Vinca alkaloids induce granulocyte-macrophage colony stimulating factor in human peripheral blood mononuclear cells.
Several anti-cancer drugs are known to have proliferation-related effects on various cells, such as an activation of some transcription factors and an induction of some cytokines. We examined the effect of anti-cancer drugs on granulocyte-macrophage colony stimulating factor (GM-CSF) induction in human peripheral blood mononuclear cells (PBMC). Increase of GM-CSF protein and mRNA were observed in PBMC after exposure to vindesine sulfate (VDS). Induction of GM-CSF protein was dose-dependent and detectable at VDS concentrations of 0.1 microgram/ml. This effect was also observed in response to treatment with other microtuble-depolymerizing agents, vincristine sulfate and vinorelbine ditartrate, but not with cisplatin, etoposide, or paclitaxel. In order to elucidate the mechanism of this phenomenon, we examined the effects of cyclohexamide and actinomycin D on the expression of GM-CSF mRNA. Both of these drugs completely inhibited GM-CSF mRNA expression after VDS exposure, implying that VDS induces de novo GM-CSF synthesis in an indirect manner. As a candidate for the initial signaling, we next examined the role of the IL-1 beta autocrine or paracrine pathways in GM-CSF induction by VDS. IL-1 beta protein and mRNA expression were induced after VDS exposure more rapidly (from 4 hours) than expression of GM-CSF (protein from 12 hours and mRNA from 8 hours). Addition of anti-IL-1 beta antibody partially inhibited induction of GM-CSF by VDS. These results suggest that GM-CSF induction by VDS is partially mediated through the initial generation of IL-1 beta in PBMC.
Ogura
K
K
First Department of Internal Medicine Showa University, Tokyo, Japan.
Ohta
S
S
Ohmori
T
T
Takeuchi
H
H
Hirose
T
T
Horichi
N
N
Okuda
K
K
Ike
M
M
Ozawa
T
T
Siba
K
K
Kasahara
K
K
Sasaki
Y
Y
Nakajima
H
H
Adachi
M
M
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007375:Interleukin-1 / Q000502:physiology; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D014748:Vinca Alkaloids / Q000494:pharmacology*; D014751:Vindesine / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; D007375:Interleukin-1; D012333:RNA, Messenger; D014748:Vinca Alkaloids; D003609:Dactinomycin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003513:Cycloheximide; D014751:Vindesine