Relationship between the structure of taxol and other taxanes on induction of tumor necrosis factor-alpha 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-alpha (TNF-alpha) 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-alpha gene expression and its cytotoxic and microtubule-stabilizing 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-alpha gene expression. The data presented in this paper demonstrate that the effects of taxol on TNF-alpha gene expression are distinct from its known cytotoxic properties.
Department of Molecular Pharmacology, Albert Einstein, College of Medicine, Bronx, New York 10461.
C A
CA
Burkhart
J W
JW
Berman
C S
CS
Swindell
S B
SB
Horwitz
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005354:Fibrosarcoma / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051379:Mice; D017239:Paclitaxel / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
D000972:Antineoplastic Agents, Phytogenic; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D014409:Tumor Necrosis Factor-alpha; D017239:Paclitaxel