IngentaConnect Exploiting Epigenetics to Eliminate Cancer: Histone Deacetylase I...

Abstract:

Merck & Co.'s filing for US FDA approval of Zolinza™ (vorinostat) in June 2006 was the first regulatory submission for a histone deacetylase (HDAC) inhibitor, an exciting new class of drugs for cancer therapy. Like the recently validated DNA methyltransferase inhibitors, HDAC inhibitors target epigenetic processes exploited by cancer cells. Histone deacetylation, the enzymatic removal of acetyl groups from histone proteins associated with genomic DNA, is a key epigenetic mechanism by which cancer cells inactivate important tumor-suppressor genes, facilitating uncontrolled proliferation. HDAC inhibitors are designed to restore normal histone acetylation to tumor cells, reducing their malignant potential. Experimental studies have shown that these drugs have a range of anticancer effects, including reactivation of tumor-suppressor genes, inhibition of angiogenesis and cell proliferation, and induction of programmed cell death (apoptosis).The two leading HDAC inhibitors vorinostat and Gloucester Pharma's romidepsin (depsipeptide) are targeted initially for therapy of cutaneous T-cell lymphoma (CTCL), a rare type of non-Hodgkin's lymphoma. Vorinostat has the advantage of being orally administered whereas romidepsin is injected intravenously. In addition, occasional cardiac abnormalities associated with romidepsin therapy are of some concern. Whereas vorinostat and romidepsin are broad-spectrum HDAC inhibitors, other compounds in development are designed to be more selective in order to avoid potential adverse effects. It is not yet known which strategy is superior. Although the CTCL market is small, vorinostat, romidepsin and many other HDAC inhibitors are undergoing early clinical development for a range of hematological cancers and solid tumors. Consequently, the commercial potential of HDAC inhibitors is massive in oncology alone; furthermore, their use may not necessarily be restricted to cancer.

The full text article is available for purchase

$54.95 plus tax

Exploiting Epigenetics to Eliminate Cancer: Histone Deacetylase Inhibitors Head Towards the Clinic