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Potent anti-tumor effects of a dual specific oncolytic adenovirus expressing apoptin in vitro and in vivo.

Li X, Liu Y, Wen Z, Li C, Lu H, Tian M, Jin K, Sun L, Gao P, Yang E, Xu X, Kan S, Wang Z, Wang Y, Jin N - Mol. Cancer (2010)

Bottom Line: When treated with Ad-hTERT-E1a-Apoptin, the subcutaneous primary tumor volume reduction was not only observed in intratumoral injection group but in systemic delivery mice.In the lung metastasis model, Ad-hTERT-E1a-Apoptin effectively suppressed pulmonary metastatic lesions.Furthermore, treatment of primary and metastatic models with Ad-hTERT-E1a-Apoptin increased mice survival.

View Article: PubMed Central - HTML - PubMed

Affiliation: Genetic Engineering Laboratory of PLA, Academy of Military Medical Sciences of PLA, Changchun, China.

ABSTRACT

Background: Oncolytic virotherapy is an attractive drug platform of cancer gene therapy, but efficacy and specificity are important prerequisites for success of such strategies. Previous studies determined that Apoptin is a p53 independent, bcl-2 insensitive apoptotic protein with the ability to specifically induce apoptosis in tumor cells. Here, we generated a conditional replication-competent adenovirus (CRCA), designated Ad-hTERT-E1a-Apoptin, and investigated the effectiveness of the CRCA a gene therapy agent for further clinical trials.

Results: The observation that infection with Ad-hTERT-E1a-Apoptin significantly inhibited growth of the melanoma cells, protecting normal human epidermal melanocytes from growth inhibition confirmed cancer cell selective adenoviral replication, growth inhibition, and apoptosis induction of this therapeutic approach. The in vivo assays performed by using C57BL/6 mice containing established primary or metastatic tumors expanded the in vitro studies. When treated with Ad-hTERT-E1a-Apoptin, the subcutaneous primary tumor volume reduction was not only observed in intratumoral injection group but in systemic delivery mice. In the lung metastasis model, Ad-hTERT-E1a-Apoptin effectively suppressed pulmonary metastatic lesions. Furthermore, treatment of primary and metastatic models with Ad-hTERT-E1a-Apoptin increased mice survival.

Conclusions: These data further reinforce the previously research showing that an adenovirus expressing Apoptin is more effective and advocate the potential applications of Ad-hTERT-E1a-Apoptin in the treatment of neoplastic diseases in future clinical trials.

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Ad-hTERT-E1a-Apoptin reduction of pulmonary metastatic melanoma and resulting survival benefits. (A) Survival curve. (B) Representative photographs of lungs from control and treatment groups. The day that the first injection performed was considered as starting day 0. Saline or Ad-mock treated mice had the worst mean survival and Ad-CMV-E1a-Apoptin or Ad-hTERT-E1a-Apoptin treated mice had the most improved mean survival (A). Furthermore, both numbers and sizes of lung tumor nodules were reduced in mice treated with Ad-CMV-E1a-Apoptin or Ad-hTERT-E1a-Apoptin compared with those treated with saline, Ad-mock, Ad-CMV-Apoptin, Ad-hTERT-Apoptin, Ad-CMV-E1a or Ad-hTERT-E1a (B). 1. Control; 2. Ad-mock; 3. Ad-CMV-Apoptin; 4. Ad-hTERT-Apoptin; 5. Ad-CMV-E1a; 6. Ad-hTERT-E1a; 7. Ad-CMV-E1a-Apoptin; 8. Ad-hTERT-E1a-Apoptin.
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Figure 5: Ad-hTERT-E1a-Apoptin reduction of pulmonary metastatic melanoma and resulting survival benefits. (A) Survival curve. (B) Representative photographs of lungs from control and treatment groups. The day that the first injection performed was considered as starting day 0. Saline or Ad-mock treated mice had the worst mean survival and Ad-CMV-E1a-Apoptin or Ad-hTERT-E1a-Apoptin treated mice had the most improved mean survival (A). Furthermore, both numbers and sizes of lung tumor nodules were reduced in mice treated with Ad-CMV-E1a-Apoptin or Ad-hTERT-E1a-Apoptin compared with those treated with saline, Ad-mock, Ad-CMV-Apoptin, Ad-hTERT-Apoptin, Ad-CMV-E1a or Ad-hTERT-E1a (B). 1. Control; 2. Ad-mock; 3. Ad-CMV-Apoptin; 4. Ad-hTERT-Apoptin; 5. Ad-CMV-E1a; 6. Ad-hTERT-E1a; 7. Ad-CMV-E1a-Apoptin; 8. Ad-hTERT-E1a-Apoptin.

Mentions: Mouse survival analysis showed that Ad-hTERT-E1a-Apoptin or Ad-CMV-E1a-Apoptin treatment significantly increased survival of mice in the lung metastasis model in comparison with the other recombinant adenoviruses-infected or saline-treated mice (Figure 5A). When the experiment was terminated on day 48, 6/10 of Ad-hTERT-E1a-Apoptin- and 5/10 of Ad-CMV-E1a-Apoptin-infected animals were alive, and the median survival time between these two groups did not differ significantly. None of the mice in the other groups were alive at the end of experiment, and the mean survival times were 15.7 days for saline-treated mice, 13.3 days for Ad-mock-infected mice, 29.6 days for Ad-CMV-Apoptin-infected mice, 29.5 days for Ad-hTERT-Apoptin-infected mice, 23.1 days for Ad-CMV-E1a-infected mice and 23.3 days for Ad-hTERT-E1a-infected mice. As shown by the representative metastasic nodules in Figure 5B, Ad-hTERT-E1a-Apoptin significantly decreased tumor burden of the mice. The lungs of mice infected with Ad-hTERT-E1a-Apoptin had minimal metastatic nodules, whereas the lungs from control or treated groups had severe metastasis. Taken together, systemic delivery of Ad-hTERT-E1a-Apoptin significantly reduced tumor burdens and provided survival benefits in a lung metastatic cancer model.


Potent anti-tumor effects of a dual specific oncolytic adenovirus expressing apoptin in vitro and in vivo.

Li X, Liu Y, Wen Z, Li C, Lu H, Tian M, Jin K, Sun L, Gao P, Yang E, Xu X, Kan S, Wang Z, Wang Y, Jin N - Mol. Cancer (2010)

Ad-hTERT-E1a-Apoptin reduction of pulmonary metastatic melanoma and resulting survival benefits. (A) Survival curve. (B) Representative photographs of lungs from control and treatment groups. The day that the first injection performed was considered as starting day 0. Saline or Ad-mock treated mice had the worst mean survival and Ad-CMV-E1a-Apoptin or Ad-hTERT-E1a-Apoptin treated mice had the most improved mean survival (A). Furthermore, both numbers and sizes of lung tumor nodules were reduced in mice treated with Ad-CMV-E1a-Apoptin or Ad-hTERT-E1a-Apoptin compared with those treated with saline, Ad-mock, Ad-CMV-Apoptin, Ad-hTERT-Apoptin, Ad-CMV-E1a or Ad-hTERT-E1a (B). 1. Control; 2. Ad-mock; 3. Ad-CMV-Apoptin; 4. Ad-hTERT-Apoptin; 5. Ad-CMV-E1a; 6. Ad-hTERT-E1a; 7. Ad-CMV-E1a-Apoptin; 8. Ad-hTERT-E1a-Apoptin.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2818692&req=5

Figure 5: Ad-hTERT-E1a-Apoptin reduction of pulmonary metastatic melanoma and resulting survival benefits. (A) Survival curve. (B) Representative photographs of lungs from control and treatment groups. The day that the first injection performed was considered as starting day 0. Saline or Ad-mock treated mice had the worst mean survival and Ad-CMV-E1a-Apoptin or Ad-hTERT-E1a-Apoptin treated mice had the most improved mean survival (A). Furthermore, both numbers and sizes of lung tumor nodules were reduced in mice treated with Ad-CMV-E1a-Apoptin or Ad-hTERT-E1a-Apoptin compared with those treated with saline, Ad-mock, Ad-CMV-Apoptin, Ad-hTERT-Apoptin, Ad-CMV-E1a or Ad-hTERT-E1a (B). 1. Control; 2. Ad-mock; 3. Ad-CMV-Apoptin; 4. Ad-hTERT-Apoptin; 5. Ad-CMV-E1a; 6. Ad-hTERT-E1a; 7. Ad-CMV-E1a-Apoptin; 8. Ad-hTERT-E1a-Apoptin.
Mentions: Mouse survival analysis showed that Ad-hTERT-E1a-Apoptin or Ad-CMV-E1a-Apoptin treatment significantly increased survival of mice in the lung metastasis model in comparison with the other recombinant adenoviruses-infected or saline-treated mice (Figure 5A). When the experiment was terminated on day 48, 6/10 of Ad-hTERT-E1a-Apoptin- and 5/10 of Ad-CMV-E1a-Apoptin-infected animals were alive, and the median survival time between these two groups did not differ significantly. None of the mice in the other groups were alive at the end of experiment, and the mean survival times were 15.7 days for saline-treated mice, 13.3 days for Ad-mock-infected mice, 29.6 days for Ad-CMV-Apoptin-infected mice, 29.5 days for Ad-hTERT-Apoptin-infected mice, 23.1 days for Ad-CMV-E1a-infected mice and 23.3 days for Ad-hTERT-E1a-infected mice. As shown by the representative metastasic nodules in Figure 5B, Ad-hTERT-E1a-Apoptin significantly decreased tumor burden of the mice. The lungs of mice infected with Ad-hTERT-E1a-Apoptin had minimal metastatic nodules, whereas the lungs from control or treated groups had severe metastasis. Taken together, systemic delivery of Ad-hTERT-E1a-Apoptin significantly reduced tumor burdens and provided survival benefits in a lung metastatic cancer model.

Bottom Line: When treated with Ad-hTERT-E1a-Apoptin, the subcutaneous primary tumor volume reduction was not only observed in intratumoral injection group but in systemic delivery mice.In the lung metastasis model, Ad-hTERT-E1a-Apoptin effectively suppressed pulmonary metastatic lesions.Furthermore, treatment of primary and metastatic models with Ad-hTERT-E1a-Apoptin increased mice survival.

View Article: PubMed Central - HTML - PubMed

Affiliation: Genetic Engineering Laboratory of PLA, Academy of Military Medical Sciences of PLA, Changchun, China.

ABSTRACT

Background: Oncolytic virotherapy is an attractive drug platform of cancer gene therapy, but efficacy and specificity are important prerequisites for success of such strategies. Previous studies determined that Apoptin is a p53 independent, bcl-2 insensitive apoptotic protein with the ability to specifically induce apoptosis in tumor cells. Here, we generated a conditional replication-competent adenovirus (CRCA), designated Ad-hTERT-E1a-Apoptin, and investigated the effectiveness of the CRCA a gene therapy agent for further clinical trials.

Results: The observation that infection with Ad-hTERT-E1a-Apoptin significantly inhibited growth of the melanoma cells, protecting normal human epidermal melanocytes from growth inhibition confirmed cancer cell selective adenoviral replication, growth inhibition, and apoptosis induction of this therapeutic approach. The in vivo assays performed by using C57BL/6 mice containing established primary or metastatic tumors expanded the in vitro studies. When treated with Ad-hTERT-E1a-Apoptin, the subcutaneous primary tumor volume reduction was not only observed in intratumoral injection group but in systemic delivery mice. In the lung metastasis model, Ad-hTERT-E1a-Apoptin effectively suppressed pulmonary metastatic lesions. Furthermore, treatment of primary and metastatic models with Ad-hTERT-E1a-Apoptin increased mice survival.

Conclusions: These data further reinforce the previously research showing that an adenovirus expressing Apoptin is more effective and advocate the potential applications of Ad-hTERT-E1a-Apoptin in the treatment of neoplastic diseases in future clinical trials.

Show MeSH
Related in: MedlinePlus