Combination of TRAIL Gene Therapy and Chemotherapy Enhances Antitumor and Antimetastasis Effects in Chemosensitive and Chemoresistant Breast Cancers

doi:doi:10.1016/S1525-0016(03)00203-X

Molecular Therapy (2003) 8, 441–448; doi: 10.1016/S1525-0016(03)00203-X

Combination of TRAIL Gene Therapy and Chemotherapy Enhances Antitumor and Antimetastasis Effects in Chemosensitive and Chemoresistant Breast Cancers

Tongyu Lin^1,*, Lidong Zhang¹, John Davis^1,2, Jian Gu¹, Masahiko Nishizaki¹, Lin Ji¹, Jack A. Roth¹, Momiao Xiong³ and Bingliang Fang^1,2

¹Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 USA
²Program in Gene Therapy and Virology, The University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030, USA
³Human Genetics Center, The University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030, USA

Correspondence: Bingliang Fang, Department of Thoracic and Cardiovascular Surgery, Unit 445, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Fax: (713) 794-4669. E-mail: Bfang@mdanderson.org.

^*Present address: Cancer Center, Sun Yat-sen University, Guangzhou 510060, China.

Received 1 April 2003; Accepted 5 June 2003.

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Abstract

We recently found that breast cancer cell lines that are resistant to chemotherapy or to the recombinant TRAIL protein are susceptible to TRAIL gene therapy. However, it is unclear whether a combination of TRAIL gene therapy and chemotherapy will have enhanced antitumor activity or can be used for the treatment of metastasis. In this study, we investigated the combined effect of TRAIL gene therapy and chemotherapeutic agents, including doxorubicin, paclitaxel, vinorelbine, gemcitabine, irinotecan, and floxuridine, in different breast cancer cell lines. In all the cell lines tested, including a breast cancer cell line that is resistant to chemotherapy, the combination of TRAIL gene therapy and cytotoxic agents had either a synergistic or an additive effect. An in vivo study showed that aerosolized administration of an adenovector expressing the GFP–TRAIL fusion protein from the human telomerase reverse transcriptase promoter (designated Ad/gTRAIL) also decreased the number of lung metastases from both doxorubicin-sensitive and doxorubicin-resistant breast cancer cell lines. The combination of TRAIL gene therapy and chemotherapy resulted in a further reduction of lung metastatic nodules with minimal toxicity. These results suggest that a combination of TRAIL gene therapy and chemotherapy is effective in the treatment of metastatic diseases.