Potential Application of Small Interfering RNA in Gastro-Intestinal Tumors

Abstract

Despite the progress made in the diagnoses and therapy of gastrointestinal cancers, these diseases are still plagued by a high mortality. Thus, novel therapeutic approaches are urgently required. In this regard, small interfering RNA (siRNA), double-stranded RNA molecules able to specifically target the mRNA of pathological genes, have the potential to be of therapeutic value. To be effective in the human body, siRNAs need to be protected against degradation. Additionally, they need to target the tumor, leaving the normal tissue untouched in an effort to preserve organ function. To accomplish these tasks, siRNAs have been formulated with smart delivery systems such has polymers and lipids. While siRNA protection is not particularly difficult to achieve, their targeting of tumor cells remains problematic. Here, after introducing the general features of gastrointestinal cancers, we describe siRNA characteristics together with representative delivery systems developed for gastrointestinal cancers. Afterward, we present a selection of research papers employing siRNAs against upper- and lower- gastrointestinal cancers. For the liver, we also consider papers using siRNAs to combat liver cirrhosis, a relevant risk factor for liver cancer development. Finally, we present a brief description of clinical trials employing siRNAs for gastrointestinal cancers.

Keywords: delivery systems; gastro-intestinal cancer; liver fibrosis; siRNAs.

Figure 1

The siRNA mechanism of action. The antisense strand of the siRNA is up-taken by a catalytic protein complex (RNA-induced silencing complex, RISC). The antisense strand drives RISC to a target mRNA, which results in specific, RISC-mediated mRNA degradation.

Figure 2

The obstacles to siRNA delivery. Systemically-released siRNAs encounter blood nucleases, which can induce siRNA rapid degradation together with the clearance by phagocytes. Extravasation, cell membrane crossing and endosomal escape are the other barriers to be overcome by siRNAs.

Figure 3

siRNA molecular targets for siRNAs. The mRNAs considered as targets for the siRNA described in the text have been listed close to the respective organ.