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J Thorac Cardiovasc Surg 2002;123:1191-1198
© 2002 The American Association for Thoracic Surgery

General Thoracic Surgery (GTS)

Antisense therapy for malignant mesothelioma with oligonucleotides targeting the bcl-xl gene product

From the Department of Thoracic and Cardiovascular Surgery, Section of Thoracic Molecular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Tex.

W.R.S. is the recipient of the University of Texas M.D. Anderson Physician-Scientist Award and Grant, and the work was also supported in part by the W.M. Keck Center for Cancer Gene Therapy.

Read at the Eighty-first Annual Meeting of The American Association for Thoracic Surgery, San Diego, Calif, May 6-9, 2001.

Received for publication May 14, 2001. Revisions requested July 9, 2001; revisions received Sept 28, 2001. Accepted for publication Oct 2, 2001. Address for reprints: W. Roy Smythe, MD, Department of Thoracic and Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 445, Houston, TX 77030 (E-mail: rsmythe{at}mdanderson.org).

Objective: Malignant pleural mesothelioma is resistant to conventional therapies and to apoptosis. The bcl-2 family genes are major determinants of apoptotic homeostasis. Malignant pleural mesothelioma lines and tumors rarely express the antiapoptotic Bcl-2 protein but routinely express the antiapoptotic protein Bcl-xl and the proapoptotic proteins Bax and Bak. We have previously shown pharmacologic inhibition of bcl-xl expression in malignant pleural mesothelioma can lead to apoptosis, so we sought to determine whether antisense oligonucleotides directed at bcl-xl messenger RNA would engender apoptosis, possibly through a "forced imbalance" of bcl-2 family proteins.
Methods: Malignant pleural mesothelioma lines REN (epithelial) and I-45 (sarcomatous) were exposed to modified bcl-xl antissense oligonecleotides directed near the messenger RNA initiation sequence with and without a liposomal delivery system. Untreated cells and bcl-xl sense oligonucleotides were controls. Cell viability was measured by colorimetric assay, and apoptosis was evaluated with Hoechst staining and sub-G₁ fluorescence-activated cell sorter analysis.
Results: Bcl-xl protein expression after antisense oligonucleotides was downwardly regulated in both cell lines relative to sense oligonucleotides (>65%). Significant cellular killing in both the I-45 and REN cell lines was achieved with antisense oligonucleotides (compared with sense oligonucleotides) without (P = .003 and .006, respectively) and with (P = .006 and .0005, respectively) liposomal delivery. Hoechst staining and sub-G₁ fluorescence-activated cell sorter analysis demonstrated apoptosis to be the mechanism of cellular death. Use of a liposomal delivery system increased therapeutic effect and allowed lower doses of antisense oligonucleotides.
Conclusion: Antisense oligonucleotides directed at the bcl-xl gene product engender apoptosis in esothelioma cell lines. The therapeutic potential of inhibiting expression of this protein in mesothelioma should be evaluated.

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