Structural requirements of taxoids for nitric oxide and tumor necrosis factor production by murine macrophages.
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 paclitaxel were examined for their potencies to induce nitric oxide (NO) and tumor necrosis factor (TNF) production by peritoneal M phi from LPS-responsive C3H/HeN, and LPS-hyporesponsive C3H/HeJ mice, and by M phi-like LPS-responsive J774.1 and its mutant LPS-hyporesponsive J7.DEF3 cells. In this structure-activity relationship study, we found that (i) the benzoyl group at the C-3' position of paclitaxel is the most important 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 between NO and TNF production by the M phi in response to compounds, except for the analogs having a tert-butoxycarbonyl (10-acetyldocetaxel) or a thiophene-2-carbonyl group at C-3'-N instead of a benzoyl group, which 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) active 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 against 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 activation.
Kirikae
T
T
Department of Microbiology, Jichi Medical School, Tochigi-ken, Japan. tkirikae@jichi.ac.jp
Ojima
I
I
Kirikae
F
F
Ma
Z
Z
Kuduk
S D
SD
Slater
J C
JC
Takeuchi
C S
CS
Bounaud
P Y
PY
Nakano
M
M
D000818:Animals; D002460:Cell Line; D005260:Female; D008262:Macrophage Activation / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D009569:Nitric Oxide / Q000096:biosynthesis*; D017239:Paclitaxel / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D017239:Paclitaxel