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J Thorac Cardiovasc Surg 2004;128:883-891
© 2004 The American Association for Thoracic Surgery

General Thoracic Surgery

Cisplatin enhances apoptosis induced by a tumor-selective adenovirus expressing tumor necrosis factor–related apoptosis-inducing ligand

^a Section of Thoracic Oncology, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Md, USA
^b Department of Thoracic and Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, Tex, USA

Read at the Eighty-fourth Annual Meeting of the American Association for Thoracic Surgery, Toronto, Ontario, Canada, April 25-28, 2004.

Received for publication April 22, 2004; revisions received June 7, 2004; accepted for publication June 16, 2004.

^* Address for reprints: Dao M. Nguyen, MD, NCI/NIH, Room 2B07, Building 10, 10 Center Dr, Bethesda, MD 20892 (E-mail: Dao_Nguyen{at}nih.gov).

BACKGROUND: Cancer cells frequently exhibit resistance to the cytotoxic effect of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). Pretreatment of TRAIL-resistant cells with cisplatin sensitizes them to this ligand. Cisplatin also has been shown to enhance adenoviral transgene expression.

OBJECTIVE: This study aims to evaluate the ability of cisplatin to enhance the expression and the cytotoxic effect of the tumor-specific adenoviral vector Ad/gTRAIL, which expresses a green fluorescent protein–TRAIL fusion protein.

METHODS: Cultured cancer cells and normal human cells were infected with Ad/gTRAIL with or without cisplatin pretreatment. Adenoviral transgene expression was determined by using flow cytometry to measure green fluorescent protein fluorescence. Cytotoxicity was measured by using thiazolyl blue tetrazolium bromide assays and an apoptosis enzyme-linked immunosorbent assay kit.

RESULTS: Green fluorescent protein–TRAIL fusion protein expression was significantly enhanced by cisplatin pretreatment in cancer cells. Cisplatin treatment before Ad/gTRAIL infection resulted in a 2- to 12-fold increase in green fluorescent protein fluorescence intensity across cancer lines. Although Ad/gTRAIL induced mild cytotoxicity in all cancer lines (inhibitory concentration of 50% values of >500 pfu/cell), pretreatment with cisplatin resulted in a dose-dependent enhancement of Ad/gTRAIL-mediated cytotoxicity, as indicated by the drastic reduction of inhibitory concentration of 50% values to 4 to 42 pfu/cell in all cell lines. There was no cytotoxicity noted in normal cells treated with both cisplatin and Ad/gTRAIL.

CONCLUSION: Cisplatin pretreatment enhances Ad/gTRAIL cytotoxicity in malignant cells while not affecting normal cells. The mechanisms underlying this effect might include both enhancement of the susceptibility of cisplatin-treated cells to TRAIL and cisplatin-mediated enhancement of TRAIL expression in Ad/gTRAIL infected cells. These findings provide a rationale for development of Ad/gTRAIL-based therapy for thoracic malignancies.