Phase I trial of vorinostat and doxorubicin in solid tumours: histone deacetylase 2 expression as a predictive marker.

摘要: Histone deacetylase inhibitors (HDACi) can sensitise cancer cells to topoisomerase by increasing their access and binding DNA. This phase I trial was designed determine the toxicity profile, tolerability, recommended II dose of escalating doses HDACi vorinostat, with weekly doxorubicin. In total, 32 patients were treated; vorinostat dosed at 400, 600, 800, or 1000 mg day−1 on days 1–3, followed doxorubicin (20 mg m−2) day 3 for 4 weeks. Maximal tolerated determined be 800 mg day−1 vorinostat. Dose-limiting toxicities grade nausea/vomiting (two out six) fatigue (one 1000 mg day−1. Non-dose-limiting 3/4 included haematological venous thromboembolism. Antitumor activity in 24 evaluable two partial responses (breast prostate cancer). Two melanoma had stable disease ⩾8 months. hyperacetylation changes peripheral blood mononuclear tumour comparable. seemed correlate pre-treatment HDAC2 expression. These findings suggest that combined this schedule a 800 mg day−1. The expression may marker predictive HDAC inhibition. regimen breast cancer, seems interesting.