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Research Articles: Therapeutics

Chemotherapy and chemosensitization of non–small cell lung cancer with a novel immunomodulatory oligonucleotide targeting Toll-like receptor 9

¹ Department of Pharmacology and Toxicology, Division of Clinical Pharmacology, ² Comprehensive Cancer Center, and ³ Gene Therapy Center, University of Alabama at Birmingham, Birmingham, Alabama and ⁴ Idera Pharmaceuticals, Inc., Cambridge, Massachusetts

Requests for reprints: Ruiwen Zhang, Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Volker Hall Room 113, 1670 University Boulevard, Birmingham, AL 35294-0019. Phone: 205-934-8558; Fax: 205-975-9330. E-mail: ruiwen.zhang{at}ccc.uab.edu

Lung cancer is a leading cause of death world-wide and the long-term survival rate for lung cancer patients is one of the lowest for any cancer. New therapies are urgently needed. The present study was designed to evaluate an immunomodulatory oligonucleotide as a novel type of therapy for lung cancer. The in vivo effects of the immunomodulatory oligonucleotides were determined in four tumor models derived from human non–small cell lung cancer (NSCLC) cell lines (A549, H1299, H358, and H520), administered alone or in combination with conventional chemotherapeutic agents used to treat lung cancer. The in vitro effects of the immunomodulatory oligonucleotide on the growth, apoptosis, and proliferation of NSCLC cells were also determined. We also examined NSCLC cells for expression of Toll-like receptor 9 (TLR9), the receptor for the immunomodulatory oligonucleotide. We showed several important findings: (a) treatment with the immunomodulatory oligonucleotide led to potent antitumor effects, inhibiting tumor growth by at least 60% in all four in vivo models; (b) combination with the immunomodulatory oligonucleotide led to enhanced effects following treatment with gemcitabine or Alimta; (c) the immunomodulatory oligonucleotide increased apoptosis, decreased proliferation, and decreased survival in A549 cells in vitro; and (d) both TLR9 mRNA and protein were expressed in NSCLC cells. The immunomodulatory oligonucleotide has potent antitumor effects as monotherapy and in combination with conventional chemotherapeutic agents, and may act directly on NSCLC cells via TLR9. The present study provides a rationale for developing the immunomodulatory oligonucleotide for lung cancer therapy. [Mol Cancer Ther 2006;5(6):1585–92]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 2/20/06; revised 3/15/06; accepted 4/13/06.

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