ABSTRACT
PURPOSE: The αvß3 integrin plays an important role in tumour-induced angiogenesis, tumour proliferation, survival and metastasis. The tetrameric RGD-based peptide, regioselectively addressable functionalized template-(cyclo-[RGDfK])4 (RAFT-RGD), specifically targets the αvß3 integrin in vitro and in vivo. The aim of this study was to evaluate the therapeutic potential of RAFT-RGD radiolabelled with ß(-) emitters in a nude mouse model of αvß3 integrin-expressing tumours. METHODS: Biodistribution and SPECT/CT imaging studies were performed after injection of (90)Y-RAFT-RGD or (177)Lu-RAFT-RGD in nude mice subcutaneously xenografted with αvß3 integrin-expressing U-87 MG cells. Experimental targeted radionuclide therapy with (90)Y-RAFT-RGD or (177)Lu-RAFT-RGD and (90)Y-RAFT-RAD or (177)Lu-RAFT-RAD (nonspecific controls) was evaluated by intravenous injection of the radionuclides into mice bearing αvß3 integrin-expressing U-87 MG tumours of different sizes (small or large) or bearing TS/A-pc tumours that do not express αvß3. Tumour volume doubling time was used to evaluate the efficacy of each treatment. RESULTS: Injection of 37 MBq of (90)Y-RAFT-RGD into mice with large αvß3-positive tumours or 37 MBq of (177)Lu-RAFT-RGD into mice with small αvß3-positive tumours caused significant growth delays compared to mice treated with 37 MBq of (90)Y-RAFT-RAD or 37 MBq of (177)Lu-RAFT-RAD or untreated mice. In contrast, injection of 30 MBq of (90)Y-RAFT-RGD had no effect on the growth of αvß3-negative tumours. CONCLUSION: (90)Y-RAFT-RGD and (177)Lu-RAFT-RGD are potent agents targeting αvß3-expressing tumours for internal targeted radiotherapy.
Subject(s)
Integrin alphaVbeta3/metabolism , Lutetium/therapeutic use , Peptides, Cyclic , Radiopharmaceuticals/therapeutic use , Yttrium Radioisotopes/therapeutic use , Animals , Cell Line, Tumor , Humans , Integrin alphaVbeta3/genetics , Lutetium/adverse effects , Lutetium/pharmacokinetics , Mice , Mice, Nude , Neoplasms, Experimental/genetics , Neoplasms, Experimental/radiotherapy , Peptides, Cyclic/adverse effects , Peptides, Cyclic/pharmacokinetics , Radiopharmaceuticals/adverse effects , Radiopharmaceuticals/pharmacokinetics , Tissue Distribution , Xenograft Model Antitumor Assays , Yttrium Radioisotopes/adverse effects , Yttrium Radioisotopes/pharmacokineticsABSTRACT
Fifteen per cent of metastatic breast cancer will develop symptomatic leptomeningeal metastases. The introduction of trastuzumab (Herceptin) therapy has improved the response rates of survival of patients with metastatic breast cancer overexpressing HER2. Although previous studies are retrospective and of limited number, involving small study groups and different types of patient management, several authors have reported a 30% incidence of leptomeningeal metastases in patients with metastatic breast cancer overexpressing HER2 who were treated with trastuzumab, while 70 to 80% of cases of the disease were controlled systemically. In order to improve control of the disease at the level of the central nervous system (CNS), routine detection of leptomeningeal metastases in high-risk patients could be offered. CA 15-3 in cerebrospinal fluid (CSF) detection might be useful in helping to diagnose CNS metastases, particularly where cytology results are negative--which applies to 30% of cases--because tumor markers are more sensitive in detecting the tumor process. Our study validate CA 15-3 measurement in CSF and reference values were given.
