Doxorubicin-induced vascular toxicity--targeting potential pathways may reduce procoagulant activity.
BACKGROUND
Previous study in mice using real-time intravital imaging revealed an acute deleterious effect of doxorubicin (DXR) on the gonadal vasculature, as a prototype of an end-organ, manifested by a reduction in blood flow and disintegration of the vessel wall. We hypothesized that this pattern may represent the formation of microthrombi. We aimed to further characterize the effect of DXR on platelets' activity and interaction with endothelial cells (EC) and to examine potential protectants to reduce DXR acute effect on the blood flow.


METHODS
The effect of DXR on platelet adhesion and aggregation were studied in vitro. For in vivo studies, mice were injected with either low molecular weight heparin (LMWH; Enoxaparin) or with eptifibatide (Integrilin(©)) prior to DXR treatment. Testicular arterial blood flow was examined in real-time by pulse wave Doppler ultrasound.


RESULTS
Platelet treatment with DXR did not affect platelet adhesion to a thrombogenic surface but significantly decreased ADP-induced platelet aggregation by up to 40% (p<0.001). However, there was a significant increase in GPIIbIIIa-mediated platelet adhesion to DXR-exposed endothelial cells (EC; 5.7-fold; p<0.001) reflecting the toxic effect of DXR on EC. The testicular arterial blood flow was preserved in mice pre-treated with LMWH or eptifibatide prior to DXR (P<0.01).


CONCLUSIONS
DXR-induced acute vascular toxicity may involve increased platelet-EC adhesion leading to EC-bound microthrombi formation resulting in compromised blood flow. Anti-platelet/anti-coagulant agents are effective in reducing the detrimental effect of DXR on the vasculature and thus may serve as potential protectants to lessen this critical toxicity.
Institute of Oncology, Davidoff Center and Rabin Medical Center, Petah-Tiqva and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Irit
I
Ben Aharon
Hadas
H
Bar Joseph
Moran
M
Tzabari
Boris
B
Shenkman
Nahid
N
Farzam
Mattan
M
Levi
Ruth
R
Shalgi
Salomon M
SM
Stemmer
Naphtali
N
Savion
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D000925:Anticoagulants / Q000494:pharmacology; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001783:Blood Flow Velocity / Q000187:drug effects; D004317:Doxorubicin / Q000633:toxicity*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017984:Enoxaparin / Q000494:pharmacology*; D000077542:Eptifibatide; D007091:Image Processing, Computer-Assisted; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010455:Peptides / Q000494:pharmacology*; D010973:Platelet Adhesiveness / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D018608:Ultrasonography, Doppler
D000903:Antibiotics, Antineoplastic; D000925:Anticoagulants; D017984:Enoxaparin; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D004317:Doxorubicin; D000077542:Eptifibatide