A novel intraperitoneal therapy for gastric cancer with DFP‐10825, a unique RNAi therapeutic targeting thymidylate synthase, in a peritoneally disseminated xenograft model
Abstract Purpose In 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 rece...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2019-12-01
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| Series: | Cancer Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cam4.2598 |
| _version_ | 1818540191067930624 |
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| author | Hidenori Ando Masakazu Fukushima Kiyoshi Eshima Taichi Hasui Taro Shimizu Yu Ishima Cheng‐Long Huang Hiromi Wada Tatsuhiro Ishida |
| author_facet | Hidenori Ando Masakazu Fukushima Kiyoshi Eshima Taichi Hasui Taro Shimizu Yu Ishima Cheng‐Long Huang Hiromi Wada Tatsuhiro Ishida |
| author_sort | Hidenori Ando |
| collection | DOAJ |
| description | Abstract Purpose In 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. Methods DFP‐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. Results Intraperitoneal 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. Conclusions Intraperitoneal 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. |
| first_indexed | 2024-12-11T21:52:04Z |
| format | Article |
| id | doaj.art-7e21acc244e143cf96839206a75c9769 |
| institution | Directory Open Access Journal |
| issn | 2045-7634 |
| language | English |
| last_indexed | 2024-12-11T21:52:04Z |
| publishDate | 2019-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj.art-7e21acc244e143cf96839206a75c97692022-12-22T00:49:25ZengWileyCancer Medicine2045-76342019-12-018177313732110.1002/cam4.2598A novel intraperitoneal therapy for gastric cancer with DFP‐10825, a unique RNAi therapeutic targeting thymidylate synthase, in a peritoneally disseminated xenograft modelHidenori Ando0Masakazu Fukushima1Kiyoshi Eshima2Taichi Hasui3Taro Shimizu4Yu Ishima5Cheng‐Long Huang6Hiromi Wada7Tatsuhiro Ishida8Department of Pharmacokinetics and Biopharmaceutics Institute of Biomedical Sciences Tokushima University Tokushima JapanDepartment of Cancer Metabolism and Therapy Institute of Biomedical Sciences Tokushima University Tokushima JapanDelta‐Fly Pharma Inc Tokushima JapanDepartment of Pharmacokinetics and Biopharmaceutics Institute of Biomedical Sciences Tokushima University Tokushima JapanDepartment of Pharmacokinetics and Biopharmaceutics Institute of Biomedical Sciences Tokushima University Tokushima JapanDepartment of Pharmacokinetics and Biopharmaceutics Institute of Biomedical Sciences Tokushima University Tokushima JapanDepartment of Thoracic Surgery Faculty of Medicine Kyoto University Kyoto JapanDepartment of Thoracic Surgery Faculty of Medicine Kyoto University Kyoto JapanDepartment of Pharmacokinetics and Biopharmaceutics Institute of Biomedical Sciences Tokushima University Tokushima JapanAbstract Purpose In 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. Methods DFP‐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. Results Intraperitoneal 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. Conclusions Intraperitoneal 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.https://doi.org/10.1002/cam4.2598DFP‐10825gastric cancerperitoneal disseminationRNAi therapeuticS‐1thymidylate synthase (TS) |
| spellingShingle | Hidenori Ando Masakazu Fukushima Kiyoshi Eshima Taichi Hasui Taro Shimizu Yu Ishima Cheng‐Long Huang Hiromi Wada Tatsuhiro Ishida A novel intraperitoneal therapy for gastric cancer with DFP‐10825, a unique RNAi therapeutic targeting thymidylate synthase, in a peritoneally disseminated xenograft model Cancer Medicine DFP‐10825 gastric cancer peritoneal dissemination RNAi therapeutic S‐1 thymidylate synthase (TS) |
| title | A novel intraperitoneal therapy for gastric cancer with DFP‐10825, a unique RNAi therapeutic targeting thymidylate synthase, in a peritoneally disseminated xenograft model |
| title_full | A novel intraperitoneal therapy for gastric cancer with DFP‐10825, a unique RNAi therapeutic targeting thymidylate synthase, in a peritoneally disseminated xenograft model |
| title_fullStr | A novel intraperitoneal therapy for gastric cancer with DFP‐10825, a unique RNAi therapeutic targeting thymidylate synthase, in a peritoneally disseminated xenograft model |
| title_full_unstemmed | A novel intraperitoneal therapy for gastric cancer with DFP‐10825, a unique RNAi therapeutic targeting thymidylate synthase, in a peritoneally disseminated xenograft model |
| title_short | A novel intraperitoneal therapy for gastric cancer with DFP‐10825, a unique RNAi therapeutic targeting thymidylate synthase, in a peritoneally disseminated xenograft model |
| title_sort | novel intraperitoneal therapy for gastric cancer with dfp 10825 a unique rnai therapeutic targeting thymidylate synthase in a peritoneally disseminated xenograft model |
| topic | DFP‐10825 gastric cancer peritoneal dissemination RNAi therapeutic S‐1 thymidylate synthase (TS) |
| url | https://doi.org/10.1002/cam4.2598 |
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