STRUCTURAL REQUIREMENTS OF TAXOIDS FOR NITRIC-OXIDE AND TUMOR-NECROSIS-FACTOR PRODUCTION BY MURINE MACROPHAGES

Citation
T. Kirikae et al., STRUCTURAL REQUIREMENTS OF TAXOIDS FOR NITRIC-OXIDE AND TUMOR-NECROSIS-FACTOR PRODUCTION BY MURINE MACROPHAGES, Biochemical and biophysical research communications, 227(1), 1996, pp. 227-235
Citations number
34
Categorie Soggetti
Biology,Biophysics
ISSN journal
0006291X
Volume
227
Issue
1
Year of publication
1996
Pages
227 - 235
Database
ISI
SICI code
0006-291X(1996)227:1<227:SROTFN>2.0.ZU;2-X
Abstract
Taxol (paclitaxel), a microtubule stabilizer with antitumor activity, mimics the actions of lipopolysaccharide (LPS) on murine macrophages ( M phi). In the present study, a variety of synthetic analogs of paclit axel were examined for their potencies to induce nitric oxide (NO) and tumor necrosis factor (TNF) production by peritoneal M phi from LPS-r esponsive C3H/HeN, and LPS-hyporesponsive C3H/HeJ mice, and by M phi-l ike LPS-responsive J774.1 and its mutant LPS-hyporesponsive J7.DEF3 ce lls. In this structure-activity relationship study, we found that (i) the benzoyl group at the C-3' position of paclitaxel is the most impor tant site to activate C3H/HeN M phi; (ii) the phenyl group at C-3' is not a requisite for the activity; (iii) there is good correlation betw een NO and TNF production by the M phi in response to compounds, excep t for the analogs having a tert-butoxycarbonyl (10-acetyldocetaxel) or a thiophene-2-carbonyl group at C-3'-N instead of a benzoyl group, wh ich is more dominant in TNF than in NO production; (iv) the compounds tested induce neither NO nor TNF production by C3H/HeJ M phi; (v) acti ve compounds to C3H/He M phi induce TNF production by J7.DEF3 cells as well as J774.1 cells; and (vi) there is no correlation between the NO /TNF inducibility to C3H/HeN M phi and growth inhibitory activity agai nst M phi-like J774.1 and J7.DEF3 cells. These data also suggest that the binding of taxoid/LPS to tubulin is not essential for the M phi ac tivation. (C) 1996 Academic Press, Inc.