Alteration of lymphocyte microtubule assembly, cytotoxicity, and activation by the anticancer drug taxol.
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 micrograms/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 micrograms/ml of taxol for 6 h; a lower but significant decrease in cytotoxicity was observed after treatment with 2 and 5 micrograms/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.
Chuang
L T
LT
Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Lotzová
E
E
Heath
J
J
Cook
K R
KR
Munkarah
A
A
Morris
M
M
Wharton
J T
JT
D000328:Adult; D000818:Animals; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D003864:Depression, Chemical; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology* / Q000633:toxicity; D012756:Sheep; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D007376:Interleukin-2; D017239:Paclitaxel