Mechanisms by which chemotherapeutic agents augment the antitumor effects of tumor necrosis factor: involvement of the pattern shift of cytokines from Th2 to Th1 in tumor lesions.
BACKGROUND
The antitumor effect exerted by tumor necrosis factor (TNF) is characteristic in that it causes central necrosis of the tumor mass. Viable tumor cells surrounding the tumor mass remain, however, even after most of the mass is necrotized, and these cells gradually regrow and form tumors. To overcome this, we analyzed the combined effects of chemotherapeutic agents used with TNF. Alkylating agents such as cyclophosphamide altered the antitumor effect qualitatively, leading to complete regression which TNF alone could not achieve. The mechanism, behind the enhancement of endogenous TNF production and expression of mRNA of various cytokines by the combination of chemotherapeutic agents with TNF inducer was investigated in Meth A fibrosarcoma.


METHODS
Seven days after the inoculation of Meth A fibrosarcoma into BALB/c mice, cyclophosphamide (CY, 100-150 mg/kg) was injected intraperitoneally, and 7 days later endogenous TNF was induced by the intradermal administration of lipopolysaccharide (LPS, 400 micrograms/kg) or intravenous injection of ONO-4007, a synthetic lipid A derivative (30 mg/kg).


RESULTS
A combination therapy of LPS or ONO-4007 with CY showed the effect of complete regression in 50-100% of tested mice, while CY, LPSp or ONO-4007 alone did not cause complete regression. The amount of endogenous TNF induced by LPSp or ONO-4007 around a tumor lesion with CY was 4-5 fold higher than that without CY. The expression of mRNA of transforming growth factor-beta was suppressed by CY seven days after the injection, and expressions of mRNA of IL-1 beta and TNF-alpha were augmented by the administration of CY 1 to 3 hours after the administration of ONO-4007.


CONCLUSIONS
Some chemotherapeutic agents thus appear to augment the antitumor effect of TNF around tumor lesions, leading to tumor regression through a mechanism in which the agent changes the host's immune status, especially around a tumor lesion and pattern shift of cytokines from Th2 to Th1.
Inagawa
H
H
Department of Molecular Medicine, Takano Hospital, Kumamoto, Japan.
Nishizawa
T
T
Honda
T
T
Nakamoto
T
T
Takagi
K
K
Soma
G
G
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage; D016207:Cytokines / Q000097:blood*; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives; D008070:Lipopolysaccharides / Q000627:therapeutic use; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008970:Molecular Weight; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects* / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage
D016207:Cytokines; D008050:Lipid A; D008070:Lipopolysaccharides; C086889:ONO 4007; D014409:Tumor Necrosis Factor-alpha; D003520:Cyclophosphamide