On the Selectivity and E/cacy of Defense PeptidesWith Respect to Cancer Cells Frederick Harris, 1 Sarah R. Dennison, 2 Jaipaul Singh, 1,2 and David A. Phoenix 3 1 School of Forensic and Investigative Sciences, University of Central Lancashire, Preston, Lancashire, United Kingdom 2 School of Pharmacy and Biomedical Science, University of Central Lancashire, Preston, Lancashire, United Kingdom 3 University of Central Lancashire, Preston, Lancashire, United Kingdom Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/med.20252 . Abstract: Here, we review potential determinants of the anticancer efficacy of innate immune peptides (ACPs) for cancer cells. These determinants include membrane-based factors, such as receptors, phosphatidylserine, sialic acid residues, and sulfated glycans, and peptide-based factors, such as residue composition, sequence length, net charge, hydrophobic arc size, hydrophobicity, and amphiphilicity. Each of these factors may contribute to the anticancer action of ACPs, but no single factor(s) makes an overriding contribution to their overall selectivity and toxicity. Differences between the anticancer actions of ACPs seem to relate to different levels of interplay between these peptide and membrane- based factors. & 2011 Wiley Periodicals, Inc. Med Res Rev 1. INTRODUCTION Globally, cancer is now the third leading cause of death, and it has been projected that within 20 years there will be circa 26 million new cancer cases and 17 million cancer deaths on an annual basis. 1 The disease is initiated by a series of cumulative genetic and epigenetic changes that occur in normal cells and is characterized by a number of specific behaviors. Cancer cells provide their own growth signals, ignore growth inhibitory signals, avoid cell death, replicate without limit, sustain angiogenesis, and invade tissues through basement membranes and capillary walls. In addition, the immune system fails to eliminate cancer cells due to the immunosuppressive effects mediated by tumor cells and tumor infiltrating host cells. 2–5 It has been predicted that preventive measures, coordinated on a global scale, provide the only feasible approach to slow and ultimately reverse the world-wide increase in cancer; but, at the moment, cancer management is the only available therapeutic option. 1 Currently, the stra- tegies of choice for cancer management focus on the conventional cytotoxic treatments: radiation therapy (RT), which is relatively precise and used to achieve local control of Correspondence to: David A. Phoenix, University of Central Lancashire, Preston PR1 2HE, UK, E-mail: daphoenix@uclan.ac.uk Medicinal Research Reviews & 2011 Wiley Periodicals, Inc.