Lentiviruses with trastuzumab bound to their envelopes can target and kill prostate cancer cells.

Abstract

In this study, we took advantage of the overexpression of human epidermal growth factor receptor 2 (HER-2) in prostate cancers to design lentiviruses with modified envelope proteins that bind antibodies to specific cell-surface antigens. When bound to trastuzumab (Herceptin, Genentech, CA), lentiviruses were able to selectively infect androgen-sensitive LNCaP and castration-resistant C4-2 human prostate cancer cell lines, both of which express high levels of HER-2. To test for a therapeutic effect, we engineered our antibody-binding lentiviruses to express thymidine kinase, which can convert the non-toxic pro-drug ganciclovir (GCV) into a cytotoxic form. LNCaP and C4-2 cells infected by these viruses were sensitive to GCV killing. In vivo, C4-2 xenograft tumors treated either intratumorally or i.v. with trastuzumab-bound lentivirus expressed luciferase, although the latter route was less tumor specific. When a prostate-specific promoter for governing luciferase expression was combined with trastuzumab-mediated delivery, there was a further enrichment in targeting viral gene expression in prostate tumors. In conclusion, we found that although prostate cancers that express high levels of HER-2 are resistant to the killing effects of trastuzumab, they can be targeted for selective gene expression and destruction by viruses with envelope proteins engineered to bind this antibody.

• Authors: K-x Zhang, M Moussavi, C Kim, E Chow, I S Chen, L Fazli, W Jia, P S Rennie
• Journal: Cancer gene therapy (Cancer Gene Ther) Vol. 16 Issue 11 Pg. 820-31 (Nov 2009) ISSN: 1476-5500 [Electronic] England
• PMID: 19373278 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• EGFR protein, human
• ERBB2 protein, human
• ErbB Receptors
• Receptor, ErbB-2
• Trastuzumab

Topics

• Animals
• Antibodies, Monoclonal (chemistry, pharmacology, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents (chemistry, pharmacology, therapeutic use)
• Blotting, Western
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• ErbB Receptors (metabolism)
• Genetic Vectors (chemistry, genetics, physiology)
• Humans
• Immunohistochemistry
• Lentivirus (chemistry, genetics, physiology)
• Male
• Mice
• Mice, Nude
• Prostatic Neoplasms (drug therapy)
• Receptor, ErbB-2 (metabolism)
• Trastuzumab
• Xenograft Model Antitumor Assays