Cisplatin, Gemcitabine, and Vorinostat (combination)

The combination of cisplatin, gemcitabine, and vorinostat is an investigational treatment regimen that has been studied primarily in clinical trials for various types of cancer, particularly non-small cell lung cancer (NSCLC) and refractory lymphomas. ## Mechanism of Action This combination therapy leverages multiple mechanisms to target cancer cells: - **Gemcitabine** is a nucleoside analog that works by blocking DNA synthesis in cancer cells, specifically at the G1/S-phase boundary[4]. It has demonstrated cytotoxic effects against a broad range of cancer cell lines. - **Cisplatin** is a platinum-based chemotherapeutic agent that causes DNA damage in cancer cells. - **Vorinostat** (also known as SAHA) is a histone deacetylase (HDAC) inhibitor that affects epigenetic regulation. It has been shown to potentiate the cytotoxicity of radiation and chemotherapeutic agents by inhibiting tumor repair of DNA double-strand breaks[5]. Vorinostat can reduce the expression of homologous recombinant repair proteins including BRCA2, BRCA1, PARP1, and RAD51[9]. The synergistic effect of this combination appears to work through several mechanisms: 1. Vorinostat enhances the antitumor activity of cisplatin by inhibiting DNA damage repair pathways[3][9]. 2. Vorinostat decreases key enzymes involved in glutathione (GSH) biosynthesis (GSS and GCLC) and GSTP1, which normally catalyzes the binding of GSH to cisplatin[9]. 3. The combination increases cytotoxic effects by increasing DNA damage[9]. ## Clinical Development This combination has been investigated in several clinical trials: - A Phase I study evaluated vorinostat in combination with gemcitabine and cisplatin in patients with advanced NSCLC. The trial suggested that vorinostat can be administered with standard doses of gemcitabine and cisplatin, and the combination showed activity in the initial treatment of metastatic NSCLC[6]. - Another study examined vorinostat combined with high-dose gemcitabine, busulfan, and melphalan with autologous stem cell transplantation in patients with refractory lymphomas[1]. - A dose-escalation study investigated vorinostat in combination with thoracic radiotherapy in NSCLC patients, with the option to continue vorinostat as a single agent or in combination with carboplatin and paclitaxel after radiation[5]. ## Dosing Information From the clinical trials, various dosing regimens have been explored: - Vorinostat: Doses ranging from 200 mg/day to 1000 mg/day[1][6] - Gemcitabine: 1000-1250 mg/m² administered on specific days of the treatment cycle[6] - Cisplatin: 75 mg/m² administered on specific days[6] The maximum tolerated dose (MTD) and optimal dosing schedule continue to be studied in clinical trials. ## Safety Profile Common toxicities associated with this combination include: - Mucositis - Dermatitis - Elevated creatinine levels - Febrile neutropenia No treatment-related deaths were reported in the studies reviewed[1][6]. This combination therapy remains investigational, and randomized trials are needed to determine whether the addition of vorinostat improves outcomes in cancer patients.

Other names

SAHA