Treatment with modified heparins inhibits experimental metastasis formation and leads, in some animals, to long-term survival.
Two chemically modified heparins with low anticoagulant activity were studied in terms of their antimetastatic activity in the B16-BL6 melanoma model. The two heparins were a very low molecular weight heparin (VLMW-H) and a low molecular weight heparin with 100% succinylation of desulfated N groups (Succ100-LMW-H). Both heparins, VLMW-H more so than Succ100-LMW-H, were highly effective in decreasing the number of lung metastasis on day 21 when administered once subcutaneously 10 min before intravenous injection of melanoma cells or 2 times/week for 3 weeks. When the time of survival was measured, both heparins did not significantly prolong survival when administered once before injection of the tumor cells. When a repeated treatment schedule was adopted over 3 weeks, both heparins led to a slight, yet significant prolongation of survival. When the repeated treatment protocol was continued beyond 3 weeks, a highly significant prolongation of survival was observed with VLMW-H and there were some long-term survivors (20% for VLMW-H and 10% for Succ-LMW-H) that remained disease-free after discontinuation of therapy on day 90. The present results confirm and reinforce the concept that heparins with reduced anticoagulant activity may have interesting therapeutic applications in the prevention of tumor metastasis.
Sciumbata
T
T
Italfarmaco S.p.A., Centro Ricerche, Cinisello Balsamo, Milano, Italia.
Caretto
P
P
Pirovano
P
P
Pozzi
P
P
Cremonesi
P
P
Galimberti
G
G
Leoni
F
F
Marcucci
F
F
D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use*; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects / Q000502:physiology; D005260:Female; D006493:Heparin / Q000031:analogs & derivatives / Q000627:therapeutic use*; D006495:Heparin, Low-Molecular-Weight / Q000031:analogs & derivatives / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000401:mortality; D015996:Survival Rate; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects
D000925:Anticoagulants; D006495:Heparin, Low-Molecular-Weight; D006493:Heparin