Hypoxia modulates the activity of a series of clinically approved tyrosine kinase inhibitors

• DOI: 10.1111/bph.12438
• Publication Date: 2013-10-12T02:22:15Z
• Authors: M Ahmadi; Z Ahmadihosseini; S J Allison; S Begum; K Rockley; M Sadiq; S Chintamaneni; R Lokwani; N Hughes; R M Phillips
• Keywords: Tirapazamine; Hypoxia

Hypoxia in tumours is known to cause resistance conventional chemotherapeutic drugs. In contrast, little about the effects of hypoxia on targeted anti-cancer This study evaluated effect a series clinically approved tyrosine kinase inhibitors (TKIs).The (0.1% oxygen) activity cytotoxic drugs (5-fluorouracil, doxorubicin and vinblastine), hypoxia-activated prodrug tirapazamine 9 TKIs was determined panel cell lines. Where had marked chemosensitivity, Western blot analysis conducted determine target expression signalling response under aerobic hypoxic conditions.Three patterns chemosensitivity were observed: hypoxia, equitoxic against cells, preferential cytotoxicity cells. Significant selectivity (independent HIF1) observed case dasatinib this correlated with ability inhibit phosphorylation Src at 530. Sorafenib significantly less effective conditions but did not correlate hypoxia-induced changes Raf/MEK/ERK signalling.Hypoxia influences contrast drugs, cells can occur. The search for hypoxia-targeted therapies has been long fruitless suggests that some could preferentially fraction tumour types.