Sodium phenylacetate (NaPa) improves the TAM effect on glioblastoma experimental tumors by inducing cell growth arrest and apoptosis.

BACKGROUND: Multiform glioblastomas represent the most aggressive brain tumors. Here, the cooperative effects of sodium phenylacetate (NaPa) and/or tamoxifen (TAM) on CNS1 and 9L glioblastoma cell lines in vitro and in an experimental animal tumor model were investigated. MATERIALS AND METHODS: The drug effects on cell cycle and apoptosis were investigated by flow cytometry. CNS1 cells were implanted subcutaneously in nude mice to form tumors which were then treated with NaPa, TAM or NaPa/TAM. RESULTS: A significant inhibitory effect of NaPa on the two glioma cell lines (LD50 of 10 mM) was observed. 10(-5) M of TAM inhibited approximately 35% of 9L cell growth, and 90% of CNS1 cell growth. When a combination of both drugs included 10(-9) M of TAM, inhibition of about 50% of 9L cell growth and 75% of CNS1 cell growth occurred. The NaPa/TAM combined treatment increased the number of G0/G1 arrested cells and apoptotic cells as compared to treatments with NaPa or TAM alone. Inhibition of CNS1 tumor growth were observed after a two week treatment with NaPa (32 mg/kg/day) or TAM (6 mg/kg/day). CONCLUSION: These results showed a synergistic effect between these two drugs on tumor cell proliferation, caused by cell cycle arrest in the G0/G1 phase and by induction of apoptosis.

"Suicide" gene therapy of breast cancer cells is only cytostatic in vitro but anti-tumoral in vivo on breast MCF7-ras tumor.

Gene therapy with Herpes Simplex Virus thymidine kinase gene (HSV-tk) is effective in various tumor models in vitro and in vivo. We compared the efficacy of the HSV-tk gene therapy in vitro and in vivo in MCF-7 and MCF7-ras cells which form tumor in athymic mice. After viral infection, cells were treated with GCV (Ganciclovir) and live cells were counted. The in vitro treatment significantly inhibited cell growth but did not induce early and late apoptosis, measured, respectively, by annexin or by propidium iodide staining and a significant cell death. The HSV-tk/GCV treatment of MCF7-ras tumor in athymic mice showed a significant inhibition of tumor development until 60 days post-treatment. Some mice showed a complete tumor eradication without tumor regrowth after the end of treatment. In conclusion, we demonstrated that the HSV-tk/GCV system is not very efficient in vitro, but very efficient in vivo in our animal breast cancer model.

Integrated transcriptome analysis of the cellular mechanisms associated with Ha-ras-dependent malignant transformation of the human breast epithelial MCF7 cell line.

To understand the cellular mechanisms of malignant transformation induced by constitutive activation of the ras oncogene (Ha-ras), we used a subtractive hybridization method (VGID) together with an integrative analytical procedure based upon literature databases in the form of extensive interaction graphs. We found 166 over- and under-expressed genes which, in the human MCF7-ras breast epithelial cell line, are involved in the different aspects of tumoral transformation such as defined signaling pathways, cellular growth, protection against apoptosis, extracellular matrix and cytoskeleton remodeling. Integrative analysis led to the construction of a physiological model defining cross-talk and signaling pathway alterations which explicitly suggested mechanisms directly involved in tumor progression. The model further suggested points and means of intervention which could induce cell death in Ha-ras-transformed cells specifically. These hypotheses were directly tested in vitro and found to be largely correct, hence indicating that these new analytical and technological approaches allow the discovery of pathology-associated cellular mechanisms and physiologically defined targets leading to phenotype-specific pharmacological interventions.