Involvement of doxorubicin-induced Fas expression in the antitumor effect of doxorubicin on Lewis lung carcinoma in vivo.
Deficiency of Fas expression is one of mechanisms involved in the immune evasion by tumors. Several antitumor drugs, such as doxorubicin (DOX) increase Fas expression in tumor cells and sensitize the cells to Fas-mediated apoptosis in vitro. However, the significance of the Fas expression in vivo is still unclear. Therefore, we examined a role of Fas expression on antitumor effect of DOX using a syngeneic tumor model of Lewis lung carcinoma (3LL) cells in C57BL/6-gld mice that lack functional Fas ligand (FasL). In vitro, anti-Fas agonistic antibody, Jo2, did not decrease a viable cell number of 3LL cells in the absence of DOX, whereas it significantly reduced the cell viability in the presence of DOX. The treatment with DOX alone at the same dose did not induce cell death. Flowcytometric analysis of Fas expression revealed that 3LL cells expressed only a marginal amount of Fas, but the treatment of the cells with DOX increased the expression of Fas in the cell surface. When splenic T cells were prepared from 3LL-bearing C57BL/6 mice, the splenic T cells significantly killed DOX-pretreated 3LL cells more than untreated 3LL cells. In the syngeneic models, DOX inhibited growth of 3LL solid tumor both in wild-type C57BL/6 mice and in Fas-deficient C57BL/6-lpr mice, but it failed in C57BL/6-gld mice, suggesting that the interaction between host FasL and tumor Fas is involved in the antitumor effect of DOX. Furthermore, Fas expression was increased in the solid tumor by the treatment of DOX. These results suggest that the antitumor effect of DOX is partly exerted by the Fas expression and host immune defense.
Yoshimoto
Yuya
Y
Drug Development Unit, Numazu Bio-Medical Research Institute, Microbial Chemistry Research Center, 18-24 Miyamoto, Numazu-shi, Shizuoka 410-0301, Japan.
Kawada
Manabu
M
Ikeda
Daishiro
D
Ishizuka
Masaaki
M
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology* / Q000627:therapeutic use; D053222:Fas Ligand Protein; D005260:Female; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019014:fas Receptor / Q000096:biosynthesis* / Q000276:immunology
D000903:Antibiotics, Antineoplastic; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D019014:fas Receptor; D004317:Doxorubicin