Premium
Single agent‐ and combination treatment with two targeted suicide gene therapy systems is effective in chemoresistant small cell lung cancer cells
Author(s) -
Michaelsen Signe R.,
Christensen Camilla L.,
Sehested Maxwell,
Cramer Frederik,
Poulsen Thomas T.,
Patterson Adam V.,
Poulsen Hans S.
Publication year - 2012
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.2630
Subject(s) - suicide gene , lung cancer , medicine , targeted therapy , cancer research , genetic enhancement , cancer , oncology , gene , biology , genetics
Background Transcriptional targeted suicide gene (SG) therapy driven by the insulinoma‐associated 1 (INSM1) promoter makes it possible to target suicide toxin production and cytotoxicity exclusively to small cell lung cancer (SCLC) cells and tumors. It remains to be determined whether acquired chemoresistance, as observed in the majority of SCLC patients, desensitizes SCLC cells to INSM1 promoter‐driven SG therapy. Methods A panel of SCLC cell lines resistant to clinically relevant chemotherapeutics was characterized regarding the expression of proteins involved in response to chemotherapy and regarding INSM1 promoter activity. Sensitivity towards INSM1 promoter‐driven SG therapy was tested using different systems: Yeast cytosine deaminase‐uracil phosphoribosyl transferase (YCD‐YUPRT) in combination with the prodrug 5‐fluorocytosine (5‐FC) or Escherichia coli nitroreductase (NTR) together with the bromomustard prodrug SN27686. Results The chemoresistant cell lines displayed heterogeneous expression profiles of molecules involved in multidrug resistance, apoptosis and survival pathways. Despite this, the INSM1 promoter activity was found to be unchanged or increased in SCLC chemoresistant cells and xenografts compared to chemosensitive variants. INSM1 promoter‐driven SG therapy with YCD‐YUPRT/5‐FC or NTR/SN27686, was found to induce high levels of cytotoxicity in both chemosensitive and chemoresistant SCLC cells. Moreover, the combination of INSM1 promoter‐driven YCD‐YUPRT/5‐FC therapy and chemotherapy, as well as the combination of INSM1 promoter‐driven YCD‐YUPRT/5‐FC and NTR/SN27686 therapy, was observed to be superior to single agent therapy in chemoresistant SCLC cells. Conclusions Collectively, the present study demonstrates that targeted SG therapy is a potent therapeutic approach for chemoresistant SCLC patients, with the highest efficacy achieved when applied as combination SG therapy or in combination with standard chemotherapy. Copyright © 2012 John Wiley & Sons, Ltd.