A non-RGD-based integrin binding peptide (ATN-161) blocks breast cancer growth and metastasis in vivo.
OBJECTIVE
Integrins are expressed by numerous tumor types including breast cancer, in which they play a crucial role in tumor growth and metastasis. In this study, we evaluated the ability of ATN-161 (Ac-PHSCN-NH2), a 5-mer capped peptide derived from the synergy region of fibronectin that binds to alpha5beta1 and alphavbeta3 in vitro, to block breast cancer growth and metastasis.


METHODS
MDA-MB-231 human breast cancer cells were inoculated s.c. in the right flank, or cells transfected with green fluorescent protein (MDA-MB-231-GFP) were inoculated into the left ventricle of female BALB/c nu/nu mice, resulting in the development of skeletal metastasis. Animals were treated with vehicle alone or by i.v. infusion with ATN-161 (0.05-1 mg/kg thrice a week) for 10 weeks. Tumor volume was determined at weekly intervals and tumor metastasis was evaluated by X-ray, microcomputed tomography, and histology. Tumors were harvested for histologic evaluation.


RESULTS
Treatment with ATN-161 caused a significant dose-dependent decrease in tumor volume and either completely blocked or caused a marked decrease in the incidence and number of skeletal as well as soft tissue metastases. This was confirmed histologically as well as radiographically using X-ray and microcomputed tomography. Treatment with ATN-161 resulted in a significant decrease in the expression of phosphorylated mitogen-activated protein kinase, microvessel density, and cell proliferation in tumors grown in vivo.


CONCLUSIONS
These studies show that ATN-161 can block breast cancer growth and metastasis, and provides a rationale for the clinical development of ATN-161 for the treatment of breast cancer.
Khalili
Parisa
P
Department of Medicine and Oncology, McGill University Health Center, Room H4.61, 687 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1.
Arakelian
Ani
A
Chen
Gaoping
G
Plunkett
Marian L
ML
Beck
Ivy
I
Parry
Graham C
GC
Doñate
Fernando
F
Shaw
David E
DE
Mazar
Andrew P
AP
Rabbani
Shafaat A
SA
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D001859:Bone Neoplasms / Q000517:prevention & control* / Q000556:secondary*; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009842:Oligopeptides / Q000494:pharmacology*; D011859:Radiography / Q000295:instrumentation; D012983:Soft Tissue Neoplasms / Q000517:prevention & control / Q000556:secondary; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D009842:Oligopeptides; D049452:Green Fluorescent Proteins; C404392:acetyl-prolyl-histidyl-seryl-cysteinyl-asparaginamide