Relationship between the Structure of Taxol and Other Taxanes on Induction of Tumor Necrosis Factor-α Gene Expression and Cytotoxicity

Taxol is an antitumor drug with cytotoxic properties that correlate with its microtubule-stabilizing activities. It has been reported that taxol parallels lipopolysaccharide in its effects on the induction of tumor necrosis factor-α (TNF-β) gene expression in macrophages (C. Bogdan and A. Ding, J. Leukocyte Biol., 52: 119-121, 1992; C. L. Manthey, M. E. Brandes, P. Y. Perera, and S. Vogel, J. Immunol., 149: 2459-2465,1992; J. M. Carboni, C. Singh, and M. A. Tepper, Natl. Cancer Inst Monogr., 15: 95-101,1993). Structure-activity studies using taxol and related taxanes have been done to determine the relationship between the effects of taxol on TNF-α gene expression and its cytotoxic and microtubule-stabi lizing activities. Using Northern blot analysis, it was found that changes in the structure of taxol that did not alter cytotoxicity did prevent the induction of TNF-α gene expression. The data presented in this paper demonstrate that the effects of taxol on TNF-α gene expression are distinct from its known cytotoxic properties.