Biodistribution and imaging of [99mTc]-HYNIC-RGD in MDA-MB-231 and NTERA-2 cancer cell xenografts.

PURPOSE: Increased expression of αvß3 integrins is involved in tumour angiogenesis. Targeting these receptors with a dedicated peptide containing the RGD sequence may provide information about the receptor status in and around the tumour and about the angiogenesis process involved. The aim of this study was to compare the uptake of [Tc]-HYNIC-RGD in two types of tumours that either express or do not express the αvß3 receptor (NTERA-2 and MDA-MB-231, respectively) and discuss the use of this tracer in experimental models of angiogenesis. PROCEDURES: Uptake of intravenously injected [Tc]-HYNIC-RGD was studied ex vivo and in vivo. Histological analysis of excised tumours was carried out. Percentages of the injected dose uptake per gram of tissue were compared between the two types of tumours and in the periphery and centre of each tumour. RESULTS: [Tc]-HYNIC-RGD was rapidly cleared from blood circulation and excreted through the kidneys. Residual activity was retained in the intestine. Tumour uptake of [Tc]-HYNIC-RGD was high and homogeneous for αvß3-positive cell lines (1.94±0.26%ID/g). Tumour uptake was weak and distributed only in the tumour periphery for αvß3-negative cell lines (0.10±0.02%ID/g, tumour periphery; 0.06±0.01%ID/g, tumour core; P=0.01). These results correlated with vessel distribution. CONCLUSION: Uptake of [Tc]-HYNIC-RGD was more intense in αvß3-positive cell lines than in αvß3-negative cell lines, but tracer distribution was more representative of angiogenic locations in αvß3-negative cell lines. Further clinical and preclinical studies are needed on the use of RGD-related tracers.

CXCR4 membrane expression in node-negative breast cancer.

CXC chemokine receptor 4 (CXCR4) has been reported to be involved in organ-specific homing of breast cancer-derived metastasis. We investigated CXCR4 expression by immunohistochemistry as a possible new prognostic factor for primary breast cancer. Two groups of women treated for breast cancer in 1991 at the Centre for the fight against cancer of Upper Normandy-France (Centre de Lutte contre le Cancer de Haute Normandie) were assessed retrospectively. CXCR4 expression was evaluated using standard immunohistochemistry. Usual prognostic factors were recorded in the computer database. Final date of follow-up was December 31, 2001. Tissues were available for 110 node-positive and 84 node-negative breast cancer patients treated in 1991. CXCR4 membrane staining was considered a strong prognostic factor for both 10-year metastasis-free- (p < 0.0001) and overall survival (p < 0.0001) in node-negative but not in node-positive breast cancer patients. CXCR4 cytoplasmic staining was not considered a significant prognostic factor. Our results suggest that CXCR4 membrane staining could be considered a new prognostic factor. Moreover, targeting CXCR4 in primary breast cancer patients may be a new therapeutic concept. However, these results warrant further investigation.

Efficacy of dendrimer-mediated angiostatin and TIMP-2 gene delivery on inhibition of tumor growth and angiogenesis: in vitro and in vivo studies.

Gene transfer is an attractive approach to fight cancer by targeting cancer cells or their vasculature. Our study reports the inhibition of tumor growth and angiogenesis by a nonviral method using dendrimers associated with 36-mer anionic oligomers (ON36) for delivering angiostatin (Kringle 1-3) and tissue inhibitor of metalloproteinase (TIMP)-2 genes. The optimal concentrations of dendrimers and ON36 for an efficient green fluorescent protein (GFP) plasmid delivery in endothelial cells (HMEC-1) and cancer cells (MDA-MB-435) were first chosen. Then the efficacy of transfection was determined by testing angiostatin and TIMP-2 secretion by Western blot and the biologic effects were evaluated. Angiostatin gene transfer markedly reduced in vitro (i) HMEC-1 but not MDA-MB-435 proliferation; (ii) HMEC-1 and MDA-MB-435 wound healing reparation; and (iii) capillary tube formation. TIMP-2 gene transfer did not affect cell proliferation but strongly inhibited (i) wound healing of HMEC-1 and MDA-MB-435 cells; and (ii) capillary tube formation. Supernatants of transfected-MDA-MB-435 cells also inhibited the formation of angiogenic networks on Matrigel, indicating a paracrine effect. In vivo, intratumoral angiostatin or TIMP-2 gene delivery using dendrimers associated with ON36 effectively inhibited tumor growth by 71% and 84%, respectively. Combined gene transfer resulted in 96% inhibition of tumor growth. Tumor-associated vascularization was also greatly reduced. These findings provide a basis for the further development of nonviral delivery of genes to fight cancer.