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. 2013 Sep;6(3):801-806.
doi: 10.3892/ol.2013.1437. Epub 2013 Jul 3.

Tissue factor-targeted lidamycin inhibits growth and metastasis of colon carcinoma

Affiliations

Tissue factor-targeted lidamycin inhibits growth and metastasis of colon carcinoma

Qing Zhang et al. Oncol Lett. 2013 Sep.

Abstract

Colon cancer is the third most common cancer in the world. The overexpression of tissue factor (TF) in colon cancer cells makes it an ideal target for colon cancer therapy. The purpose of the present study was to develop a TF-targeting energized fusion protein, mlFVII-LDP-AE, which is composed of a mouse Factor VII light chain (mlFVII) as the targeting domain conjugated to the highly cytotoxic antibiotic lidamycin (LDM, LDP-AE) as the effector domain. The potential efficacy of mlFVII-LDP-AE for mouse colon cancer therapy was tested in a mouse colon cancer subcutaneous xenograft model and a live metastasis model in BALB/c mice. mlFVII-LDP-AE showed a tumor growth inhibition rate of 91.2% (at a dose of 0.8 mg/kg) and a tumor metastasis inhibition rate of 84.7% (at a dose of 0.6 mg/kg). The results showed that mlFVII-LDP-AE was able to effectively inhibit the growth and metastasis of mouse colon cancer. As human TF and FVII have features similar to those of mice, human FVII light chain (hlFVII)-targeted LDM (hlFVII-LDP-AE) may be expected to have therapeutic potential for human colon cancer.

Keywords: colon carcinoma; factor VII; lidamycin; metastasis; tissue factor.

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Figures

Figure 1
Figure 1
(A) Domain diagram of recombinant protein mlFVII-LDP. (B) SDS-PAGE (lane 2) detection of mlFVII-LDP. (C) Schematic representations of the dissociation of LDM into AE and LDP and the reconstitution of mlFVII-LDP-AE. (D) Analysis of the energized fusion protein, mlFVII-LDP-AE, was performed via reverse-phase HPLC. His6, purifying tag composed of six Histidines; mlFVII, light chain of mouse factor VII; (G4S)3, flexible linker composed of triplicate GGGGS; LDP, apoprotein of lidamycin; AE, chromophore of lidamycin; HPLC, high-performance liquid chromatography; AU, absorbance unit.
Figure 2
Figure 2
Expression of tissue factor (TF) in human and mouse cell lines. (A) Expression of TF in human cell lines analyzed by western blotting. (B) Expression of TF in mouse cancer cell lines analyzed by fluorescence-activated cell sorting (FACS).
Figure 3
Figure 3
Growth inhibition by mlFVII-LDP-AE in mouse colon cancer 26 (C26) xenografts in BALB/c mice. (A) Image of the tumors removed from the mice at end of experiment. (B) Statistical results of the tumor weights. *P<0.05 vs. the group treated with PBS. #P<0.05 vs. the group treated with LDM. LDM, lidamycin; PBS, phosphate-buffered saline; mlFVII-LDP-AE, mouse FVII light chain (mlFVII)-targeted LDM.
Figure 4
Figure 4
Metastasis inhibition by mlFVII-LDP-AE in mouse colon cancer 26 (C26) cells in BALB/c mice. (A) Number of metastatic nodes on liver surfaces of mice. * P<0.05 vs. the group treated with PBS. **P<0.01 vs. the group treated with PBS. # P<0.05 vs. the group treated with LDM,. (B) Representative images of liver metastases in the groups treated with LDM and mlFVII-LDP-AE. Arrows, metastatic nodes. LDM, lidamycin; PBS, phosphate-buffered saline; mlFVII-LDP-AE, mouse FVII light chain (mlFVII)-targeted LDM.
Figure 5
Figure 5
Mean body weights of mice in each group. (A) Tumor growth inhibition experiment. (B) Tumor metastasis inhibition experiment. LDM, lidamycin; PBS, phosphate-buffered saline; mlFVII-LDP-AE, mouse FVII light chain (mlFVII)-targeted LDM.

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