Tumor growth modulates macrophage nitric oxide production following paclitaxel administration.
The antineoplastic agent paclitaxel (Taxol) mimics bacterial lipopolysaccharide (LPS) in normal host macrophages (Mphis), enhancing antitumor cytotoxicity in vitro. Because paclitaxel is used as an antitumor chemotherapeutic agent and tumor growth alters Mphi phenotype and function, we assessed effector molecule production and cytotoxic activity by normal host and tumor-bearing host (TBH) Mphis following paclitaxel administration. Paclitaxel treatment, duplicating human chemotherapeutic regimens, primed normal host splenic Mphis for enhanced production of the cytotoxic mediator nitric oxide (NO); in contrast, paclitaxel's NO-inducing activity was significantly suppressed in TBHs. In contrast to NO regulation, Mphi capacity for tumor necrosis factor-alpha (TNF-alpha) production in both normal hosts and TBHs was enhanced by paclitaxel administration. Although tumor growth modulated paclitaxel-induced Mphi NO production, paclitaxel administration enhanced both normal host and TBH Mphi cytotoxic antitumor activity. Blocking NO with a competitive inhibitor abrogated Mphi cytotoxicity, suggesting paclitaxel-induced TBH Mphi NO production, although suboptimal, remains sufficient to mediate antitumor activity. These data demonstrate that paclitaxel's in vivo immune activities are differentially regulated during tumor burden and suggest that paclitaxel's immunotherapeutic functions may contribute to its success as an anticancer agent.
Mullins
D W
DW
Department of Biology, Virginia Polytechnic Institute and State University, Blacksburg 24061-0406, USA.
Burger
C J
CJ
Elgert
K D
KD
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D007371:Interferon-gamma / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000096:biosynthesis*; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use*; D012513:Sarcoma, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000972:Antineoplastic Agents, Phytogenic; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma; D017239:Paclitaxel