DNAzyme targeting c-jun suppresses skin cancer growth.
Worldwide, one in three cancers is skin-related, with increasing incidence in many populations. Here, we demonstrate the capacity of a DNAzyme-targeting c-jun mRNA, Dz13, to inhibit growth of two common skin cancer types-basal cell and squamous cell carcinomas-in a therapeutic setting with established tumors. Dz13 inhibited tumor growth in both immunodeficient and immunocompetent syngeneic mice and reduced lung nodule formation in a model of metastasis. In addition, Dz13 suppressed neovascularization in tumor-bearing mice and zebrafish and increased apoptosis of tumor cells. Dz13 inhibition of tumor growth, which required an intact catalytic domain, was due in part to the induction of tumor immunity. In a series of good laboratory practice-compliant toxicology studies in cynomolgus monkeys, minipigs, and rodents, the DNAzyme was found to be safe and well tolerated. It also did not interfere in more than 70 physiologically relevant in vitro bioassays, suggesting a reduced propensity for off-target effects. If these findings hold true in clinical trials, Dz13 may provide a safe, effective therapy for human skin cancer.
Cai H, Santiago FS, Prado-Lourenco L, Wang B, Patrikakis M, Davenport MP, Maghzal GJ, Stocker R, Parish CR, Chong BH, Lieschke GJ, Wong TW, Chesterman CN, Francis DJ, Moloney FJ, Barnetson RS, Halliday GM, Khachigian LM
Centre for Vascular Research, University of New South Wales, Sydney, New South Wales 2052, Australia.
SourceScience translational medicine 4:139 2012 Jun 20 pg 139ra82
Cell Line, Tumor
Dose-Response Relationship, Drug
Proto-Oncogene Proteins c-jun
Pub Type(s)Journal Article
Research Support, Non-U.S. Gov't