Intratumoral injection of oligonucleotides to the NF kappa B binding site inhibits cachexia in a mouse tumor model

Cancer cachexia, characterized by anorexia, weight loss and progressive tis sue wasting, has been postulated to be mediated by Various cytokines. Howev er, the precise mechanism of cachexia induction is not fully explained. We have developed synthetic double-stranded oligodeoxynucleotides (ODN) as 'de coy' cis-elements that block the binding of nuclear factors to promoter reg ions of targeted genes, resulting in the inhibition of gene transactivation in vivo as well as in vitro. This novel molecular strategy could be useful for treating a broad range of human diseases including cancer. In this stu dy, we injected decoy ODN targeting the transcriptional factor NF-kappaB (N F kappa B) binding cis-elements, which are essential for transactivation of gene expression of cytokines, directly into tumors of adenocarcinoma colon 26 in mice, in order to examine whether or not cachexia is alleviated by in hibiting the action of cytokines. Tumor growth was not affected by transfec tion of NF kappa B decoy ODN as compared with scrambled decoy ODN. Neverthe less, transfection of NF kappa B decoy, but not scrambled decoy, ODN result ed in attenuation of the reductions in body weight, epididymal fat, gastroc nemius muscle mass and food intake, which were induced by the tumor presenc e. Interleukin 6 mRNA in the tumor was also markedly decreased by the trans fection of NF kappa B decoy ODN. It is known that the transcriptional facto r E2F plays a pivotal role in the coordinated transactivation of cell cycle regulatory genes. Therefore, we hypothesized that the introduction of synt hetic double-stranded DNA with high affinity for E2F in vivo as 'decoy' cis -elements might inhibit the tumor growth of colon26, resulting in turn in i nhibition of cachexia induction. However, injection of E2F decoy ODN failed to inhibit tumor growth and cachexia induction, as compared with mismatche d decoy ODN. Overall, the present study demonstrated that cachexia induced by adenocarcinoma colon26 was inhibited by blocking of NF kappa B, using a navel molecular decoy strategy, without an effect on tumor growth, and also that tumor growth and cachexia induction in the colon26 model were not aff ected by E2F decoy ODN. These results suggest that cytokines regulated by N F kappa B may play a pivotal role in the induction of cachexia by colon26, providing a new therapeutic strategy for cancer cachexia.