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 SCLC cells and tumors. It remains, however, to be investigated if acquired chemo-resistance, 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 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 E.coli nitroreductase (NTR) together with the bromomustard prodrug SN27686.
RESULTS: The chemo-resistant cell lines displayed heterogeneous expression profiles of molecules involved in multi-drug resistance (MDR), apoptosis and survival pathways. Despite this, the INSM1 promoter activity was found to be unchanged or increased in SCLC chemo-resistant cells and xenografts compared to chemo-sensitive variants. INSM1 promoter-driven SG therapy with YCD-YUPRT/5-FC or NTR/SN27686, was found to induce high levels of cytotoxicity in both chemo-sensitive and -resistant SCLC cells. Moreover, the combination of INSM1 promoter-driven YCD-YUPRT/5-FC therapy and chemotherapy and the combination of INSM1 promoter-driven YCD-YUPRT/5-FC and NTR/SN27686 therapy were observed to be superior to single agent therapy in chemo-resistant SCLC cells.
CONCLUSIONS: Collectively, this study demonstrates that targeted SG therapy is a potent therapeutic approach for chemo-resistant SCLC patients with highest efficacy achieved when applied as combination SG therapy or in combination with standard chemotherapy. Copyright © 2012 John Wiley & Sons, Ltd.
Authors: Michaelsen SR, Christensen CL, Sehested M, Cramer F, Poulsen TT, Patterson AV, Poulsen HS
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