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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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Changes of tumor hemodynamic indexes after treatments.ZdTha inhibited tumor growth with prolonged reductions of tumor relative blood volume (rBV), relative blood flow (rBF), and tumor vessel permeability. (A) The rBV change in the ZdTha group remained at a lower level than that of the Zd group (P = 0.0003) until day 6, then it increased at 12 d. (B) A significant reduction in tumor rBF at 2 d was noted in the ZdTha group, but not the other 3 groups (P<0.05 for all 3 groups). (C) The tumor volume transfer constant (Ktrans) change was much lower In the ZdTha group compared to controls at 4 h (P<0.0001), 2 d (P = 0.0026), and 6 d (P = 0.0500). This indicated that combined ZdTha therapy enhanced the transient reduction in tumor vessel permeability. (D) Compared to controls, the ZdTha group maintained low tumor fractional volumes, ve, from 2 d (P = 0.0420) to 12 d (P = 0.0812), except at 6 d. In the Tha group, ve sharply rose at 12 d. This group exhibited a relatively large amount of necrosis, which may cause an increase in extracellular fluid, compared to the other groups. The rectangular shadow indicates the transient window of tumor vessel normalization induced by the combined ZdTha treatment (Tables S3, S4).
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pone-0041140-g005: Changes of tumor hemodynamic indexes after treatments.ZdTha inhibited tumor growth with prolonged reductions of tumor relative blood volume (rBV), relative blood flow (rBF), and tumor vessel permeability. (A) The rBV change in the ZdTha group remained at a lower level than that of the Zd group (P = 0.0003) until day 6, then it increased at 12 d. (B) A significant reduction in tumor rBF at 2 d was noted in the ZdTha group, but not the other 3 groups (P<0.05 for all 3 groups). (C) The tumor volume transfer constant (Ktrans) change was much lower In the ZdTha group compared to controls at 4 h (P<0.0001), 2 d (P = 0.0026), and 6 d (P = 0.0500). This indicated that combined ZdTha therapy enhanced the transient reduction in tumor vessel permeability. (D) Compared to controls, the ZdTha group maintained low tumor fractional volumes, ve, from 2 d (P = 0.0420) to 12 d (P = 0.0812), except at 6 d. In the Tha group, ve sharply rose at 12 d. This group exhibited a relatively large amount of necrosis, which may cause an increase in extracellular fluid, compared to the other groups. The rectangular shadow indicates the transient window of tumor vessel normalization induced by the combined ZdTha treatment (Tables S3, S4).

Mentions: Compared to the controls, tumor rBV decreased dramatically at 4 h, presumably due to a rapid vascular shutdown induced by Zd in both the Zd and ZdTha groups (both P<0.0001). This was followed by a rapid rebound at 2 d in the Zd group (no longer significantly different compared to controls; P = 0.4003), but not in the ZdTha group (significantly lower than controls; P = 0.0020). The rBVs in the ZdTha group remained at a lower level than those of the Zd group (P = 0.0003) until day 6, but this difference become non-significant at 12 d (P = 0.0979). In contrast, both Tha and control groups showed comparable decreases in the rBV over time (Fig. 5A, Fig.6, Table S3). A significant reduction in tumor rBF at 2 d was only noted in the ZdTha group compared to the other 3 groups (P = 0.0240, 0.0020, and 0.0401 for control, Zd and Tha groups, respectively); this was followed by an increase to the level of pretreatment (Fig. 5B, Fig.6, Table S3).


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)

Changes of tumor hemodynamic indexes after treatments.ZdTha inhibited tumor growth with prolonged reductions of tumor relative blood volume (rBV), relative blood flow (rBF), and tumor vessel permeability. (A) The rBV change in the ZdTha group remained at a lower level than that of the Zd group (P = 0.0003) until day 6, then it increased at 12 d. (B) A significant reduction in tumor rBF at 2 d was noted in the ZdTha group, but not the other 3 groups (P<0.05 for all 3 groups). (C) The tumor volume transfer constant (Ktrans) change was much lower In the ZdTha group compared to controls at 4 h (P<0.0001), 2 d (P = 0.0026), and 6 d (P = 0.0500). This indicated that combined ZdTha therapy enhanced the transient reduction in tumor vessel permeability. (D) Compared to controls, the ZdTha group maintained low tumor fractional volumes, ve, from 2 d (P = 0.0420) to 12 d (P = 0.0812), except at 6 d. In the Tha group, ve sharply rose at 12 d. This group exhibited a relatively large amount of necrosis, which may cause an increase in extracellular fluid, compared to the other groups. The rectangular shadow indicates the transient window of tumor vessel normalization induced by the combined ZdTha treatment (Tables S3, S4).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3399789&req=5

pone-0041140-g005: Changes of tumor hemodynamic indexes after treatments.ZdTha inhibited tumor growth with prolonged reductions of tumor relative blood volume (rBV), relative blood flow (rBF), and tumor vessel permeability. (A) The rBV change in the ZdTha group remained at a lower level than that of the Zd group (P = 0.0003) until day 6, then it increased at 12 d. (B) A significant reduction in tumor rBF at 2 d was noted in the ZdTha group, but not the other 3 groups (P<0.05 for all 3 groups). (C) The tumor volume transfer constant (Ktrans) change was much lower In the ZdTha group compared to controls at 4 h (P<0.0001), 2 d (P = 0.0026), and 6 d (P = 0.0500). This indicated that combined ZdTha therapy enhanced the transient reduction in tumor vessel permeability. (D) Compared to controls, the ZdTha group maintained low tumor fractional volumes, ve, from 2 d (P = 0.0420) to 12 d (P = 0.0812), except at 6 d. In the Tha group, ve sharply rose at 12 d. This group exhibited a relatively large amount of necrosis, which may cause an increase in extracellular fluid, compared to the other groups. The rectangular shadow indicates the transient window of tumor vessel normalization induced by the combined ZdTha treatment (Tables S3, S4).
Mentions: Compared to the controls, tumor rBV decreased dramatically at 4 h, presumably due to a rapid vascular shutdown induced by Zd in both the Zd and ZdTha groups (both P<0.0001). This was followed by a rapid rebound at 2 d in the Zd group (no longer significantly different compared to controls; P = 0.4003), but not in the ZdTha group (significantly lower than controls; P = 0.0020). The rBVs in the ZdTha group remained at a lower level than those of the Zd group (P = 0.0003) until day 6, but this difference become non-significant at 12 d (P = 0.0979). In contrast, both Tha and control groups showed comparable decreases in the rBV over time (Fig. 5A, Fig.6, Table S3). A significant reduction in tumor rBF at 2 d was only noted in the ZdTha group compared to the other 3 groups (P = 0.0240, 0.0020, and 0.0401 for control, Zd and Tha groups, respectively); this was followed by an increase to the level of pretreatment (Fig. 5B, Fig.6, Table S3).

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