Tumor hypoxia has been considered to be a potential therapeutic target, because
hypoxia is a common feature of solid
tumors and is associated with their malignant phenotype. In the present study, we investigated the antitumor effect of hypoxic cell radiosensitizer,
TX-1877 in inhibiting angiogenesis and liver
metastasis on
pancreatic cancer xenograft model. The antitumor effects of
TX-1877 were tested against various human tumor cell lines using cell proliferation assay. Nude mice bearing s.c. or orthotopically implanted human SUIT-2 were treated with
TX-1877 alone, irradiation alone or
TX-1877 and irradiation.
Tumor volume, survival, expression of angiogenic molecules and liver
metastasis were evaluated in treatment versus control groups. In vitro,
TX-1877 inhibited the proliferation and potentiated the radiosensitivity of various
pancreatic cancer cell lines. In an orthotopic model,
tumors from nude mice injected with
pancreatic cancer cells and treated with
TX-1877 and irradiation showed significant reductions in volume (p<0.05 versus control,
TX-1877 alone or irradiation alone). Quantitative real-time reverse transcription-PCR and immunohistochemical analysis revealed that treatment with
TX-1877 alone or with
TX-1877 and irradiation inhibited expression of the angiogenic molecules,
vascular endothelial growth factor;
basic fibroblast growth factor,
interleukin-8 and
matrix metalloproteinase 9 more than control or did treatment with irradiation alone. These treatments also induced apoptosis in
cancer cells. These data show that treatment of
TX-1877 and irradiation decreased growth of human
pancreatic cancer, suppressed angiogenesis and inhibited liver
metastasis, leading to prolonged survival.