Further studies are needed to evaluate ID4s role in BRCA1 transcrip tional activity and as a potential marker of BRCA1 expression. Both in vitro and in vivo studies have demonstrated cytotoxic efficacy of single agent HDAC inhibitors in OC and breast cancer cell models. In our study, increasing doses of the HDAC inhibitor M344 down regulated AGI-6780? BRCA1 protein expression in all cell lines examined except for the highest dose in MCF7 breast cancer cells. This could be due to a negative feed back loop involving the BRCA1 and HDAC1 proteins complexing with CtBP on the BRCA1 promoter to inhibit its transcription. A significant alteration in HDAC1 function and BRCA1 protein levels by the HDAC inhibitor M344 could allevi ate the repression and cause an upregulation of BRCA1 transcription and subsequent protein expression.

Since there is limited data in breast and ovarian cancer, stu dies conducted in other tumor cell models suggest the combination of HDAC inhibitors and DNA targeted agents is a rational therapeutic approach in the treat ment of OC. In the human oral squamous cell carci noma cell line, HSC 3, SAHA enhanced cisplatin induced apoptosis. The study by Chen et al. demonstrated a histone deacetylation independent mechanism whereby HDAC inhibitors sensitized pros tate cancer cell lines to DNA damaging chemotherapeu tic drugs, bleomycin, doxorubicin and etoposide. In their study, pretreatment of prostate cancer cells with HDAC inhibitors led to increased acetylation of Ku70 and impaired Ku70 function in repairing DNA double strand breaks resulting in enhance cell killing via a DNA repair mediated mechanism.

The HDAC inhibitor, PCI 24781, after treatment of Hodgkin and non Hodg kin lymphoma cells with a PARP inhibitor, resulted in a synergistic increase in apoptosis and a decrease in RAD51 expression. Recent clinical trials have evaluated HDAC inhibitors in solid tumors, both as a single agent and in combination with chemotherapy. A phase II study con ducted by the Gynecologic Oncology Group, examined oral vorinostat in the treatment of persistent or recur rent epithelial ovarian or primary peritoneal carcinoma in patients who were platinum resistant refractory. In the twenty seven women enrolled, the incidence of signifi cant toxicity was low, but only two had a progression free interval over 6 months. A better response was seen in a phase II study combining valproic acid, the demethylating agent hydralazine, and chemotherapy in various resistant solid tumors including breast and ovarian cancer. Twelve of fifteen patients overcame resistance to chemotherapy and showed either Anacetrapib partial response or stable disease, although some hematologic toxicity was observed.