Abstract
PurposeIn advanced gastric cancer, peritoneal dissemination is a life‐threatening mode of metastasis. Since the treatment options with conventional chemotherapy remain limited, any novel therapeutic strategy that could control such metastasis would improve the outcome of treatment. We recently developed a unique RNA interference therapeutic regimen (DFP‐10825) consisting of short hairpin RNA against thymidylate synthase (TS shRNA) and cationic liposomes. The treatment with DFP‐10825 has shown remarkable antitumor activity in peritoneally disseminated human ovarian cancer–bearing mice via intraperitoneal administration. In this study, we expanded DFP‐10825 to the treatment of peritoneally disseminated gastric cancer.MethodsDFP‐10825 was administered intraperitoneally into mice with intraperitoneally implanted human gastric cancer cells (MKN45 or NCI‐N87). Antitumor activity and host survival benefits were monitored. Intraperitoneal distribution of fluorescence‐labeled DFP‐10825 was monitored in this MKN45 peritoneally disseminated mouse model.ResultsIntraperitoneal injection of DFP‐10825 suppressed tumor growth in two peritoneally disseminated cancer models (MKN45 and NCI‐N87) and increased the survival time of the MKN45 model without severe side effects. Throughout the treatment regimen, no significant body weight loss was associated with the administration of DFP‐10825. Interestingly, after intraperitoneal injection, fluorescence‐labeled DFP‐10825 retained for more than 72 hours in the peritoneal cavity and selectively accumulated in disseminated tumors.ConclusionsIntraperitoneal injection of DFP‐10825 demonstrated effective antitumor activity without systemic severe adverse effects via the selective delivery of RNAi molecules into disseminated tumors in the peritoneal cavity. Our current study indicates that DFP‐10825 could become an alternative option to improve the outcomes of patients with peritoneally disseminated gastric cancer.
Highlights
Gastric cancer is the fifth most common cancer around the world and is the third leading cause of cancer‐related death.[1]
We recently developed the DFP‐10825 formulation, which is a unique RNAi molecule consisting of shRNA against thymidylate synthase (TS) and a cationic liposome, which is intended for local administration[11] and systemic injection.[12]
We showed that intraperitoneal injection of DFP‐10825 induced desired tumor growth suppression in two different types of peritoneally disseminated gastric cancer models (MKN45 and NCI‐N87) (Figures 2A,B and 3A) and increased the survival time of a MKN45 peritoneally disseminated gastric cancer model (Figure 1A) without severe side effects (Figures 1B, 2C and 3B)
Summary
Gastric cancer is the fifth most common cancer around the world and is the third leading cause of cancer‐related death.[1]. Several clinical studies have elucidated the advantages of intraperitoneal chemotherapy for gastric peritoneal dissemination.[8,9] no effective treatment has yet improved the survival rates of patients, because intraperitoneal anticancer agents tend to be rapidly removed from the peritoneal cavity via the circulatory system, which prevents the administration of a therapeutic concentration to the peritoneal cavity within a sufficient therapeutic window.[10] a novel therapeutic approach that would control peritoneal dissemination in advanced gastric cancer is required to increase the survival rates of patients. The present study shows that intraperitoneal delivery of DFP‐10825 could be a feasible therapeutic approach to treat peritoneally disseminated gastric cancer
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