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Synergistic antitumor effect of adenovirus armed with Drosophila melanogaster deoxyribonucleoside kinase and nucleoside analogs for human breast carcinoma in vitro and in vivo.

Tang M, Zu C, He A, Wang W, Chen B, Zheng X - Drug Des Devel Ther (2015)

Bottom Line: To enhance the anti-tumor efficacy of Dm-dNK and maintain its substrate specificity and safety control in the meantime, the conditionally replicative gene-viral system, ZD55-dNK (which contains the selective replication adenovirus, ZD55, encoded with Dm-dNK), was investigated in pushing a deeper development of this strategy.ZD55-dNK also greatly improved the antineoplastic effect in vitro and in breast cancer xenograft in vivo.The concomitant use of ZD55-dNK and DFDC is possibly a novel and promising approach to breast cancer treatment, and further investigation on the safe control of excessive virus replication and the efficacy of this approach in humans is warranted.

View Article: PubMed Central - PubMed

Affiliation: Department of Breast Surgery, The First Hospital of China Medical University, People's Republic of China.

ABSTRACT

Background: Suicide gene therapy in cancer can selectively kill tumors without damaging normal tissues. Drosophila melanogaster multisubstrate deoxyribonucleoside kinase (Dm-dNK), an original suicide kinase, makes use of the carcinomatous suicide gene therapy for broader substrate specificity and a higher catalytic rate.

Methods: To enhance the anti-tumor efficacy of Dm-dNK and maintain its substrate specificity and safety control in the meantime, the conditionally replicative gene-viral system, ZD55-dNK (which contains the selective replication adenovirus, ZD55, encoded with Dm-dNK), was investigated in pushing a deeper development of this strategy. Selective replication, cell killing efficacy, and cytotoxicity, in combination with chemotherapy, were applied to two breast cell lines (MDA231 and MCF7 cells), two normal cell lines (WI38 and MRC5 cells), and the MCF7 xenograft model in vivo.

Results: The preclinical study showed that ZD55-dNK, combined with 2',2'-difluorodeoxycytidine (DFDC), synergistically inhibited adenovirus replication in vitro but maintained specifically cancer cell killing efficacy. ZD55-dNK also greatly improved the antineoplastic effect in vitro and in breast cancer xenograft in vivo.

Conclusion: The concomitant use of ZD55-dNK and DFDC is possibly a novel and promising approach to breast cancer treatment, and further investigation on the safe control of excessive virus replication and the efficacy of this approach in humans is warranted.

No MeSH data available.


Related in: MedlinePlus

Cell cytotoxic activity of ZD55–dNK in combination with BVDU and DFDC.Notes: (A) Combination effects with BVDU in the breast neoplastic cell line (MCF7), upper left; combination effects with DFDC in the MCF7 cell line, upper right; combination effects with BVDU in the nonneoplastic cell line (MRC5), lower left; combination effects with DFDC in the MRC5 cell line, lower right. The cells were infected with the infection (MOI) of 0, 0.001, 0.01, 0.1, 1 and 10 pfu/cell, respectively. The Y-axis illustrates the MOI concentrations. (B) The optical patterns of the cytopathological effect. (C) FACS assay examination for the cell apoptosis. *P<0.05 represents the cell cytotoxicity in ZD55–dNK group compared to the ZD55 group.Abbreviations: BVDU, (E)-5-(2-bromovinyl)-2′-deoxyuridine; DFDC, difluorodeoxycytidine; dNK, deoxyribonucleoside kinase; FACS, fluorescence-activated cell sorting; MOI, multiplicity of infection; PI, propidium iodide; TCID50, tissue culture infectious dose 50 assay; WtAd, replicative adenovirus.
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f4-dddt-9-3301: Cell cytotoxic activity of ZD55–dNK in combination with BVDU and DFDC.Notes: (A) Combination effects with BVDU in the breast neoplastic cell line (MCF7), upper left; combination effects with DFDC in the MCF7 cell line, upper right; combination effects with BVDU in the nonneoplastic cell line (MRC5), lower left; combination effects with DFDC in the MRC5 cell line, lower right. The cells were infected with the infection (MOI) of 0, 0.001, 0.01, 0.1, 1 and 10 pfu/cell, respectively. The Y-axis illustrates the MOI concentrations. (B) The optical patterns of the cytopathological effect. (C) FACS assay examination for the cell apoptosis. *P<0.05 represents the cell cytotoxicity in ZD55–dNK group compared to the ZD55 group.Abbreviations: BVDU, (E)-5-(2-bromovinyl)-2′-deoxyuridine; DFDC, difluorodeoxycytidine; dNK, deoxyribonucleoside kinase; FACS, fluorescence-activated cell sorting; MOI, multiplicity of infection; PI, propidium iodide; TCID50, tissue culture infectious dose 50 assay; WtAd, replicative adenovirus.

Mentions: The synergistic impact on cell toxicity by combining ZD55–dNK with the chemotherapy medicine, BVDU, and DFDC relative to ZD55, DL1520, or WtAd with medicine was investigated in the breast neoplastic cell line (MCF7) and the human non-neoplastic cell line (MRC-5). The experiment of MTT assay showed that ZD55–dNK in the presence of prodrugs had an ability to destroy breast carcinoma cells more effectively than additional three viruses, on the contrary in the non-carcinoma MRC-5 cells, ZD55–dNK with drugs decreased cytotoxic activity compared with the additional viruses (P<0.05, Figure 4A). DFDC was more sensitive to ZD55–dNK than BVDU. The derivatives DFDC-TP phosphorylated by ZD55–dNK restrained duplication of the adenovirus. The optical patterns of the cytopathological effect verify these data (Figure 4B). The FACS assay sustains the finding of MTT as well (Figure 4C). The ZD55–dNK (MOI =1) with 10 μM DFDC led to the greatest amount of cell apoptosis (86%±10%, right upper and lower quadrants) in the MCF7 carcinoma cells, which was 50% greater than ZD55 and DL1520 with DFDC. In the MRC5 cell line with 10 μM DFDC, apoptosis of 10%±3% was mediated by ZD55–dNK, which was obviously lower than ZD55, DL1520, and WtAd.


Synergistic antitumor effect of adenovirus armed with Drosophila melanogaster deoxyribonucleoside kinase and nucleoside analogs for human breast carcinoma in vitro and in vivo.

Tang M, Zu C, He A, Wang W, Chen B, Zheng X - Drug Des Devel Ther (2015)

Cell cytotoxic activity of ZD55–dNK in combination with BVDU and DFDC.Notes: (A) Combination effects with BVDU in the breast neoplastic cell line (MCF7), upper left; combination effects with DFDC in the MCF7 cell line, upper right; combination effects with BVDU in the nonneoplastic cell line (MRC5), lower left; combination effects with DFDC in the MRC5 cell line, lower right. The cells were infected with the infection (MOI) of 0, 0.001, 0.01, 0.1, 1 and 10 pfu/cell, respectively. The Y-axis illustrates the MOI concentrations. (B) The optical patterns of the cytopathological effect. (C) FACS assay examination for the cell apoptosis. *P<0.05 represents the cell cytotoxicity in ZD55–dNK group compared to the ZD55 group.Abbreviations: BVDU, (E)-5-(2-bromovinyl)-2′-deoxyuridine; DFDC, difluorodeoxycytidine; dNK, deoxyribonucleoside kinase; FACS, fluorescence-activated cell sorting; MOI, multiplicity of infection; PI, propidium iodide; TCID50, tissue culture infectious dose 50 assay; WtAd, replicative adenovirus.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4507493&req=5

f4-dddt-9-3301: Cell cytotoxic activity of ZD55–dNK in combination with BVDU and DFDC.Notes: (A) Combination effects with BVDU in the breast neoplastic cell line (MCF7), upper left; combination effects with DFDC in the MCF7 cell line, upper right; combination effects with BVDU in the nonneoplastic cell line (MRC5), lower left; combination effects with DFDC in the MRC5 cell line, lower right. The cells were infected with the infection (MOI) of 0, 0.001, 0.01, 0.1, 1 and 10 pfu/cell, respectively. The Y-axis illustrates the MOI concentrations. (B) The optical patterns of the cytopathological effect. (C) FACS assay examination for the cell apoptosis. *P<0.05 represents the cell cytotoxicity in ZD55–dNK group compared to the ZD55 group.Abbreviations: BVDU, (E)-5-(2-bromovinyl)-2′-deoxyuridine; DFDC, difluorodeoxycytidine; dNK, deoxyribonucleoside kinase; FACS, fluorescence-activated cell sorting; MOI, multiplicity of infection; PI, propidium iodide; TCID50, tissue culture infectious dose 50 assay; WtAd, replicative adenovirus.
Mentions: The synergistic impact on cell toxicity by combining ZD55–dNK with the chemotherapy medicine, BVDU, and DFDC relative to ZD55, DL1520, or WtAd with medicine was investigated in the breast neoplastic cell line (MCF7) and the human non-neoplastic cell line (MRC-5). The experiment of MTT assay showed that ZD55–dNK in the presence of prodrugs had an ability to destroy breast carcinoma cells more effectively than additional three viruses, on the contrary in the non-carcinoma MRC-5 cells, ZD55–dNK with drugs decreased cytotoxic activity compared with the additional viruses (P<0.05, Figure 4A). DFDC was more sensitive to ZD55–dNK than BVDU. The derivatives DFDC-TP phosphorylated by ZD55–dNK restrained duplication of the adenovirus. The optical patterns of the cytopathological effect verify these data (Figure 4B). The FACS assay sustains the finding of MTT as well (Figure 4C). The ZD55–dNK (MOI =1) with 10 μM DFDC led to the greatest amount of cell apoptosis (86%±10%, right upper and lower quadrants) in the MCF7 carcinoma cells, which was 50% greater than ZD55 and DL1520 with DFDC. In the MRC5 cell line with 10 μM DFDC, apoptosis of 10%±3% was mediated by ZD55–dNK, which was obviously lower than ZD55, DL1520, and WtAd.

Bottom Line: To enhance the anti-tumor efficacy of Dm-dNK and maintain its substrate specificity and safety control in the meantime, the conditionally replicative gene-viral system, ZD55-dNK (which contains the selective replication adenovirus, ZD55, encoded with Dm-dNK), was investigated in pushing a deeper development of this strategy.ZD55-dNK also greatly improved the antineoplastic effect in vitro and in breast cancer xenograft in vivo.The concomitant use of ZD55-dNK and DFDC is possibly a novel and promising approach to breast cancer treatment, and further investigation on the safe control of excessive virus replication and the efficacy of this approach in humans is warranted.

View Article: PubMed Central - PubMed

Affiliation: Department of Breast Surgery, The First Hospital of China Medical University, People's Republic of China.

ABSTRACT

Background: Suicide gene therapy in cancer can selectively kill tumors without damaging normal tissues. Drosophila melanogaster multisubstrate deoxyribonucleoside kinase (Dm-dNK), an original suicide kinase, makes use of the carcinomatous suicide gene therapy for broader substrate specificity and a higher catalytic rate.

Methods: To enhance the anti-tumor efficacy of Dm-dNK and maintain its substrate specificity and safety control in the meantime, the conditionally replicative gene-viral system, ZD55-dNK (which contains the selective replication adenovirus, ZD55, encoded with Dm-dNK), was investigated in pushing a deeper development of this strategy. Selective replication, cell killing efficacy, and cytotoxicity, in combination with chemotherapy, were applied to two breast cell lines (MDA231 and MCF7 cells), two normal cell lines (WI38 and MRC5 cells), and the MCF7 xenograft model in vivo.

Results: The preclinical study showed that ZD55-dNK, combined with 2',2'-difluorodeoxycytidine (DFDC), synergistically inhibited adenovirus replication in vitro but maintained specifically cancer cell killing efficacy. ZD55-dNK also greatly improved the antineoplastic effect in vitro and in breast cancer xenograft in vivo.

Conclusion: The concomitant use of ZD55-dNK and DFDC is possibly a novel and promising approach to breast cancer treatment, and further investigation on the safe control of excessive virus replication and the efficacy of this approach in humans is warranted.

No MeSH data available.


Related in: MedlinePlus