Tumor growth modulates macrophage nitric oxide production following paclitaxel administration

• Published in: International journal of immunopharmacology Vol. 20; no. 10; pp. 537 - 551
• Main Authors: Mullins, D.W., Burger, C.J., Elgert, K.D.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Science 01.10.1998
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents, Phytogenic - pharmacology; Antineoplastic Agents, Phytogenic - therapeutic use; Biological and medical sciences; Chemotherapy; Cytotoxicity; Cytotoxicity, Immunologic - drug effects; Immunomodulators; Interferon-gamma - pharmacology; Macrophages; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Male; Medical sciences; Mice; Mice, Inbred BALB C; Nitric oxide; Nitric Oxide - biosynthesis; Paclitaxel; Paclitaxel - pharmacology; Paclitaxel - therapeutic use; Pharmacology. Drug treatments; Sarcoma, Experimental - drug therapy; Sarcoma, Experimental - immunology; Sarcoma, Experimental - metabolism; Tumor necrosis factor- α; Tumor Necrosis Factor-alpha - biosynthesis; Cytotoxicity; Tumor necrosis factor- α; Macrophages; Nitric oxide; Paclitaxel; Antineoplastic agent; Animal model; Sarcoma; Immunomodulation; Gene product; Cytokine; Rodentia; Fibrosarcoma; Splenocyte; Malignant tumor; Gene expression; In vitro; In vivo; Vertebrata; Mammalia; Mouse; Animal; Taxane derivatives; Tumor progression; Tumor necrosis factor α; Macrophage
• ISSN: 0192-0561; 1879-3495
• DOI: 10.1016/S0192-0561(98)00047-2

The antineoplastic agent paclitaxel (Taxol TM) mimics bacterial lipopolysaccharide (LPS) in normal host macrophages (M φs), enhancing antitumor cytotoxicity in vitro. Because paclitaxel is used as an antitumor chemotherapeutic agent and tumor growth alters M φ phenotype and function, we assessed effector molecule production and cytotoxic activity by normal host and tumor-bearing host (TBH) M φs following paclitaxel administration. Paclitaxel treatment, duplicating human chemotherapeutic regimens, primed normal host splenic M φs for enhanced production of the cytotoxic mediator nitric oxide (NO); in contrast, paclitaxels NO-inducing activity was significantly suppressed in TBHs. In contrast to NO regulation, M φ capacity for tumor necrosis factor- α (TNF- α) production in both normal hosts and TBHs was enhanced by paclitaxel administration. Although tumor growth modulated paclitaxel-induced M φ NO production, paclitaxel administration enhanced both normal host and TBH M φ cytotoxic antitumor activity. Blocking NO with a competitive inhibitor abrogated M φ cytotoxicity, suggesting paclitaxel-induced TBH M φ NO production, although suboptimal, remains sufficient to mediate antitumor activity. These data demonstrate that paclitaxels in vivo immune activities are differentially regulated during tumor burden and suggest that paclitaxels immunotherapeutic functions may contribute to its success as an anticancer agent.