Enhancement of anticancer effect of interferon-γ gene transfer against interferon-γ-resistant tumor by depletion of tumor-associated macrophages.
Tumor-associated macrophages (TAMs) negatively affect the therapeutic effects of anticancer agents. To examine the role of TAMs in interferon (IFN)-γ gene therapy, we selected two types of solid tumors, which varied in the number of TAMs, and investigated the effects of IFN-γ gene transfer on tumor growth. Many TAMs were detected in the solid tumors of murine adenocarcinoma colon-26 cells, whereas few TAMs were detected in murine melanoma B16-BL6 cells. IFN-γ gene transfer hardly suppressed the growth of colon-26 tumors, whereas it was effective in suppressing the growth of B16-BL6 tumors. The antiproliferative effects of IFN-γ on cultured colon-26 cells were similar to those on cultured B16-BL6 cells. To evaluate the role of TAMs, we injected clodronate liposomes (CLs) modified with poly(ethylene glycol) (PEG) to functionally deplete TAMs in tumor-bearing mice. Repeated injections of PEG-CLs significantly retarded the growth of colon-26 tumors and combination with IFN-γ gene transfer further inhibited the growth. In contrast, PEG-CLs hardly retarded the growth of B16-BL6 tumors. These results clearly indicate that TAM depletion is effective in enhancing the therapeutic effect of IFN-γ in TAM-repleted and IFN-γ-resistant tumors.
Department of Biopharmaceutics and Drug Metabolism and ‡Department of Molecular Microbiology, Graduate School of Pharmaceutical Science, Kyoto University , Sakyo-ku, Kyoto 606-8501, Japan.
Tsuyoshi
T
Kiyota
Yuki
Y
Takahashi
Kanitta
K
Watcharanurak
Makiya
M
Nishikawa
Saori
S
Ohara
Mitsuru
M
Ando
Yoshihiko
Y
Watanabe
Yoshinobu
Y
Takakura
D000818:Animals; D045744:Cell Line, Tumor; D015316:Genetic Therapy; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010957:Plasmids / Q000235:genetics; D011092:Polyethylene Glycols / Q000737:chemistry; D014407:Tumor Cells, Cultured
D011092:Polyethylene Glycols; D007371:Interferon-gamma