05. Results Synergistic effect of paclitaxel and ABT 737 on HB cells ABT 737 en

Fur thermore, hypoxia is not the only limiting factor of proliferation in a small tumor, but other limiting factors, such as the physical JNJ-7706621 solubility space, distribution of nutrients and drugs, metabolism and removal of waste products, may also be utilized as therapeutic targets. These and other factors could also be evaluated in a similar screen study. Treatment results of children suffering from hepatoblas toma have been improved impressively during recent years. Current treatment strategies include neoadjuvant chemotherapy regimens and surgery in standard risk HB, achieving a 3 year overall survival probability of 96%. However, the outcome of patients with high risk HB and relapsed HB is still poor. To improve outcome, therapy has been intensified using second line cystostatic drugs in the standard treat ment protocol for high risk HB.

Paclitaxel is mainly used in treatment regimes for ovarian, breast and non small cell lung cancer. It has also been applied in pae diatric patients with refractory malignancies and has been proposed as potential agent against high risk HB. Paclitaxel LDN193189 分子量 stabilizes microtubules and as a result, interferes with the normal breakdown of microtubules during cell division. This mitotic inhibitor promotes apoptosis as a secondary effect. Apoptosis is an important factor in anticancer treat ment and targeting this cell death mechanism has been constituted a promising alternative treatment option. HB cells express high amounts of anti apoptotic mole cules encoded by genes of the Bcl family.

Bcl 2, an important member of this family, blocks cytochrome 価格 LY2228820 C release by sequestering pro apoptotic BH3 only pro teins such as tBid, Bad, Bax, and Bim. Bcl 2 overexpres sion plays a central role in resistance to chemotherapy in multiple malignancies including HB. Small BH3 mimetic molecules facilitate the activation of pro apop totic Bcl proteins by binding to the hydrophobic groove in Bcl 2 and Bcl XL thus sensitizing tumour cells for apoptosis. One of these molecules, ABT 737, was developed as an anti tumour agent, induces apoptosis by selectively inhibiting the anti apoptotic proteins Bcl 2, Bcl XL, and Bcl W. ABT 737 as a single agent has shown activity against several hematopoietic cell lines and some solid tumour cell lines, whereas efficiency was high in small cell lung carcinoma only.

Because ABT 737 does not block Mcl 1, it is anticipated that this drug will be most effective as a single agent against tumours that express low levels of these pro survival protein. Thus, ABT 737 may be active also in HB tumours, as gene expression analysis revealed a 2 fold lower expression of Mcl 1 in native HB tissue than in normal liver tissue. Highly synergistic in vivo effects have been described when combining ABT 737 with established chemotherapeutic drugs. In HB cells ABT 737 also induces apoptosis and enhances the effect of cytotoxic drugs, CDDP, paclitaxel and etoposide commonly used in treat ment protocols of HB. In this study we describe the effects of ABT 737 in combination with paclitaxel in HB xenografts. Methods Drugs ABT 737 and its enantiomer were kindly provided by Abbott. For in vitro studies ABT 737 and its enantiomer were dissolved in DMSO at 1 mM and diluted with medium to a final concentration in the cell culture of 0. 01, 0. 1, 0.