Inhibition of experimental lung metastases of Lewis lung carcinoma cells by chemically modified heparin with reduced anticoagulant activity.
Heparin, a widely used anticoagulant, is known to have anti-metastatic activity, although the mechanism is not fully understood. In the present study, we investigated the mechanism of this anti-metastatic activity using periodate-oxidized and borohydride-reduced heparin with low anticoagulant activity (LAC heparin). The anticoagulant activity of LAC heparin is markedly reduced to almost the control level in terms of prothrombin time in vitro, and no hemorrhagic complication was observed with injection of LAC heparin into mice in vivo. LAC heparin injected intravenously with Lewis lung carcinoma cells or 10 min before tumor cell injection significantly inhibited, to the same extent as intact heparin and in a dose- and time-dependent manner, the lung colonization that develops after intravenous injection (i.v.) of tumor cells. Flow cytometric analysis revealed that Lewis lung carcinoma cells strongly express heparan sulfate on their surface. Both the LAC heparin and intact heparin inhibited the adhesion and invasion of tumor cells to Matrigel-coated dishes in vitro without significant effect on the tumor cell growth. LAC heparin also significantly diminished tumor cell retention in the lung after i.v. of LacZ gene-tagged Lewis lung carcinoma cells. These results suggest that LAC heparin may prevent tumor cells from attachment to the subendothelial matrix of lung capillaries by competitively inhibiting cell surface heparan sulfate functions and suppress lung colonization.
Yoshitomi
Yasuo
Y
Department of Biotechnology, Faculty of Engineering, Kyoto Sangyo University, Motoyama Kamigamo, Kita-ku, Kyoto 603-8555, Japan.
Nakanishi
Hayao
H
Kusano
Yuri
Y
Munesue
Seiichi
S
Oguri
Kayoko
K
Tatematsu
Masae
M
Yamashina
Ikuo
I
Okayama
Minoru
M
D000818:Animals; D000925:Anticoagulants / Q000737:chemistry* / Q000627:therapeutic use*; D001894:Borohydrides / Q000494:pharmacology; D018827:Carcinoma, Lewis Lung / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006493:Heparin / Q000737:chemistry* / Q000627:therapeutic use*; D006497:Heparan Sulfate / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D010504:Periodic Acid / Q000494:pharmacology; D015996:Survival Rate; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000925:Anticoagulants; D001894:Borohydrides; D006493:Heparin; D006497:Heparan Sulfate; D010504:Periodic Acid; C025364:sodium borohydride; C009288:metaperiodate