The novel hypoxic cell radio sensitizer, TX-1877 has antitumor activity through suppression of angiogenesis and inhibits liver metastasis on xenograft model of pancreatic cancer

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. (c) 2008 Elsevier Ireland Ltd. All rights reserved.