Heparin and
low molecular weight heparin (
LMWH) are widely used for treatment of
cancer patients with
thrombosis, a common complication of malignant disease. Several recent prospective clinical studies indicate that
heparin might improve outcomes of human
cancer. Meanwhile, experimental evidence from mouse models consistently demonstrates that
heparin efficiently inhibits
metastasis. We have previously shown that P- and
L-selectin play independent roles in supporting the initial stages of hematogeneous
metastasis.
Heparin is a known potent inhibitor of such
selectin-mediated interactions. Here we provide evidence that the absence of both P- and
L-selectin (PL -/- mice) dramatically improved survival in an experimental
metastasis model. The use of clinically acceptable amounts of
heparin did not further aff5ct
metastasis rates in such mice. However, a non-
anticoagulant derivative of
heparin with P- and
L-selectin inhibitory properties reduced
metastasis to similar levels as observed in PL -/- mice. The virtual elimination of
metastasis by a single treatment with a modified
heparin without
anticoagulant activity strongly suggests that
heparin primarily reduces metastatic disease by inhibiting P- and
L-selectin interactions. However, such heparins could have further effects at higher doses.