Of interest here is that both calicheamicin and download the handbook reactive oxygen species produce 3phosphoglyolate blocking groups in DNA, which, if not processed efficiently, will result in strand breaks. The combin ation of a 3PG bistrand DNA damage inducer and a re active oxygen species inducer may result in complex locally damaged sites which in turn may contribute to the large increase in the double strand break response seen with the drug combination. Tipifarnib Inhibitors,Modulators,Libraries has many potential molecular targets in AML cells and we ac knowledge that any one of these may contribute to the mechanism of its activity and interaction with GO. How ever, the importance of the DDR in the interaction emerged strongly from our initial phosphokinome profiling. Sensitivity to GO tipifarnib in vitro varied from 0% to 100% in our cohort.

We reported strong correlations be tween the toxicity Inhibitors,Modulators,Libraries induced by the combination and the toxicities of the individual drugs. The lack of relationship between CD33 expression levels and GO toxicity was un surprising, given that this has already been explored ex tensively, with evidence for and against the expected association. Jedema and colleagues have Inhibitors,Modulators,Libraries previ ously noted that the failure of excess free CD33 antibody to block GO mediated toxicity in primary AML blasts is concentration dependent, and occurs at concentrations greater than 1 ngml. These authors found evidence for antibody uptake by endocytosis, and their work was predicated on the finding in a clinical study that CD33 expression did not clearly correlate with GO response.

Walter and col leagues found that CD33 expression had a statisti cally significant correlation with outcome in 276 AML patients treated with GO monotherapy, but this effect was small and therefore had minimal predictive value. We and others have previously reported a role for Pgp in GO sensitivity. Inhibitors,Modulators,Libraries In the current study we have shown that Inhibitors,Modulators,Libraries a significant association remains when tipi farnib is used together with GO, despite the role of tipi farnib as a Pgp inhibitor. Normal haematopoietic CD34 ously that leukaemic CD34CD38 subsets express Pgp at the same levels as more mature cells in the sample. so we could not expect Pgp over expression to account for differences in chemosensitivity between bulk cells found and CD34CD38 cells in the same individuals. Conclusions In summary, this study is the first to assess combining GO with tipifarnib, both of which separately have shown clinical efficacy in AML. This drug combination tar gets AML cells in vitro including the CD34CD38 cells associated with chemoresistance. The activation of a DDR pathway by GO is amplified by its combination with tipifarnib.