Development of antisense oligonucleotide therapy for cancer.
| Project/Area Number |
09670531
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Shinshu University |
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Principal Investigator |
AOKI Yuji Shinshu University, The 2nd Department of internal Medicine, Instructor, 医学部・第2内科, 助手 (50240792)
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| Project Period (FY) |
1997 – 1998
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| Project Status |
Completed (Fiscal Year 1998)
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| Budget Amount *help |
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1998: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1997: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Keywords | antisense oligoDNA / c-raf / pancreatic cancer / hepatoma / synthetic carriers / C-raf |
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| Research Abstract |
Such rational approach to suppress target genes as antisense oligodeoxynucleotide (ODN) gene therapy is very attractive, but still has some problems concerning delivery and specificity. In this study, antiproliferative effects of phosphodiester (PO ; nuclease-sensitive) and phosphorothioate (PS ; nuclease-resistant) antisense ODN targeted against c-raf mRNA on pancreatic cancer (HS766T) and hepatoma (SK-HEP) cells in vitro and in vivo were assessed using poly (lysine/serine) copolymers conjugated with polyethylene glycol (PLSP) or cationic lipopolyamines (Transfectam) as carriers.
The antiproliferative effect of the PO antisense ODN was greater than that of the PS DON, either compelxed with PLSP (2 muM ODN) or the Transfectam (0.5 muM ODN). The c-raf mRNA levels assessed by RT-PCR were reduced by both P0 and PS antisense ODN, but the antiproliferative effects were mainly unrelated to antisense mechanisms. SK-HEP cells were inoculated into the peritoneal cavity of nude mice to make a peritoneal dissemination model, and tumor formation on the mesentery, liver hilus and liver were macroscopically assessed, including the occurrence of acites. With the intraperitoneal administration of the ODN/Transfectam complexes (3 mu. g ODN ; twice a week 6 times in total) 3 weeks after the inoculation of SK-HEP cells, the antitumor effects of the respective complexes in vivo were much the same as those seen in the in-vitro experiment. When 6 "mug of ODN was used, multiple skin ulcers were observed on the mice that received the PS antisense complexes. Our study suggests that P0 antisense ODN might be potent as an antitumor agent and used in safe for the antisense ODN therapy for cancer.
Now, I am planning to search for new target genes and to modify carriers in an attempt to improve the specificity for cancer cells or tissue.
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Report
(3 results)
Research Products
(3 results)
