| Abstrakt: |
Paclitaxel (TAXOL™) activates in vitromacrophage (Mø) expression of proinflammatory and cytotoxic mediators, including IL‐12, tumor necrosis factor α (TNF‐α), and nitric oxide (NO). However, tumors dysregulate Mø through soluble suppressor molecules, and it is possible that tumors evade paclitaxel‐mediated immune effector function through the production of immunomodulatory molecules and inhibition of Mø function in situ. Because Mø activation in the tumor microenvironment is a desirable goal of anti‐tumor immunotherapy, we evaluated whether tumor‐derived immunomodulatory factors dysregulate paclitaxel‐mediated Mø activation. Tumor cell‐derived supernatant suppressed paclitaxel's capacity to induce IL‐12, TNF‐α, and NO production by RAW264.7 Mø. Tumor factors also dysregulated paclitaxel‐induced expression of a HIV‐LTR, promoter‐driven luciferase construct in RAW264.7 Mø, suggesting that tumors may inhibit a broad range of Mø functionality. Depletion studies revealed that IL‐10 and transforming growth factor‐β1(TGF‐β1), but not prostaglandin E2(PGE2), impaired paclitaxel‐mediated activation, suggesting that abrogation of these factors in situmight restore paclitaxel's activating capacity and enhance anti‐tumor efficacy. |
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