using B6D2F1 mice, suggesting that the toxicity produced by daily treatments of 30 mg/kg 5 FU and above is not strain speciWc. Furthermore, even though the combined treatment did not produce a statistically signiWcant eVect on tumour growth over PXD101 alone, there was an observable beneWt to this combination over single compound treatment . It has been previously Dihydroquercetin demonstrated that the combination of the HDACi SAHA with 5 FU and irinotecan, in hepatoma cell lines, enhanced their antiproliferative and apoptotic eVects in a triple combination . Dual compound incubations, on the other hand, did not produce any superior responses over single compound alone. In a second study, SAHA was also combined with 5 FU using both pre and post HDACi incubation schedules in a breast cancer cell line .
These authors found no enhanced anti clonogenic activity over single agent alone, and concluded that only reagents that target DNA, such as Topoisomerase inhibitors, are likely Rolipram molecular weight to produce synergy with HDACi. This is based on the Wnding that treatment with HDACi creates hyper acetylated histones leading to the relaxation of DNA around chromatin , allowing increased access to the DNA. It has become clear that this is a simpliWed view since many of the cellular consequences of HDACi treatment are non histone related and does not take into account the eVects of HDAC inhibition on transcription . DiVerences between these previously published studies and the data shown here could be due to a number of factors including diVerences in cell type, scheduling, assay format and the HDACi that was used.
Indeed, it is probable that diVerences in the 5 FU metabolism pathways between breast, hepatoma and colorectal cancer cell lines are a major contributor towards this discrepancy. In summary, synergy Bay 43-9006 price was produced by the combination of PXD101 and 5 FU in vitro, with enhanced antitumour eVects in vivo in multiple models, as predicted. This data provides validation for the use of HDACi and 5 FU combinations in cancer treatment. Based on this solid biological basis, the rationale for combination therapy using PXD101 and 5 FU has been established. A Phase Ib dose escalation proof of concept clinical trial evaluating PXD101 combination therapy with 5 FU for advanced solid tumours and colorectal cancer has been initiated.Clinical trials have shown the high anti myeloma activity of the proteasome inhibitor bortezomib.
The present study examined the activity of bortezomib combined with PXD101, a histone deacetylase inhibitor, against multiple myeloma and osteoclastogenesis. Treatment of myeloma cell lines with combinations of bortezomib and PXD101 led to synergistic inhibition CYP450 inhibitor of proliferation and induction of cell death. The combination significantly decreased the viability of primary human CD138+ myeloma cells but not of bone marrow mononuclear cells. Further studies showed a dose dependent activation of caspases 3, 8 and 9 and nuclear fragmentation in myeloma cells. Bortezomib/PXD101 treatment markedly triggered reactive oxygen species generation that was nausea accompanied by p53, H2A.X and p38 mitogen activated protein kinase phosphorylation. ROS generation could be blocked by the free radical scavenger N acetyl l cysteine. The combination of bortezomib and PXD101 also resulted.