Combinations of PARP, hedgehog and HDAC inhibitors with standard drugs.

Objective methods for data analysis for the assessment of additivity, synergy, and antagonism that can be applied rigorously to cell-based and in vivo preclinical data have been defined. The Combination Index method has been most widely applied. This brief report discusses poly(ADP-ribose) polymerase (PARP) inhibitors, hedgehog inhibitors, and histone deacetylase inhibitors as examples of experimental agents used in combinations where additivity and synergy have been assessed. PARP, hedgehog, and HDAC inhibitors have demonstrated single agent activity in a limited spectrum of malignancies. Expanded application of these compounds may come from combination regimens. Several PARP inhibitors appear to be additive to synergistic with standard agents in cell culture; however, no determinations for additivity/synergy have been applied with these compounds in vivo. Hedgehog inhibitors have demonstrated interesting activity in some preclinical models and have been studied in vivo with gemcitabine. However, no analyses for additivity were conducted in these studies. Numerous studies have demonstrated additivity/synergy with several HDAC inhibitors and standard anticancer drugs in cell culture. Clinical trials with combination regimens are on-going with compounds from each of these classes based primarily upon limited cell culture data. Thus, there is still a distance to go in making optimal use of preclinical models to aid in the selection of combination regimens worthy of clinical trial.