CD133 and CD44 are cell surface markers that have been used to isolate

Specifically, cells were inoculated with 1 ml syringes with 30 gauge hypodermic needles in an open technique under direct visualization into the right lung tissue of SCID mice anesthetized by gas anesthesia. buy ABT-737 Tumor growthmetastases were imaged weekly using bioluminescence by IVIS 200 imaging system from Caliper Corporation. Mice were anesthetized and 30 mg Kg of D luciferin in PBS was administered by intraperitoneal injection. Ten minutes after injec tion, bioluminescence was imaged with a charge coupled device camera with an imaging time of 2 min. At the end of the experiment, or when mice become moribund, all of the mice were euthanized and individual organs harvested for evaluation of tumor size. distant metastases was determined by bioluminescence of luci ferase expressing cells.<br><br> Statistical methods Data were presented as the mean standard deviation. To assess the statistical significance of differences, students t test was performed. The data were consid ered statistically significant when the P value was less than 0. 05. Introduction Although significant advances have been AEB071 425637-18-9 made in the treat ment of acute lymphoblastic leukemia especially in children, only 30 40% of adults have a long term survival. A major subclass of ALL with a specially poor progno sis in both adults and children is that of Philadelphia chromosome positive ALL. The Ph chromosome is generated by a reciprocal t translocation. It is found in around 30% of cases of adult ALL and is the hallmark of chronic myeloid leukemia.<br><br> The deregulated tyrosine kinase activity of the chimeric BcrAbl protein in these leu kemias phosphorylates a broad range of substrates, many of which are key cellular AG-014699 459868-92-9 signal transduction proteins. The tyrosine kinase inhibitor imatinib became the first line therapy in the conventional treatment of CML, with a rela tively selective targeting of the ATP binding site of BcrAbl. However, the emergence of resistance to imatinib remains a major problem especially for those patients with advanced CML, or with Ph positive ALL. This is due to point mutations in the BcrAbl kinase domain, including the most frequent T315I and E225K mutations. Sec ond generation tyrosine kinase inhibitors, such as nilotinib, dasatinib and bosutinib are capable of targeting the major ity of imatinib resistant mutations, but none of them are ef fective against leukemia cells harboring the T315I mutation.<br><br> Thus, the need to find a more effective treatment for leukemia patients with this mutation is obvious. Aurora kinases are key regulators of cell division and deregulation of this activity can result in aneuploidy and carcinogenesis. Therefore, they are attractive tar gets for anticancer therapy. Several small molecule inhibitors of Aurora kinases with various properties are in clinical trials including PHA 739358. MLN8054 and AZD1152. PHA 739358 is a pan Aurora kinases inhibitor with activity against all Aurora kinase family members. Interestingly, and of importance for the potential use of this compound against poor prognosis ALL, Gontarewicz et al, using Bcr Abl constructs transfected into the BaF3 cell line, showed that PHA 739358 is also effective against imatinib resistant BcrAbl mutants including the T315I.