched natural killer or T-cells were treated with 0.2–10 µg/ml of taxol for various times and tested for cytotoxicity against the K562 cell line and the ovarian cell line, OV-2774. Taxol caused a dose- and time-dependent suppression of lymphocyte cytotoxicity. The most pronounced suppression was noted after treatment with 10 µg/ml of taxol for 6 h; a lower but significant decrease in cytotoxicity was observed after treatment with 2 and 5 µg/ml of taxol. In addition, taxol inhibited activation of lymphocytes with interleukin 2; however, the cytotoxicity of interleukin 2-preactivated lymphocytes was less sensitive to taxol treatment. Mechanism studies showed that taxol was not directly toxic to lymphocytes and did not alter their ability to form conjugates with target cells. Taxol treatment decreased a rate of kinetics of lysis and lymphocyte recycling ability. The immunofluorescence and electron microscopic analysis showed polymerization of microtubules in taxol-treated lymphocytes. These data demonstrate that taxol impairs lymphocyte cytotoxic function and activation and indicate the role of microtubules in these functions. Clinically, these findings suggest that activation of lymphocytes prior to taxol treatment may increase the therapeutic benefit of this drug.
This research was supported by the National Cancer Institute Grants RO1 CA55597 and T32CA09623, the Florence Maude Thomas Cancer Research Professorship endowment, and the Pawelek fund. E. L. is a recipient of Florence Maude Thomas Cancer Research Professorship.