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CpG Immunomer DNA Enhances Antisense Protein Kinase A RI Inhibition of Multidrug-Resistant Colon Carcinoma Growth in Nude Mice: Molecular Basis for Combinatorial Therapy

Authors' Affiliations: ¹ Basic Research Laboratory, Cellular Biochemistry Section and ² Laboratory of Tumor, Immunology and Biology, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Yoon S. Cho-Chung, National Cancer Institute, Building 10, Room 5B05, 9000 Rockville Pike, Bethesda, MD 20892-1750. Phone: 301-496-4020; Fax: 301-480-8587; E-mail: yc12b{at}nih.gov.

Purpose: CpG DNAs induce cytokines, activate natural killer cells, and elicit vigorous T-cell response leading to antitumor effects. Antisense oligodeoxynucleotides targeted against the RI subunit of protein kinase A (antisense PKA RI) induce growth arrest, apoptosis, and differentiation in a variety of cancer cell lines in vitro and in vivo. This study investigated the use of a combinatorial therapy consisting of the RNA-DNA second-generation antisense PKA RI and the CpG immunomer (CpG DNA linked through 3'-3' linkage containing two accessible 5' ends).

Experimental Design: HCT-15 multidrug-resistant colon carcinoma growth in nude mice was used as an experimental model. The inhibitory effect on tumor growth and apoptotic activity of antisense RI and CpG immunomer, singly and in combination, were measured by tumor growth, levels of RI subunit, and antiapoptotic and proapoptotic proteins. Effect on host-immune system was measured by mouse spleen size, interleukin-6 (IL-6) levels in mouse blood, and nuclear factor-B (NF-B) transcription activity in mouse spleen cells.

Results: In combination, CpG immunomer and antisense PKA RI induced additive/supra-additive effect on the inhibition of tumor growth. Antisense RI but not CpG immunomer increased Bax and Bak proapoptotic protein levels and decreased Bcl-2 and RI protein levels in tumor cells. CpG immunomer but not antisense RI induced an enlargement of mouse spleen, increased IL-6 levels in mouse blood, and increased NF-B transcription activity in mouse spleen cells.

Conclusions: These results show that type I PKA down-regulation and induction of apoptosis in tumor cells by antisense PKA RI, and host-immune stimulation by CpG immunomer are responsible at the molecular level for the supra-additive effects of tumor growth inhibition. Thus, antisense PKA RI and CpG immunomer in combination work cooperatively and as tumor-targeted therapeutics to treat human cancer.