Single‐injection ornithine decarboxylase‐directed antisense therapy using atelocollagen to suppress human cancer growth

• Published in: Cancer Vol. 109; no. 5; pp. 993 - 1002
• Main Authors: Nakazawa, Kunihiko, Nemoto, Takahiro, Hata, Tomoko, Seyama, Yousuke, Nagahara, Shunji, Sano, Akihiko, Itoh, Hiroshi, Nagai, Yutaka, Kubota, Shunichiro
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-03-2007; Wiley-Liss
• Subjects: Animals; antisense oligonucleotides; atelocollagen; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - drug effects; Collagen - administration & dosage; Drug Delivery Systems - methods; growth suppression; human cancer; Humans; Medical sciences; Mice; Mice, Nude; Neoplasms, Experimental - drug therapy; ODC; Oligonucleotides, Antisense - administration & dosage; Ornithine Decarboxylase - genetics; Ornithine Decarboxylase Inhibitors; Tumors; Human; Enzyme; Growth; Single dose; atelocollagen; Lyases; Ornithine decarboxylase; Malignant tumor; Antisense oligonucleotide; ODC; Carbon-carbon lyases; Cancerology; Treatment; growth suppression; human cancer; Carboxy-lyases; antisense oligonucleotides; Cancer
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.22483

BACKGROUND
Substantial evidence supports a direct role of ornithine decarboxylase (ODC) in the development and maintenance of human tumors. Although antisense oligonucleotide therapy targeting various genes are useful for cancer treatment, 1 of the major limitations is the problem of delivery. A novel antisense oligonucleotide delivery method is described that allows prolonged sustainment and release of ODC antisense oligonucleotides in vivo using atelocollagen.
METHODS
The effect of ODC antisense oligonucleotides in the atelocollagen on cell growth of gastrointestinal cancer (MKN 45 and COLO201) and rhabdomyosarcoma (RD) was studied in vitro using a cell‐counting method with a hemocytometer. In vivo, the effect of intratumoral, intramuscular, and intraperitoneal single administration of ODC antisense oligonucleotides in the atelocollagen on tumor growth of MKN45, COLO201, and RD cells was studied. ODC activity and polyamine contents were measured.
RESULTS
In vitro, ODC antisense oligonucleotides in the atelocollagen remarkably suppressed MKN45, COLO201, and RD cell growth. A single administration of antisense oligonucleotides in the atelocollagen via 3 routes remarkably suppressed the growth of MKN45, COLO201, and RD tumor over a period of 35–42 days.
CONCLUSIONS
As various human cancers significantly express ODC, the results strongly suggest that this new antisense method may be of considerable value for treatment of human cancers. Cancer 2007;109:993–1002. © 2007 American Cancer Society.
In vitro, ornithine decarboxylase antisense oligonucleotides in the atelocollagen remarkably suppressed MKN45, COLO201, and RD cell growth. A single administration of antisense oligonucleotides in the atelocollagen via 3 routes remarkably suppressed the growth of MKN45, COLO201, and RD tumor transplanted in nude mice.