TAXOL, A MICROTUBULE-STABILIZING ANTINEOPLASTIC AGENT, DIFFERENTIALLYREGULATES NORMAL AND TUMOR-BEARING HOST MACROPHAGE NITRIC-OXIDE PRODUCTION

Taxol, a potent antitumor chemotherapeutic, promotes:in vitro cytotoxi c antitumor activities by normal host macrophage (M phi s). Because tu mor growth induces functional changes among M phi populations, we dete rmined whether fibrosarcoma growth (Meth-KDE) modified M phi responsiv eness to the activating agent taxol. Tumors induce tumor-distal M phi populations to become immune suppressor cells, partially through overp roduction of the cytotoxic and proinflammatory molecules nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha). Beneficial to the tu mor-bearing host (TBH) when released by tumor-proximal M phi s, NO and TNF-alpha suppress lymphoproliferation and fail to impart antitumor a ctivity when expressed in tumor-distal compartments. We report that ta xol differentially regulated normal host and TBH M phi production of t he immunosuppressive molecule NO by tumor-distal M phi populations. In response to IFN-gamma-priming and taxol triggering, TBH M phi s incre ase their production of NO as compared to resting M phi s; however, un like normal host M phi s, taxol-induced TBH M phi NO production was si gnificantly suboptimal. Modulation of TBH M phi NO production in tumor -distal compartments may alleviate M phi-mediated suppression of T-cel l proliferative responses, yet promote sufficient NO production by tum or-associated M phi s to affect cytotoxicity. Collectively, these data leave implications for immunotherapeutic activities by the anticancer drug taxol.