Non-anti-coagulant heparin inhibits metastasis but not primary tumor growth.
Experimental and clinical studies indicate that low molecular weight heparins (LMWH) may inhibit cancer and/or metastasis. The purpose of this study was to investigate whether it is possible to design non-anti-coagulant, anti-metastatic compounds based on heparin. The LMWH Tinzaparin and a series of non-anti-coagulant (NAC) heparin derivatives, varying in size from 2,500 to 10,000 Da, were tested for their anti-metastatic activity in an experimental B16F10 metastasis model. The most promising NAC heparin drug candidate and Tinzaparin were further evaluated in B16F10 model with spontaneous metastasis from a primary subcutaneous tumor. In the experimental model, Tinzaparin, NAC2500, and NAC6000 were inactive whereas both NAC8000 and NAC10000 significantly inhibited the number of induced experimental metastases by 69 and 73%, respectively. NAC8000 was chosen over NAC10000 for further studies because of its lower molecular weight with an expected better bioavailability. In the spontaneous model, Tinzaparin had no inhibitory effect on metastatic activity. In contrast, NAC8000 significantly inhibited the number of metastases by 58%. Neither Tinzaparin nor NAC8000 inhibited primary subcutaneous tumor growth. Together, these results indicate that the anti-metastatic effect of heparin derivatives is not a result of anti-coagulant activity. The non-anti-coagulant NAC8000 specifically inhibits early establishment of tumor cells, but not primary tumor growth. Therefore, NAC8000 is a promising non-anti-coagulant compound for preventing tumor metastasis.
Kragh
Michael
M
Department of Pharmacology, LEO Pharma A/S, 55 Industriparken, DK-2750, Ballerup, Denmark.
Binderup
Lise
L
Vig Hjarnaa
Pernille-Julia
PJ
Bramm
Erik
E
Johansen
Kristian B
KB
Frimundt Petersen
Christian
C
D000818:Animals; D000925:Anticoagulants / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002240:Carbohydrate Sequence; D045744:Cell Line, Tumor; D005260:Female; D006495:Heparin, Low-Molecular-Weight / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008546:Melanoma, Experimental / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D015394:Molecular Structure; D009362:Neoplasm Metastasis / Q000473:pathology / Q000517:prevention & control*; D013997:Time Factors; D000078222:Tinzaparin; D016896:Treatment Outcome
D000925:Anticoagulants; D006495:Heparin, Low-Molecular-Weight; D000078222:Tinzaparin