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Management of malignant pleural effusion by suicide gene therapy in advanced stage lung cancer: a case series and literature review

Cancer Gene Therapy volume 19, pages 593–600 (2012)Cite this article

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Abstract

Gene therapy can be defined as the transfer of genetic material into a cell for therapeutic purposes. Cytosine deaminase (CD) transferred into tumor cells by an adenoviral vector (Ad.CD), can convert the antifungal drug fluorocytosine (5-FC) to the antimetabolite 5-fluorouracil (5-FU), which kills not only the transfected tumor cells but also their neighbors by the so-called ‘bystander effect’. After testing a protocol for Ad.CD transfer and lung tumor burden control in a Lewis mouse model, we used this technique in the management of lung cancer patients with malignant pleural effusion (MPE): two cases are presented investigating the possible enhancement of anticancer effect in both non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) by local activation of the pro-drug 5-FC. Results were discussed in parallel to a literature review on the topic. 5-FC and Ad.CD were administered intratumorally to Lewis mouse lung carcinoma and the effect was monitored by tumor size and electromicroscopy. Two patients with advanced stage lung cancer (1SCLC, 1NSCLC), which developed MPE during first-line treatment were administered 1012 plaque-forming unit (pfu) Ad.CD by intrapleural instillation, in two doses (day1 and day7). Instillation was performed when the pleural fluid was ⩽200 ml. In addition, they received 5-FC 500 mg four times daily for 14 days. Lung tumor regression and successful transfer of adenoviral particles were observed in treated animals. Patients presented complete regression of pleural effusion as monitored by computerized tomography scan. Neutrapenia and anemia were the most severe adverse effect presented (grade III/grade IV 100%). The increased toxicity followed by the intrapleural gene therapy indicates the augmentation of anticancer effect of transformed pro-drug 5-FC to active 5-FU. The obtained data indicate that intrapleural gene therapy may be a useful tool, adjunct to chemotherapy, in the management of MPE related to lung cancer.

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Acknowledgements

The adenovirus vector was provided by Professor A Deisseroth, Yale University School of Medicine, and cultured in the research laboratory of the Lung Tumor Research Section of the Pulmonary Department Aristotle Univ. Medical School. The animal experiments were carried out in the Theagenion Anticancer Hospital research institute. Electron microscopy was performed by Dr Louisa Oikonomou-Andriopoulou, Professor of Histology & Embryology Department, Aristotle Univ. Medical School.

Author contributions

PZ, EC, TK and KZ wrote the manuscript. KZ, TK and PZ treated the patients. TK performed the statistical analysis. WH, EG, NK, EC and KZ provided useful insights and comments.

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Authors and Affiliations

  1. Pulmonary Department-Oncology Unit, ‘G. Papanikolaou’ General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece

    P Zarogoulidis, T Kontakiotis & K Zarogoulidis

  2. Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece

    E Chatzaki

  3. II Medical Clinic, Hospital Coburg, University of Würzburg, Coburg, Germany

    W Hohenforst-Schmidt

  4. Department of Materials Science & Engineering, Biomaterials Science & Engineering, University of Florida, Gainesville, FL, USA

    E P Goldberg

  5. Theagen Anticancer Institute Research Laboratory, Thessaloniki, Greece

    G Galaktidou

  6. Department of Chemistry, Biochemistry Laboratory, University of Patras, Patras, Greece

    N Karamanos

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Zarogoulidis, P., Chatzaki, E., Hohenforst-Schmidt, W. et al. Management of malignant pleural effusion by suicide gene therapy in advanced stage lung cancer: a case series and literature review. Cancer Gene Ther 19, 593–600 (2012). https://doi.org/10.1038/cgt.2012.36

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