PNC-28 is a p53 peptide from its mdm-2-binding domain (residues 17–26), which contains the penetratin sequence enabling cell penetration on its carboxyl terminal end. We have found that this peptide induces necrosis, but not apoptosis, of a variety of human tumor cell lines, including several with homozygous deletion of p53, and a ras-transformed rat acinar pancreatic carcinoma cell line, BMRPA1. Tuc3. On the other hand, PNC-28 has no effect on untransformed cells, such as rat pancreatic acinar cells, BMRPA1, and human breast epithelial cells and no effect on the differentiation of human stem cells. In this study, we now test PNC-28 in vivo for its ability to block the growth of BMRPA1. Tuc3 cells. When administered over a 2-week period in the peritoneal cavities of nude mice containing simultaneously transplanted tumors, PNC-28 causes complete destruction of these tumors. When delivered concurrently with tumor explantation at a remote site, PNC-28 causes a complete blockade of any tumor growth during its 2-week period of administration and 2 weeks posttreatment, followed by weak tumor growth that plateaus at low tumor sizes compared with tumor growth in the presence of a control peptide. When administered after tumor growth has occurred at a site remote from the tumor, PNC-28 causes a decrease in tumor size followed by a slow increase in tumor growth that is significantly slower than growth in the presence of control peptide. These results suggest that PNC-28 may be effective in treating cancers especially if delivered directly to the tumor. © 2006 Wiley-Liss, Inc.