Abstract

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.

Links

Publisher Full Text

Authors

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

Institution

Centre for Vascular Research, University of New South Wales, Sydney, New South Wales 2052, Australia.

Source

Science translational medicine 4:139 2012 Jun 20 pg 139ra82

MeSH

Animals
Apoptosis
Cell Line, Tumor
DNA, Catalytic
Dose-Response Relationship, Drug
Humans
Immunity, Cellular
Mice
Proto-Oncogene Proteins c-jun
Skin Neoplasms
Zebrafish

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22723462