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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

Observation of the antineoplastic effects of ZD55–dNK with DFDC in xenograft mice.Notes: (A) Tumor volume examination of the xenograft mice after the combination treatment with or without DFDC. (B) The cumulative survival of group PBS, ZD55–dNK and dNK + DFDC. The antineoplastic effects were assessed in the MCF7 xenograft model in vivo with subcutaneous neoplasms. *P<0.05 represents the tumor volume in ZD55–dNK + DFDC group compared to the PBS or ZD55 group. P=0.0146 represents the cumulative survival in ZD55–dNK + DFDC group compared to the ZD55–dNK group.Abbreviations: DFDC, difluorodeoxycytidine; dNK, deoxyribonucleoside kinase; PBS, phosphate-buffered saline.
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f6-dddt-9-3301: Observation of the antineoplastic effects of ZD55–dNK with DFDC in xenograft mice.Notes: (A) Tumor volume examination of the xenograft mice after the combination treatment with or without DFDC. (B) The cumulative survival of group PBS, ZD55–dNK and dNK + DFDC. The antineoplastic effects were assessed in the MCF7 xenograft model in vivo with subcutaneous neoplasms. *P<0.05 represents the tumor volume in ZD55–dNK + DFDC group compared to the PBS or ZD55 group. P=0.0146 represents the cumulative survival in ZD55–dNK + DFDC group compared to the ZD55–dNK group.Abbreviations: DFDC, difluorodeoxycytidine; dNK, deoxyribonucleoside kinase; PBS, phosphate-buffered saline.

Mentions: The anticancer efficacy of combination treatment was assessed in the MCF7 xenograft model in vivo with subcutaneous neoplasms in treatment with ZD55–dNK with or without DFDC (Figure 6A). Statistically significant antitumoral effect with respect to neoplasm size was examined the ZD55–dNK in the DFDC-treated groups (1295.03±326.63 mm3) compared with ZD55–dNK virus only (2670.78±159.43 mm3) or the mock control group (3101.29±336.61 mm3, P<0.05). Furthermore, the mean survival time of group PBS, ZD55–dNK, and DNK + DFDC were 22 days, 30.5 days, and 52.5 days, respectively. Moreover, group C significantly prolonged the survival time compared to the group B (P=0.0146, Figure 6B). These data demonstrate that combination therapy of MCF7 xenografts with ZD55–dNK/DFDC elicited a significant antitumor effect.


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)

Observation of the antineoplastic effects of ZD55–dNK with DFDC in xenograft mice.Notes: (A) Tumor volume examination of the xenograft mice after the combination treatment with or without DFDC. (B) The cumulative survival of group PBS, ZD55–dNK and dNK + DFDC. The antineoplastic effects were assessed in the MCF7 xenograft model in vivo with subcutaneous neoplasms. *P<0.05 represents the tumor volume in ZD55–dNK + DFDC group compared to the PBS or ZD55 group. P=0.0146 represents the cumulative survival in ZD55–dNK + DFDC group compared to the ZD55–dNK group.Abbreviations: DFDC, difluorodeoxycytidine; dNK, deoxyribonucleoside kinase; PBS, phosphate-buffered saline.
© Copyright Policy
Related In: Results  -  Collection

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

f6-dddt-9-3301: Observation of the antineoplastic effects of ZD55–dNK with DFDC in xenograft mice.Notes: (A) Tumor volume examination of the xenograft mice after the combination treatment with or without DFDC. (B) The cumulative survival of group PBS, ZD55–dNK and dNK + DFDC. The antineoplastic effects were assessed in the MCF7 xenograft model in vivo with subcutaneous neoplasms. *P<0.05 represents the tumor volume in ZD55–dNK + DFDC group compared to the PBS or ZD55 group. P=0.0146 represents the cumulative survival in ZD55–dNK + DFDC group compared to the ZD55–dNK group.Abbreviations: DFDC, difluorodeoxycytidine; dNK, deoxyribonucleoside kinase; PBS, phosphate-buffered saline.
Mentions: The anticancer efficacy of combination treatment was assessed in the MCF7 xenograft model in vivo with subcutaneous neoplasms in treatment with ZD55–dNK with or without DFDC (Figure 6A). Statistically significant antitumoral effect with respect to neoplasm size was examined the ZD55–dNK in the DFDC-treated groups (1295.03±326.63 mm3) compared with ZD55–dNK virus only (2670.78±159.43 mm3) or the mock control group (3101.29±336.61 mm3, P<0.05). Furthermore, the mean survival time of group PBS, ZD55–dNK, and DNK + DFDC were 22 days, 30.5 days, and 52.5 days, respectively. Moreover, group C significantly prolonged the survival time compared to the group B (P=0.0146, Figure 6B). These data demonstrate that combination therapy of MCF7 xenografts with ZD55–dNK/DFDC elicited a significant antitumor effect.

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