Effect of MCM09, an active site-directed inhibitor of factor Xa, on B16-BL6 melanoma lung colonies in mice.
BACKGROUND
Treatment with anticoagulant drugs has shown potential inhibitory effect on tumor invasion, although the relationship with clotting inhibition was not clear.


OBJECTIVE
The aim of our study was to evaluate the potential antitumor activity of MCM09, a newly developed, active site-directed, small molecule inhibitor of factor Xa (FXa) [WO0216312], and to relate the findings to anticlotting potency.


METHODS
MCM09 (0.1-10 mg kg(-1)) or heparin (H; 10 mg kg(-1)) was injected intravenously (i.v.), with 5 x 10(4) B16-BL6 melanoma cells, in C57BL/6 mice. Mice were killed after 18 days, to count lung colonies. Ex vivo anticoagulant activity was measured by activated partial thromboplastin time (APTT) on mouse plasma.


CONCLUSIONS
MCM09, a selective inhibitor of FXa (IC-50 = 2.4 nm against human FXa), inhibited in a dose-dependent manner B16-BL6 melanoma lung colonies in mice. Mean lung metastasis number was 20.9 +/- 4.8 in controls (n = 10), 1.2 +/- 0.4 in mice treated with H, 10 mg kg(-1) i.v. (P < 0.01), 0.9 +/- 0.3, 9.2 +/- 2.2 and 15.5 +/- 2.6 in mice treated with MCM09, at 10 (P < 0.01), 1 (P < 0.05) and 0.1 mg kg(-1) i.v. (ns), respectively. MCM09 (10 mg kg(-1) i.v.) significantly prolonged APTT (57.1 +/- 10.2 s) 30 min after i.v. injection when compared with controls (25.3 +/- 1.6 s; P < 0.05). Lung colonies were 74.2-72.6% reduced by MCM09 (10 mg kg(-1)) given 60 or 120 min before cells, but not by MCM09 given 60 min thereafter, suggesting a direct cell interaction as a mechanism underlying antitumor activity.
Rossi
C
C
Consorzio Mario Negri Sud, Santa Maria Imbaro (CH), Italy.
Hess
S
S
Eckl
R W
RW
di Lena
A
A
Bruno
A
A
Thomas
O
O
Poggi
A
A
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D065427:Factor Xa Inhibitors; D005260:Female; D006493:Heparin / Q000494:pharmacology; D008175:Lung Neoplasms / Q000473:pathology / Q000517:prevention & control* / Q000556:secondary; D008546:Melanoma, Experimental / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D010314:Partial Thromboplastin Time; D010879:Piperazines / Q000494:pharmacology*; D011714:Pyrans / Q000494:pharmacology*; D013997:Time Factors
D000925:Anticoagulants; D000970:Antineoplastic Agents; D065427:Factor Xa Inhibitors; D010879:Piperazines; D011714:Pyrans; C510349:WO0216312; D006493:Heparin