TUMOR-GROWTH MODULATES MACROPHAGE NITRIC-OXIDE PRODUCTION FOLLOWING PACLITAXEL ADMINISTRATION

The antineoplastic agent paclitaxel (Taxol(TM)) mimics bacterial lipop olysaccharide (LPS) in normal host macrophages (M phi s), enhancing an titumor cytotoxicity in vitro. Because paclitaxel is used as an antitu mor chemotherapeutic agent and tumor growth alters M phi phenotype and function, we assessed effector molecule production and cytotoxic acti vity by normal host and tumor-bearing host (TBH) M phi s following pac litaxel administration. Paclitaxel treatment, duplicating human chemot herapeutic regimens, primed normal host splenic M phi s for enhanced p roduction of the cytotoxic mediator nitric oxide (NO); in contrast, pa clitaxel's NO-inducing activity was significantly suppressed in TBHs. In contrast to NO regulation, M phi capacity for tumor necrosis,factor -alpha (TNF-alpha) production in both normal hosts and TBHs was enhanc ed by paclitaxel administration. although tumor growth modulated pacli taxel-induced M phi NO production, paclitaxel administration enhanced both normal host and TBH M phi cytotoxic antitumor activity; Blocking NO with a competitive inhibitor abrogated M phi cytotoxicity; suggesti ng paclitaxel-induced TBH M phi NO production, although suboptimal, re mains sufficient to mediate antitumor activity. These data demonstrate that paclitaxel's in vivo immune activities are differentially regula ted during tumor burden and suggest that paclitaxel's immunotherapeuti c functions may contribute to its success as an anticancer agent. (C) 1998 International Society for Immunopharmacology. Published by Elsevi er Science Ltd.