As shown in Figure 4A, treatment with both temozolomide and PKRA7 prolonged the onset of neurological selleck kinase inhibitor signs of tumor burden compared to mice receiving control, temozolomide or PKRA7 alone, indicating an enhanced effect of combinational therapy with the agents in inhibiting intracranial glioma growth in nude mice (mean survival of 49.8 days for PKRA7 plus temozolomide vs 44.6 days for either temozolomide or PKRA7 alone vs 38.6 days for control). Figure 4 PKRA7 enhances the efficacy of chemotherapeutic drugs to reduce glioblastoma and pancreatic xenograft tumor growth. For pancreatic cancer, gemcitabine is one of the main chemotherapeutic drugs currently used in the clinic and it was tested previously in combination therapy studies involving AsPc-1 cells [30].

In our experiments, 5��105 AsPc-1 cells were subcutaneously implanted into nude mice that were treated with PKRA7 and gemcitabine (100 mg/kg) 7 days later. As shown in Figure 4B, it is clear that tumors from mice received both gemcitabine and PKRA7 were significantly smaller than those from mice treated with only gemcitabine or PKRA7. These results suggest that combinational therapy with gemcitabine and PKRA7 could have a stronger anti-tumor effect than the standard therapy to reduce pancreatic cancer xenograft tumor growth in our model. Discussion Tumorigenesis is a complex process that involves much more than proliferating tumor cells. The tumor cells are aided and supported by the surrounding tumor stromal microenvironment that is rich with a heterogeneous mix of cells such as fibroblasts, endothelial cells and immune cells [31].

These cells respond to signals from the expanding tumor by secreting factors of their own that can perpetuate the growth signal, remodel the extracellular matrix, contribute to angiogenesis and redirect the role of immune cells. Angiogenesis has long been understood to be an important part of tumorigenesis and many studies have been done to block this process [32]. While important angiogenic factors have been identified such as VEGF, therapeutics against the VEGF signaling pathway have not been proven to be universally successful. Indeed, many cancers are resistant to anti-VEGF therapy or become refractory to administration of these therapies, resulting in recurrence that is sometimes more aggressive Cilengitide than the primary tumor [14], [16], [33]�C[38]. There is a need to identify and target additional signaling pathways that may contribute to angiogenesis or other processes that have been shown to be important for tumor progression such as macrophage infiltration.