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Enhanced antitumor efficacy of a vascular disrupting agent combined with an antiangiogenic in a rat liver tumor model evaluated by multiparametric MRI.

Chen F, Feng Y, Zheng K, De Keyzer F, Li J, Feng Y, Cona MM, Wang H, Jiang Y, Yu J, Marchal G, Verfaillie C, De Geest B, Oyen R, Ni Y - PLoS ONE (2012)

Bottom Line: We found no significant increases in Zd-induced circulating EPCs or plasma SDF-1α.ZdTha showed improved therapeutic efficacy in solid tumors compared to either agent alone.The therapeutic effects were successfully tracked in vivo with multiparametric MRI.

View Article: PubMed Central - PubMed

Affiliation: Theragnostic Laboratory, Department of Imaging and Pathology, University Hospital, University of Leuven, Leuven, Belgium. feng.chen@med.kuleuven.be

ABSTRACT
A key problem in solid tumor therapy is tumor regrowth from a residual viable rim after treatment with a vascular disrupting agent (VDA). As a potential solution, we studied a combined treatment of a VDA and antiangiogenic. This study was approved by the institutional ethical committee for the use and care of laboratory animals. Rats with implanted liver tumors were randomized into four treatment groups: 1) Zd6126 (Zd); 2) Thalidomide (Tha); 3) Zd in combination with Tha (ZdTha); and 4) controls. Multiparametric MRIs were performed and quantified before and after treatment. Circulating endothelial progenitor cells (EPCs) and plasma stromal cell-derived factor-1α (SDF-1α) were monitored. Tumor apoptosis, necrosis, and microvessels were verified by histopathology. A single use of Zd or Tha did not significantly delay tumor growth. The combined ZdTha showed enhanced antitumor efficacy due to synergistic effects; it induced a cumulative tumor apoptosis or necrosis, which resulted in significant delay in tumor growth and reduction in the viable tumor rim; it also reduced tumor vessel permeability; and it improved tumor hemodynamic indexes, most likely via a transient normalization of tumor vasculature induced by Tha. A stepwise linear regression analysis showed that the apparent diffusion coefficient was an independent predictor of tumor growth. We found no significant increases in Zd-induced circulating EPCs or plasma SDF-1α. ZdTha showed improved therapeutic efficacy in solid tumors compared to either agent alone. The therapeutic effects were successfully tracked in vivo with multiparametric MRI.

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Related in: MedlinePlus

Study design.Rats were randomly assigned into the following 4 groups: (group 1) Zd alone (n = 11); (group 2) Tha alone (n = 11); (group 3) ZdTha (n = 12); (group 4) untreated controls (n = 10). For groups 2 and 3, Tha (200 mg/kg) was injected intraperitoneally (i.p.) six times, on days (d) -1, 0, 1, 2, 6, and 10. For groups 1 and 3, Zd (50 mg/kg) was injected once intravenously (i.v.) on day 0. The controls were injected on days 0, 1, 2, 6, and 10 with the vehicles (solvents) of both agents (i.v. and i.p.) at the same time points that the other groups were injected. For all groups, MRI was performed before, and at 4 h, 2 d, 6 d, and 12 d after the initial treatment. Before the baseline, 4 h, and 2 d MRIs, rat tails were incised to collect blood samples for monitoring the levels of circulating EPCs and plasma SDF-1α in both Zd and ZdTha groups. At the end of the experiment, animals were sacrificed for histopathology examinations. (Zd, Zd6126; Tha, Thalidomide; ZdTha, Zd6126+Thalidomide; i.p., intra-peritoneal injection; i.v., intravenous injection; MRI, Magnetic resonance imaging; FACS, Fluorescence-activated cell sorting; EPCs, endothelial progenitor cells; VEGFR, vascular endothelial growth factor receptor; SDF-1α, stromal cell-derived factor-1α; HE, hematoxylin-eosin staining; IHC, Immunohistochemistry; MVD, microvessel density; TUNEL, terminal deoxynucleotidyl transferase biotin dUTP nick end labeling).
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pone-0041140-g001: Study design.Rats were randomly assigned into the following 4 groups: (group 1) Zd alone (n = 11); (group 2) Tha alone (n = 11); (group 3) ZdTha (n = 12); (group 4) untreated controls (n = 10). For groups 2 and 3, Tha (200 mg/kg) was injected intraperitoneally (i.p.) six times, on days (d) -1, 0, 1, 2, 6, and 10. For groups 1 and 3, Zd (50 mg/kg) was injected once intravenously (i.v.) on day 0. The controls were injected on days 0, 1, 2, 6, and 10 with the vehicles (solvents) of both agents (i.v. and i.p.) at the same time points that the other groups were injected. For all groups, MRI was performed before, and at 4 h, 2 d, 6 d, and 12 d after the initial treatment. Before the baseline, 4 h, and 2 d MRIs, rat tails were incised to collect blood samples for monitoring the levels of circulating EPCs and plasma SDF-1α in both Zd and ZdTha groups. At the end of the experiment, animals were sacrificed for histopathology examinations. (Zd, Zd6126; Tha, Thalidomide; ZdTha, Zd6126+Thalidomide; i.p., intra-peritoneal injection; i.v., intravenous injection; MRI, Magnetic resonance imaging; FACS, Fluorescence-activated cell sorting; EPCs, endothelial progenitor cells; VEGFR, vascular endothelial growth factor receptor; SDF-1α, stromal cell-derived factor-1α; HE, hematoxylin-eosin staining; IHC, Immunohistochemistry; MVD, microvessel density; TUNEL, terminal deoxynucleotidyl transferase biotin dUTP nick end labeling).

Mentions: The rats were randomly assigned into the following 4 groups (n = 12 in each group; Fig.1): 1) Zd group: The VDA, Zd (AstraZeneca, Cheshire, UK), was dissolved with 4 portions of 8.4% sodium carbonate and 1 portion of phosphate-buffered saline (PBS), pH 7.4. On day 0, one dose of 50 mg/kg Zd was injected intravenously (i.v.) into each animal; 2) Tha group: Stock solutions of the antiangiogenic agent, Tha (Pharmaceutical Factory, Changzhou, China), were prepared in DMSO (Sigma-Aldrich NV/SA, Bornem, Belgium). The stock solution was injected intraperitoneally (i.p.) at a dose of 200 mg/kg, six times at regular intervals during the experiment; [17] 3) ZdTha group: first dose of Tha was injected 24 h in advance of Zd; 4) control group: animals were i.v. and i.p. injected with the vehicles (solvents) of both agents at the same time points that the other groups were injected. For all groups, MRI was performed before, and at 4 h, 2 days (d), 6 d, and 12 d after the initial treatment. Before the baseline, 4 h and 2 d MRI, rat tails were incised to collect blood samples for monitoring the levels of circulating endothelial progenitor cells (EPCs) and plasma stromal cell-derived actor-1α (SDF-1α) in both Zd and ZdTha groups. This is to find if there is any increased circulating EPCs induced by a VDA. [18] At the end of the experiment, animals were sacrificed for histopathology examinations.


Enhanced antitumor efficacy of a vascular disrupting agent combined with an antiangiogenic in a rat liver tumor model evaluated by multiparametric MRI.

Chen F, Feng Y, Zheng K, De Keyzer F, Li J, Feng Y, Cona MM, Wang H, Jiang Y, Yu J, Marchal G, Verfaillie C, De Geest B, Oyen R, Ni Y - PLoS ONE (2012)

Study design.Rats were randomly assigned into the following 4 groups: (group 1) Zd alone (n = 11); (group 2) Tha alone (n = 11); (group 3) ZdTha (n = 12); (group 4) untreated controls (n = 10). For groups 2 and 3, Tha (200 mg/kg) was injected intraperitoneally (i.p.) six times, on days (d) -1, 0, 1, 2, 6, and 10. For groups 1 and 3, Zd (50 mg/kg) was injected once intravenously (i.v.) on day 0. The controls were injected on days 0, 1, 2, 6, and 10 with the vehicles (solvents) of both agents (i.v. and i.p.) at the same time points that the other groups were injected. For all groups, MRI was performed before, and at 4 h, 2 d, 6 d, and 12 d after the initial treatment. Before the baseline, 4 h, and 2 d MRIs, rat tails were incised to collect blood samples for monitoring the levels of circulating EPCs and plasma SDF-1α in both Zd and ZdTha groups. At the end of the experiment, animals were sacrificed for histopathology examinations. (Zd, Zd6126; Tha, Thalidomide; ZdTha, Zd6126+Thalidomide; i.p., intra-peritoneal injection; i.v., intravenous injection; MRI, Magnetic resonance imaging; FACS, Fluorescence-activated cell sorting; EPCs, endothelial progenitor cells; VEGFR, vascular endothelial growth factor receptor; SDF-1α, stromal cell-derived factor-1α; HE, hematoxylin-eosin staining; IHC, Immunohistochemistry; MVD, microvessel density; TUNEL, terminal deoxynucleotidyl transferase biotin dUTP nick end labeling).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3399789&req=5

pone-0041140-g001: Study design.Rats were randomly assigned into the following 4 groups: (group 1) Zd alone (n = 11); (group 2) Tha alone (n = 11); (group 3) ZdTha (n = 12); (group 4) untreated controls (n = 10). For groups 2 and 3, Tha (200 mg/kg) was injected intraperitoneally (i.p.) six times, on days (d) -1, 0, 1, 2, 6, and 10. For groups 1 and 3, Zd (50 mg/kg) was injected once intravenously (i.v.) on day 0. The controls were injected on days 0, 1, 2, 6, and 10 with the vehicles (solvents) of both agents (i.v. and i.p.) at the same time points that the other groups were injected. For all groups, MRI was performed before, and at 4 h, 2 d, 6 d, and 12 d after the initial treatment. Before the baseline, 4 h, and 2 d MRIs, rat tails were incised to collect blood samples for monitoring the levels of circulating EPCs and plasma SDF-1α in both Zd and ZdTha groups. At the end of the experiment, animals were sacrificed for histopathology examinations. (Zd, Zd6126; Tha, Thalidomide; ZdTha, Zd6126+Thalidomide; i.p., intra-peritoneal injection; i.v., intravenous injection; MRI, Magnetic resonance imaging; FACS, Fluorescence-activated cell sorting; EPCs, endothelial progenitor cells; VEGFR, vascular endothelial growth factor receptor; SDF-1α, stromal cell-derived factor-1α; HE, hematoxylin-eosin staining; IHC, Immunohistochemistry; MVD, microvessel density; TUNEL, terminal deoxynucleotidyl transferase biotin dUTP nick end labeling).
Mentions: The rats were randomly assigned into the following 4 groups (n = 12 in each group; Fig.1): 1) Zd group: The VDA, Zd (AstraZeneca, Cheshire, UK), was dissolved with 4 portions of 8.4% sodium carbonate and 1 portion of phosphate-buffered saline (PBS), pH 7.4. On day 0, one dose of 50 mg/kg Zd was injected intravenously (i.v.) into each animal; 2) Tha group: Stock solutions of the antiangiogenic agent, Tha (Pharmaceutical Factory, Changzhou, China), were prepared in DMSO (Sigma-Aldrich NV/SA, Bornem, Belgium). The stock solution was injected intraperitoneally (i.p.) at a dose of 200 mg/kg, six times at regular intervals during the experiment; [17] 3) ZdTha group: first dose of Tha was injected 24 h in advance of Zd; 4) control group: animals were i.v. and i.p. injected with the vehicles (solvents) of both agents at the same time points that the other groups were injected. For all groups, MRI was performed before, and at 4 h, 2 days (d), 6 d, and 12 d after the initial treatment. Before the baseline, 4 h and 2 d MRI, rat tails were incised to collect blood samples for monitoring the levels of circulating endothelial progenitor cells (EPCs) and plasma stromal cell-derived actor-1α (SDF-1α) in both Zd and ZdTha groups. This is to find if there is any increased circulating EPCs induced by a VDA. [18] At the end of the experiment, animals were sacrificed for histopathology examinations.

Bottom Line: We found no significant increases in Zd-induced circulating EPCs or plasma SDF-1α.ZdTha showed improved therapeutic efficacy in solid tumors compared to either agent alone.The therapeutic effects were successfully tracked in vivo with multiparametric MRI.

View Article: PubMed Central - PubMed

Affiliation: Theragnostic Laboratory, Department of Imaging and Pathology, University Hospital, University of Leuven, Leuven, Belgium. feng.chen@med.kuleuven.be

ABSTRACT
A key problem in solid tumor therapy is tumor regrowth from a residual viable rim after treatment with a vascular disrupting agent (VDA). As a potential solution, we studied a combined treatment of a VDA and antiangiogenic. This study was approved by the institutional ethical committee for the use and care of laboratory animals. Rats with implanted liver tumors were randomized into four treatment groups: 1) Zd6126 (Zd); 2) Thalidomide (Tha); 3) Zd in combination with Tha (ZdTha); and 4) controls. Multiparametric MRIs were performed and quantified before and after treatment. Circulating endothelial progenitor cells (EPCs) and plasma stromal cell-derived factor-1α (SDF-1α) were monitored. Tumor apoptosis, necrosis, and microvessels were verified by histopathology. A single use of Zd or Tha did not significantly delay tumor growth. The combined ZdTha showed enhanced antitumor efficacy due to synergistic effects; it induced a cumulative tumor apoptosis or necrosis, which resulted in significant delay in tumor growth and reduction in the viable tumor rim; it also reduced tumor vessel permeability; and it improved tumor hemodynamic indexes, most likely via a transient normalization of tumor vasculature induced by Tha. A stepwise linear regression analysis showed that the apparent diffusion coefficient was an independent predictor of tumor growth. We found no significant increases in Zd-induced circulating EPCs or plasma SDF-1α. ZdTha showed improved therapeutic efficacy in solid tumors compared to either agent alone. The therapeutic effects were successfully tracked in vivo with multiparametric MRI.

Show MeSH
Related in: MedlinePlus