cis-3, 4', 5-Trimethoxy-3'-aminostilbene disrupts tumor vascular perfusion without damaging normal organ perfusion.
OBJECTIVE
Targeting tumor vasculature by colchicine site microtubule inhibitors is a new approach in cancer therapy. Here we investigate cis-3, 4', 5-trimethoxy-3'-aminostilbene (stilbene 5c) in its effect on tumor vascular perfusion, pharmacokinetics, toxicity and therapeutic efficacy in a mouse xenograft model.


METHODS
Tumor xenograft model was established with subcutaneous injection of UCI-101 ovarian cancer cells into nude mice. Tumor blood perfusion was investigated by dynamic contrast-enhanced (DCE) MRI studies. Pharmacokinetic studies were performed by LC/MS/MS to quantify the concentrations of stilbene 5c in plasma. Tumor size was measured by the long and short axes of tumor to calculate tumor volume. Mouse cardiac function study was determined by Doppler echocardiography using the Vevo770TM imaging system. Microvascular density was determined by CD34 staining of tissue sections.


RESULTS
Stilbene 5c selectively suppresses tumor perfusion without damaging normal organ perfusion in DCE-MRI studies. Histological sections of normal organs treated with stilbene 5c do not reveal any major toxicity in H&E staining. Microvascular density determined by CD34 staining is unchanged in normal organs, but significantly decreased in tumor after stilbene 5c treatment. Biodistribution study shows that stilbene 5c is not detectable in heart and lung, rapidly decreased in brain, liver, and kidney, but remains high in tumor for more than 3 h after IV injection of stilbene 5c, suggesting preferential accumulation in tumor. Mice treated with 5 days of stilbene 5c had negligible cardiac toxicity based on their normal left ventricular ejection fraction. In vivo efficacy study of stilbene 5c showed that it only suppresses tumor growth by 40% if used alone, but combination with bevacizumab is significantly better.


CONCLUSIONS
Stilbene 5c is a useful vascular disrupting agent and combination with bevacizumab could be a promising therapy for cancer.
Durrant
David
D
Department of Internal Medicine, Massey Cancer Center, Virginia Commonwealth University, 1101 E. Marshall Street, Richmond, VA 23298, USA.
Corwin
Frank
F
Simoni
Daniele
D
Zhao
Ming
M
Rudek
Michelle A
MA
Salloum
Fadi N
FN
Kukreja
Rakesh C
RC
Fatouros
Panos P
PP
Lee
Ray M
RM
D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy; D009928:Organ Specificity; D012039:Regional Blood Flow / Q000187:drug effects; D013267:Stilbenes / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D014018:Tissue Distribution; D018608:Ultrasonography, Doppler; D014471:Umbilical Veins / Q000166:cytology; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D018952:Antigens, CD34; D013267:Stilbenes; C529077:cis-3,4',5-trimethoxy-3'-aminostilbene