Immunomodulatory effects of docetaxel on human lymphocytes.
Docetaxel is an antineoplastic taxoid that interferes with microtubule polymerization dynamics and is used clinically to treat advanced cancers. Because microtubules play significant roles in T lymphocyte activation and function we characterized the in vitro immunomodulatory properties of docetaxel. Effects of docetaxel on lectin-induced peripheral blood mononuclear cell (PBMC) proliferation were measured by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and proliferating cell nuclear antigen (PCNA) staining. In addition, apoptosis was measured by annexin V staining and cell activation by determination of CD25 and CD71 cell surface expression. Intracellular calcium kinetics in lectin-activated Jurkat T lymphocytes exposed to docetaxel were investigated. Th1 cytokine production was assessed in T lymphocytes by intracellular cytokine staining. Docetaxel significantly inhibited PBMC proliferation and promoted apoptosis of lectin-activated PBMCs. Docetaxel significantly decreased expression of CD71 but not that of CD25. Docetaxel altered intracellular calcium homeostasis but did not affect Th1 cytokine production in T lymphocytes. In conclusion we demonstrate that docetaxel, although exerting significant antiproliferative effects on lymphocytes and promoting activation-induced apoptosis does affect only partially lymphocyte activation and function and does not affect Th1 cytokine production. These results suggest maintenance of lymphocyte functions important for host tumor surveillance and suggest that this compound may have a role in the treatment of cancer arising organ transplant recipients.
Si
Ming-Sing
MS
Transplantation Immunology Laboratory, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA 94305-5407, USA.
Imagawa
David K
DK
Ji
Ping
P
Wei
Xunbin
X
Holm
Bari
B
Kwok
Jennifer
J
Lee
Michael
M
Reitz
Bruce A
BA
Borie
Dominic C
DC
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D015703:Antigens, CD / Q000096:biosynthesis; D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D000077143:Docetaxel; D006801:Humans; D037102:Lectins / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D011990:Receptors, Transferrin; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology*; D013997:Time Factors
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; C068126:CD71 antigen; D016207:Cytokines; D037102:Lectins; D018809:Proliferating Cell Nuclear Antigen; D015375:Receptors, Interleukin-2; D011990:Receptors, Transferrin; D043823:Taxoids; D000077143:Docetaxel