Profile of cytokines produced in tumor tissue after administration of cyclophosphamide in a combination therapy with tumor necrosis factor.
BACKGROUND
Recent studies have shown that locoregional administration of tumor necrosis factor (TNF) or production of endogenous TNF in tumor tissue with a chemotherapeutic agent showed considerable antitumor effect without severe toxicities. To analyze the immunological role of chemotherapeutic agents in locoregional TNF therapy, the effect of cyclophosphamide (CY) on cytokine production after ONO-4007 treatment was examined.


METHODS
Seven days after inoculation of Meth A fibrosarcoma in BALB/c mice, CY (100-150 mg/kg) was injected intraperitoneally and, after another 7 days, ONO-4007 (30 mg/kg) was injected intravenously. A competitive PCR quantitative analysis of the induced cytokine messenger RNA (mRNA) was performed for IL-12 (p40), TGF-beta, TNF-alpha, IL-1beta, IL-10 and IL-6.


RESULTS
The antitumor effect of ONO-4007 was enhanced by preadministration of CY. CY significantly enhanced IL-12 (p40) mRNA compared to that by ONO-4007 alone. No increase in TGF-beta mRNA was observed in either treatment.


CONCLUSIONS
The preadministration of CY enhances IL-12 production in tumor tissues and shifts the cytokine profile to the dominant Th1 type.
Department of Molecular Biology, Nagoya City University School of Medicine, Mizuho-cho, Nagoya 467-8601, Japan.
Kunio
K
Takiguchi
Takeru
T
Nakamoto
Hiroyuki
H
Inagawa
Chie
C
Kohchi
Takashi
T
Nishizawa
Naofumi
N
Nagasue
Gen-Ichiro
G
Soma
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D003520:Cyclophosphamide / Q000008:administration & dosage; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D004357:Drug Synergism; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D016207:Cytokines; D008050:Lipid A; C086889:ONO 4007; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D003520:Cyclophosphamide