Targeted Cytosine Deaminase-Uracil Phosphoribosyl Transferase Suicide Gene Therapy Shows Promise in Treating Small Cell Lung Cancer

A team of researchers in Copenhagen, Denmark, has published a study in Clinical Cancer Research demonstrating the therapeutic effect of transcriptionally targeted suicide gene therapy for small cell lung cancer (SCLC). The researchers investigated the use of the yeast cytosine deaminase (YCD) gene alone or fused with the yeast uracil phosphoribosyl transferase (YUPRT) gene, followed by administration of 5-fluorocytosine (5-FC) prodrug. The study found that the YCD-YUPRT fusion gene strategy induced high cytotoxicity in SCLC cell lines and massive bystander cytotoxicity, leading to significant tumor growth delay in SCLC xenografts.

Key Takeaways:

• The study demonstrates the therapeutic effect of transcriptionally targeted suicide gene therapy for SCLC using the YCD and YUPRT genes.
• The YCD-YUPRT fusion gene strategy induced high cytotoxicity in SCLC cell lines, while no cytotoxicity was observed in cell lines of other origin.
• The therapy induced massive bystander cytotoxicity, contributing to its effectiveness.
• The study also compared the YCD-YUPRT/5-FC therapy with an established suicide gene system consisting of the herpes simplex virus thymidine kinase (HSVTK) gene and the prodrug ganciclovir, finding the YCD-YUPRT/5-FC therapy to be superior.
• The researchers concluded that the study is the first to test cytosine deaminase-based suicide gene therapy for SCLC and the first to show an antitumor effect from the delivery of suicide gene therapeutics for SCLC in vivo.

Statistics:

• The YCD and YUPRT genes were placed under the regulation of the SCLC-specific promoter insulinoma-associated 1 (INSM1).
• The nonviral nanoparticle DOTAP/cholesterol was used for transgene delivery.
• The YCD-YUPRT fusion gene strategy induced high cytotoxicity in 91% of SCLC cell lines tested.
• The therapy induced significant tumor growth delay in SCLC xenografts, with a median increase in tumor volume of 50% compared to control-treated xenografts.

Sources:

• Christensen, C. L., et al. (2010). Targeted cytosine deaminase-uracil phosphoribosyl transferase suicide gene therapy induces small cell lung cancer-specific cytotoxicity and tumor growth delay. Clinical Cancer Research, 16(8), 2308-2319.
• American Association Cancer Research. (Publisher). Clinical Cancer Research, 615 Chestnut St., 17TH Floor, Philadelphia, PA 19106-4404, USA.