5'-,3'-inverted thymidine-modified antisense oligodeoxynucleotide targeting midkine. Its design and application for cancer therapy.
Oligodeoxynucleotides modified at both 5'- and 3'-ends with inverted thymidine (5'-,3'-inverted T) were introduced as new reagents for antisense strategies. These modifications were performed to make the oligodeoxynucleotides resistant to nucleases. The effectiveness of these oligodeoxynucleotides was evaluated in terms of inhibition of synthesis of midkine (MK), a heparin-binding growth factor, and consequent inhibition of growth of CMT-93 mouse rectal carcinoma cells. 5'-,3'-Inverted T antisense MK suppressed synthesis of MK by CMT-93 cells and their growth in culture. Furthermore, 5'-,3'-inverted T oligodeoxynucleotides exhibited less cytotoxicity and better stability than phosphorothioate oligodeoxynucleotides. When 5'-,3'-inverted T antisense MK was mixed with atelocollagen, and injected into CMT-93 tumors pregrown in nude mice, tumor growth was markedly suppressed as compared with tumors injected with sense controls. The suppressive effect of 5'-,3'-inverted T antisense MK on tumor growth was stronger than that of phosphorothioate antisense MK. These findings indicated the usefulness of inverted thymidine-modified antisense oligodeoxynucleotides as a new reagent instead of phosphorothioate-modified oligodeoxynucleotides.
Takei
Yoshifumi
Y
Department of Biochemistry, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Kadomatsu
Kenji
K
Itoh
Hiroshi
H
Sato
Waichi
W
Nakazawa
Kunihiko
K
Kubota
Shunichiro
S
Muramatsu
Takashi
T
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D016207:Cytokines; D015195:Drug Design; D004355:Drug Stability; D008297:Male; D051379:Mice; D000078792:Midkine; D009374:Neoplasms, Experimental / Q000188:drug therapy; D020319:Oligodeoxyribonucleotides, Antisense / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D016207:Cytokines; D020319:Oligodeoxyribonucleotides, Antisense; D000078792:Midkine