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.