Scriptaid effects on breast cancer cell lines.

In breast cancer tumor expression of estrogen receptors (ERs) is important as a marker of prognosis and mostly as a predictor of response to endocrine therapy. In fact, the loss of α-ER expression leads to unresponsiveness to anti-hormone treatment. In a significant fraction of breast cancers, this loss of expression is a result of epigenetic mechanisms, such as DNA methylation and histone deacetylation, within the α-ER promoter. Previous studies have shown that pharmacologic inhibition of these mechanisms using the DNA methyltransferase inhibitor, 5-aza-2-deoxycytidine (AZA), and the histone deacetylase (HDAC) inhibitor, Trichostatin A (TSA), results in expression of functional α-ER mRNA and protein. Moreover, the activity of a novel HDAC inhibitor, Scriptaid, has been shown to induce inhibition of tumor growth in breast cancer and to cause re-expression of functional α-ER in α-ER negative breast cancer cells. We sought to better characterize the effects of Scriptaid on cell growth, apoptosis, and α-ER expression in α-ER-positive (MCF-7), α-ER-negative (MDA-MB-231), and α-ER-negative/Her-2 over-expressing (SKBr-3) human breast cancer cell lines. In all of these cell lines Scriptaid treatment resulted in significant growth inhibition and apoptosis, and RT-PCR confirmed an increase of α-ER mRNA transcript in MDA-MB-231 after 48 h of Scriptaid treatment. Furthermore, following treatment with Scriptaid, the formerly unresponsive MDA-MB-231 and SKBr-3 breast cancer cells became responsive to tamoxifen. These results show that the HDAC inhibitor Scriptaid is able to sensitize tamoxifen hormone-resistant breast cancer cells, and that Scriptaid or related HDAC inhibitors are candidates for further study in breast cancer.

Epigenome: a new target in cancer therapy.

Until short time ago we considered cancer as the result of genetic mutations, but recent studies have shown that genetic mutations are not the only responsible for tumorigenesis. Although the genome contains all the information needed to encode the entire set of proteins, the expression of this information is regulated by the epigenome. Hypermethylation is one of the best known epigenetic events in mammalian cells. Over the last few years, many studies have found that other epigenetic events, such as deacetylation and methylation of histones, are involved in the complex mechanism that regulates promoter transcription. Hypermethylation or histone de-acetylation within the promoter of a tumor suppressor gene led to the silencing of that gene, as well as a deletion or a mutation. Pre-neoplastic lesions often show aberrant methylation and the frequency of aberrations increases with the progression of disease. Hypermethylation events can occur early in tumorigenesis, involving the disruption of pathways that may predispose cells to malignant transformation. The exact interplay of these factors in transcriptional repression activity is not yet well understood. Inhibitors of some of these are currently being studied as new drugs able to restore protein expression in cancer cells and to promote apoptosis and differentiation. Demethylating agents and histone deacetylase inhibitors are candidates for becoming potent new drugs in cancer therapy. This paper reviews current knowledge about epigenetic factors in the development of cancer and their role as new targets in anticancer therapy.

High activity of salvage treatment with biweekly paclitaxel-gemcitabine combination in heavily pretreated breast cancer patients.

The treatment of refractory metastatic breast cancer is primarily palliative, without a significant impact on overall survival. Among the innovative combinations in this unfavourable setting, paclitaxel and gemcitabine showed a possible synergistic action and an encouraging activity in some clinical trials. This phase II study was carried out to evaluate paclitaxel-gemcitabine combination in very heavily pretreated advanced breast cancer on a bi-weekly schedule.Thirty-nine women with advanced breast cancer were treated with paclitaxel 150 mg/m2 as 3 hrs infusion, and gemcitabine 1,500 mg/m2 as 30 mins infusion, both drugs administered on days 1, 15, with cycles repeated every 28 days. All but two patients received granulocyte colony stimulating factor (G-CSF) on days 7 to 9 and 20 to 22 of every cycle. More than two third (71%) of the patients had previously received two or more chemotherapy regimens for advanced disease, including almost all active agents in this disease. Objective responses were observed in 18 out of 34 evaluable patients (53%; 95% CI, 36% to 70%). Disease remained stable in 7 patients (21%). Responses by sites were 67% in soft tissue and in bone, and 48% in visceral disease. Median time to progression and overall survival were 9 and 20 months, respectively. Treatment was well tolerated, with G3-4 neutropenia in 8%, and G 1-2 thrombocytopenia in 13% of the patients; non-hematological toxicities were mild, with G3 hepatotoxicity in 5% of the patients, and G3 peripheral neurotoxicity in 10% of the patients. Biweekly paclitaxel/gemcitabine combination with G-CSF support appears to be very active as salvage therapy in heavily pretreated breast cancer patients, with a very favourable safety profile.