ABSTRACT
BACKGROUND AND PURPOSE: Hypoxia in tumours is known to cause resistance to conventional chemotherapeutic drugs. In contrast, little is known about the effects of hypoxia on targeted anti-cancer drugs. This study evaluated the effect of hypoxia on a series of clinically approved tyrosine kinase inhibitors (TKIs). EXPERIMENTAL APPROACH: The effect of hypoxia (0.1% oxygen) on the activity of conventional cytotoxic drugs (5-fluorouracil, doxorubicin and vinblastine), the hypoxia-activated prodrug tirapazamine and 9 TKIs was determined in a panel of cell lines. Where hypoxia had a marked effect on chemosensitivity, Western blot analysis was conducted to determine the effect of hypoxia on target expression and the effect of TKIs on cell signalling response under aerobic and hypoxic conditions. KEY RESULTS: Three patterns of chemosensitivity were observed: resistance under hypoxia, equitoxic activity against hypoxic and aerobic cells, and preferential cytotoxicity to hypoxic cells. Significant hypoxia selectivity (independent of HIF1) was observed in the case of dasatinib and this correlated with the ability of dasatinib to inhibit phosphorylation of Src at tyrosine 530. Sorafenib was significantly less effective under hypoxic conditions but resistance did not correlate with hypoxia-induced changes in Raf/MEK/ERK signalling. CONCLUSIONS AND IMPLICATIONS: Hypoxia influences the activity of TKIs but in contrast to conventional cytotoxic drugs, preferential activity against hypoxic cells can occur. The search for hypoxia-targeted therapies has been long and fruitless and this study suggests that some clinically approved TKIs could preferentially target the hypoxic fraction of some tumour types.
Subject(s)
Antineoplastic Agents/pharmacology , Neoplasms/enzymology , Oxygen/metabolism , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Apoptosis/drug effects , Cell Hypoxia , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors , Extracellular Signal-Regulated MAP Kinases/metabolism , Humans , Inhibitory Concentration 50 , MAP Kinase Kinase Kinases/antagonists & inhibitors , MAP Kinase Kinase Kinases/metabolism , MCF-7 Cells , Molecular Targeted Therapy , Neoplasms/pathology , Phosphorylation , Protein-Tyrosine Kinases/metabolism , Signal Transduction/drug effects , raf Kinases/antagonists & inhibitors , raf Kinases/metabolism , src-Family Kinases/antagonists & inhibitors , src-Family Kinases/metabolismABSTRACT
SUMMARY: Fractures have a significant impact on the quality of life for the patient in addition to an enormous indirect cost in lost productivity for our economy. While majority of fractures heal uneventfully, some fail to heal even after many months resulting in nonunion. INTRODUCTION: Sternal nonunions, although rare, are particularly onerous for the patient given the magnitude of impact on quality of life. METHODS: Current treatment for fracture nonunions emphasizes various approaches to surgical fixation in addition to bone grafting. These treatments are aggressive and have a variety of drawbacks, rendering them suboptimal as a therapeutic approach. CONCLUSION: Based on the success of teriparatide in animal studies to accelerate fracture healing, there is growing interest in using this drug in humans for the same purpose. We report a case of what we believe to be the first successful use of teriparatide in the healing of a sternal nonunion fracture.
