Morpholino antisense oligomer targeting human midkine: Its application for cancer therapy

• Published in: International journal of cancer Vol. 114; no. 3; pp. 490 - 497
• Main Authors: Takei, Yoshifumi, Kadomatsu, Kenji, Yuasa, Kanako, Sato, Waichi, Muramatsu, Takashi
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 10.04.2005; Wiley-Liss
• Subjects: Animals; atelocollagen; Biological and medical sciences; Cell Proliferation; Colonic Neoplasms - pathology; Cytokines - biosynthesis; Cytokines - metabolism; Down-Regulation; heparin‐binding growth factor; Humans; Male; Medical sciences; Mice; Mice, Nude; midkine; molecular target; Morpholines; Neoplasms - genetics; Neoplasms - therapy; Nerve Growth Factors; Oligonucleotides, Antisense - pharmacology; Oligonucleotides, Antisense - therapeutic use; Other treatments; Prostatic Neoplasms - pathology; stability; toxicity; Transfection; Transplantation, Heterologous; Treatment. General aspects; Tumors; Antineoplastic agent; toxicity; Prostate carcinoma; Prostate disease; Targeting; atelocollagen; Cancerology; Established cell line; Intestinal disease; Male genital diseases; Midkine; stability; Human; Urinary system disease; Rodentia; Malignant tumor; Antisense oligonucleotide; heparin-binding growth factor; molecular target; Colonic disease; Vertebrata; Mammalia; Treatment; Mouse; Animal; Digestive diseases; Gene therapy; Colon carcinoma; Growth factor
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.20781

Overexpression of a heparin‐binding growth factor, midkine (MK), has been observed in many malignancies, making it an attractive therapeutic target. We used morpholino antisense oligomers to downregulate human MK expression in human prostate (PC‐3) and colon carcinoma (SW620) cells, and determined the practical advantages of this anticancer therapeutic. Morpholino antisense oligomers directed against MK caused a dramatic and sequence‐specific decrease of the target protein level, resulting in the inhibition of growth and anchorage‐independent growth of the transfected cells. Furthermore, MK morpholino antisense oligomers exhibited a significant anticancer effect in the PC‐3‐ and SW620‐xenograft models. In comparison with phosphorothioate‐modified oligodeoxynucleotide, morpholino oligomers showed 2 major advantages, stability and non‐toxicity. MALDI‐TOF mass spectrometric analysis showed that morpholino antisense oligomers were completely stable in the presence of serum nuclease(s). Serological examinations demonstrated no toxicity of MK morpholino antisense oligomers. Our study indicates that inhibition of MK expression by morpholino antisense oligomer is a promising novel and safe therapeutic strategy for cancers. © 2004 Wiley‐Liss, Inc.