Mechanisms of heparin induced anti-cancer activity in experimental cancer models.
BACKGROUND
Retrospective analyses of clinical trials and prospective clinical studies have suggested that heparins may have an effect on cancer survival. This putative anti-cancer activity of heparins is supported by data from studies in animal tumour models.


OBJECTIVE
To clarify the various potential mechanisms of heparin anti-cancer activity we evaluated the data from pre-clinical studies in which heparins have been tested as anti-cancer therapy.


METHODS
Pre-clinical studies, published between 1960 and 2005 were assessed. Data were collected on the type and dose of heparin used, duration of exposure to heparin, interval between heparin administration and cancer cell inoculation, and the animal tumour model used. In addition, a distinction was made in the analysis between heparin effects on the primary tumour or on established metastases and effects on the metastatic potential of infused cells.


RESULTS
Heparins seemed to affect the formation of metastasis rather than the growth of primary tumours. Chemically modified heparins with no or limited anticoagulant activity also showed anti-metastatic properties. Possible mechanisms to explain the effects on the process of metastases include inhibition of blood coagulation, inhibition of cancer cell-platelet and -endothelial interactions by selectin inhibition and inhibition of cell invasion and angiogenesis.


CONCLUSIONS
The anti-cancer activity of heparins depends more on inhibition of metastasis formation than on the effects on primary tumour growth. These effects are probably related to both coagulation and non-coagulation dependent factors. For a definitive proof of the anti-cancer activity of heparins in the clinic, prospective randomized trials especially in patients with early metastatic disease or in the adjuvant setting are urgently needed.
Niers
T M H
TM
Department of Medical Oncology, Academic Medical Centre, University of Amsterdam F4-223, Meibergdreef 9, 1100 DE Amsterdam, The Netherlands.
Klerk
C P W
CP
DiNisio
M
M
Van Noorden
C J F
CJ
Büller
H R
HR
Reitsma
P H
PH
Richel
D J
DJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005966:Glucuronidase / Q000187:drug effects; D019812:Heparan Sulfate Proteoglycans / Q000037:antagonists & inhibitors; D006493:Heparin / Q000494:pharmacology*; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019087:Selectins / Q000187:drug effects; D000099175:Heparanase
D000970:Antineoplastic Agents; D005966:Glucuronidase; D019812:Heparan Sulfate Proteoglycans; D006493:Heparin; D019087:Selectins; D000099175:Heparanase