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Effective treatment of chemoresistant breast cancer in vitro and in vivo by a factor VII-targeted photodynamic therapy.

Duanmu J, Cheng J, Xu J, Booth CJ, Hu Z - Br. J. Cancer (2011)

Bottom Line: The efficacy of fVII-tPDT was tested in vitro and in vivo and was compared with non-targeted PDT for treatment of chemoresistant breast cancer.Moreover, fVII-tPDT was effective and safe for the treatment of chemoresistant breast tumours in the nude mouse model.We conclude that fVII-tPDT is effective and safe for the treatment of chemoresistant breast cancer, presumably by simultaneously targeting both the tumour neovasculature and chemoresistant cancer cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06520, USA.

ABSTRACT

Background: The purpose of this study was to test a novel, dual tumour vascular endothelial cell (VEC)- and tumour cell-targeting factor VII-targeted Sn(IV) chlorin e6 photodynamic therapy (fVII-tPDT) by targeting a receptor tissue factor (TF) as an alternative treatment for chemoresistant breast cancer using a multidrug resistant (MDR) breast cancer line MCF-7/MDR.

Methods: The TF expression by the MCF-7/MDR breast cancer cells and tumour VECs in MCF-7/MDR tumours from mice was determined separately by flow cytometry and immunohistochemistry using anti-human or anti-murine TF antibodies. The efficacy of fVII-tPDT was tested in vitro and in vivo and was compared with non-targeted PDT for treatment of chemoresistant breast cancer. The in vitro efficacy was determined by a non-clonogenic assay using crystal violet staining for monolayers, and apoptosis and necrosis were assayed to elucidate the underlying mechanisms. The in vivo efficacy of fVII-tPDT was determined in a nude mouse model of subcutaneous MCF-7/MDR tumour xenograft by measuring tumour volume.

Results: To our knowledge, this is the first presentation showing that TF was expressed on tumour VECs in chemoresistant breast tumours from mice. The in vitro efficacy of fVII-tPDT was 12-fold stronger than that of ntPDT for MCF-7/MDR cancer cells, and the mechanism of action involved induction of apoptosis and necrosis. Moreover, fVII-tPDT was effective and safe for the treatment of chemoresistant breast tumours in the nude mouse model.

Conclusions: We conclude that fVII-tPDT is effective and safe for the treatment of chemoresistant breast cancer, presumably by simultaneously targeting both the tumour neovasculature and chemoresistant cancer cells. Thus, this dual-targeting fVII-tPDT could also have therapeutic potential for the treatment of other chemoresistant cancers.

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Factor VII (fVII) targeting enhances the effect of SnCe6 PDT, and fVII-tPDT is effective in eradicating MCF-7/MDR cancer cells. (A and B) The EC50 of SnCe6 was 2.8 and 35.8 μ in fVII-tPDT and ntPDT (18 J cm–2, laser fluence) for MCF-7/MDR cells, respectively. (C) MCF-7/MDR cells had a laser fluence-dependent response to fVII-tPDT (2 μ SnCe6) but had no response to ntPDT (2 μ SnCe6).
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fig2: Factor VII (fVII) targeting enhances the effect of SnCe6 PDT, and fVII-tPDT is effective in eradicating MCF-7/MDR cancer cells. (A and B) The EC50 of SnCe6 was 2.8 and 35.8 μ in fVII-tPDT and ntPDT (18 J cm–2, laser fluence) for MCF-7/MDR cells, respectively. (C) MCF-7/MDR cells had a laser fluence-dependent response to fVII-tPDT (2 μ SnCe6) but had no response to ntPDT (2 μ SnCe6).

Mentions: Note that we did not test the ntPDT control using unconjugated SnCe6 in this animal study. The reason is as follows. (1) We showed in the Results section below that the projected half-maximal effective concentration (EC50) of laser fluence in ntPDT using 2 μ unconjugated SnCe6 was 5571.6 J cm–2 in vitro in tissue culture plates, whereas the EC50 of laser fluence in fVII-tPDT (2 μ SnCe6 in fVII-SnCe6 conjugate) was 300-fold less (18.3 J cm–2; Figure 2C). Therefore, we anticipate that ntPDT at 2 μ SnCe6 and 65 J cm–2 would not have any effect on inhibiting the tumour growth in vivo in mice. (2) We carried out four animal experiments in our recent studies on fVII-tPDT for treatment of chemosensitive breast cancer, and three of the ntPDTs using fVII-verteporfin or fVII-SnCe6 conjugate were tested and compared with fVII-tPDT and we did not observe any effect of ntPDT on inhibiting the tumour growth (Hu et al, 2010a, 2010b).


Effective treatment of chemoresistant breast cancer in vitro and in vivo by a factor VII-targeted photodynamic therapy.

Duanmu J, Cheng J, Xu J, Booth CJ, Hu Z - Br. J. Cancer (2011)

Factor VII (fVII) targeting enhances the effect of SnCe6 PDT, and fVII-tPDT is effective in eradicating MCF-7/MDR cancer cells. (A and B) The EC50 of SnCe6 was 2.8 and 35.8 μ in fVII-tPDT and ntPDT (18 J cm–2, laser fluence) for MCF-7/MDR cells, respectively. (C) MCF-7/MDR cells had a laser fluence-dependent response to fVII-tPDT (2 μ SnCe6) but had no response to ntPDT (2 μ SnCe6).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3101942&req=5

fig2: Factor VII (fVII) targeting enhances the effect of SnCe6 PDT, and fVII-tPDT is effective in eradicating MCF-7/MDR cancer cells. (A and B) The EC50 of SnCe6 was 2.8 and 35.8 μ in fVII-tPDT and ntPDT (18 J cm–2, laser fluence) for MCF-7/MDR cells, respectively. (C) MCF-7/MDR cells had a laser fluence-dependent response to fVII-tPDT (2 μ SnCe6) but had no response to ntPDT (2 μ SnCe6).
Mentions: Note that we did not test the ntPDT control using unconjugated SnCe6 in this animal study. The reason is as follows. (1) We showed in the Results section below that the projected half-maximal effective concentration (EC50) of laser fluence in ntPDT using 2 μ unconjugated SnCe6 was 5571.6 J cm–2 in vitro in tissue culture plates, whereas the EC50 of laser fluence in fVII-tPDT (2 μ SnCe6 in fVII-SnCe6 conjugate) was 300-fold less (18.3 J cm–2; Figure 2C). Therefore, we anticipate that ntPDT at 2 μ SnCe6 and 65 J cm–2 would not have any effect on inhibiting the tumour growth in vivo in mice. (2) We carried out four animal experiments in our recent studies on fVII-tPDT for treatment of chemosensitive breast cancer, and three of the ntPDTs using fVII-verteporfin or fVII-SnCe6 conjugate were tested and compared with fVII-tPDT and we did not observe any effect of ntPDT on inhibiting the tumour growth (Hu et al, 2010a, 2010b).

Bottom Line: The efficacy of fVII-tPDT was tested in vitro and in vivo and was compared with non-targeted PDT for treatment of chemoresistant breast cancer.Moreover, fVII-tPDT was effective and safe for the treatment of chemoresistant breast tumours in the nude mouse model.We conclude that fVII-tPDT is effective and safe for the treatment of chemoresistant breast cancer, presumably by simultaneously targeting both the tumour neovasculature and chemoresistant cancer cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06520, USA.

ABSTRACT

Background: The purpose of this study was to test a novel, dual tumour vascular endothelial cell (VEC)- and tumour cell-targeting factor VII-targeted Sn(IV) chlorin e6 photodynamic therapy (fVII-tPDT) by targeting a receptor tissue factor (TF) as an alternative treatment for chemoresistant breast cancer using a multidrug resistant (MDR) breast cancer line MCF-7/MDR.

Methods: The TF expression by the MCF-7/MDR breast cancer cells and tumour VECs in MCF-7/MDR tumours from mice was determined separately by flow cytometry and immunohistochemistry using anti-human or anti-murine TF antibodies. The efficacy of fVII-tPDT was tested in vitro and in vivo and was compared with non-targeted PDT for treatment of chemoresistant breast cancer. The in vitro efficacy was determined by a non-clonogenic assay using crystal violet staining for monolayers, and apoptosis and necrosis were assayed to elucidate the underlying mechanisms. The in vivo efficacy of fVII-tPDT was determined in a nude mouse model of subcutaneous MCF-7/MDR tumour xenograft by measuring tumour volume.

Results: To our knowledge, this is the first presentation showing that TF was expressed on tumour VECs in chemoresistant breast tumours from mice. The in vitro efficacy of fVII-tPDT was 12-fold stronger than that of ntPDT for MCF-7/MDR cancer cells, and the mechanism of action involved induction of apoptosis and necrosis. Moreover, fVII-tPDT was effective and safe for the treatment of chemoresistant breast tumours in the nude mouse model.

Conclusions: We conclude that fVII-tPDT is effective and safe for the treatment of chemoresistant breast cancer, presumably by simultaneously targeting both the tumour neovasculature and chemoresistant cancer cells. Thus, this dual-targeting fVII-tPDT could also have therapeutic potential for the treatment of other chemoresistant cancers.

Show MeSH
Related in: MedlinePlus