Anti-tumor efficacy of a transcriptional replication-competent adenovirus, Ad-OC-E1a, for osteosarcoma pulmonary metastasis

Xiong Li, Chaeyong Jung, You Hong Liu, Kyung Hee Bae, Yan Ping Zhang, Hong Ji Zhang, Dale VanderPutten, Meei Huey Jeng, Thomas Gardner, Chinghai Kao

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17 Citations (Scopus)

Abstract

Background: Osteosarcoma (OSA) is the most frequent type of primary malignant bone tumor and is apt to occur in children and young adults. Pulmonary metastasis (OSPM) is the major reason for its fatal outcome. Osteocalcin (OC) is a major noncollagenous bone protein whose, expression is limited almost exclusively to bone marrow and osteotropic tumors. OC is also known to express in cell lines with bone metastasis feathers. Gene therapy strategies with the OC promoter directing the replication of adenovirus in a tumor-specific manner are a potential modality for OSPM therapy. Methods: We detected OC mRNA expression by R NA in situ hybridization in OSA and OSPM samples from patients, and tested OC promoter transcriptional activity in OSA and non-OSA cell lines. Then we used a transcriptional replication-competent adenovirus, Ad-OC-E1a, to treat OSPM, and evaluated its tumor-specific replication and killing activities in vitro as well as anti-OSPM efficacy in vivo via systemic delivery. Results: OC mRNA was detected in all types of OSA tissues, including OSPM tissues. The transcriptional activity of the OC promoter was much higher in a OSPM cell line SAOS-2LM7 and primary OSA cell line MG63 than in non-OSA cell lines, including cell lines from breast cancer, colon cancer, and liver cancer. Ad-OC-E1a expressed E1a protein only in MG63 and SAGS-2LM7, which indicated that adenovirus E1a was under strict control by the OC promoter. Ad-OC-E1la demonstrated killing and viral replication activity close to wild-type adenovirus levels in MG63 and SAOS-2LM7, but the killing and viral replication activities were attenuated significantly in cells expressing low OC transcriptional activity. To test whether Ad-OC-E1a could be used to target human OSPM in vivo, SAOS-2LM7 pulmonary metastasis models in nude mice were induced and treated by tail-vein injection with Ad-OC-E1a. Compared to tumor nodules in the lung in groups treated with PBS or control virus, the quantity of metastasized tumor nodules decreased significantly. Adenovirus-infected cells were stained immunohistochemically only inside and around the OSPM nodules but spared normal lung tissue and other organs. Conclusions: These data demonstrated that OC promoter could direct adenovirus replication by controlling the E1a gene to target human OSPM in a tumor-specific manner, providing an efficient tool to develop a feasible therapeutic modality for OSPM.

Original languageEnglish
Pages (from-to)679-689
Number of pages11
JournalJournal of Gene Medicine
Volume8
Issue number6
DOIs
StatePublished - Jun 2006

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Osteocalcin
Osteosarcoma
Adenoviridae
Neoplasm Metastasis
Lung
Neoplasms
Cell Line
Liver Neoplasms
Bone and Bones
Colonic Neoplasms
Feathers
Messenger RNA
Fatal Outcome
Nude Mice
Genetic Therapy
In Situ Hybridization
Tail
Young Adult
Veins

Keywords

  • Adenovirus
  • Gene therapy
  • Osteocalcin promoter
  • Osteosarcoma
  • Pulmonary metastasis
  • Targeting

ASJC Scopus subject areas

  • Genetics

Cite this

Anti-tumor efficacy of a transcriptional replication-competent adenovirus, Ad-OC-E1a, for osteosarcoma pulmonary metastasis. / Li, Xiong; Jung, Chaeyong; Liu, You Hong; Bae, Kyung Hee; Zhang, Yan Ping; Zhang, Hong Ji; VanderPutten, Dale; Jeng, Meei Huey; Gardner, Thomas; Kao, Chinghai.

In: Journal of Gene Medicine, Vol. 8, No. 6, 06.2006, p. 679-689.

Research output: Contribution to journalArticle

Li, Xiong ; Jung, Chaeyong ; Liu, You Hong ; Bae, Kyung Hee ; Zhang, Yan Ping ; Zhang, Hong Ji ; VanderPutten, Dale ; Jeng, Meei Huey ; Gardner, Thomas ; Kao, Chinghai. / Anti-tumor efficacy of a transcriptional replication-competent adenovirus, Ad-OC-E1a, for osteosarcoma pulmonary metastasis. In: Journal of Gene Medicine. 2006 ; Vol. 8, No. 6. pp. 679-689.
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abstract = "Background: Osteosarcoma (OSA) is the most frequent type of primary malignant bone tumor and is apt to occur in children and young adults. Pulmonary metastasis (OSPM) is the major reason for its fatal outcome. Osteocalcin (OC) is a major noncollagenous bone protein whose, expression is limited almost exclusively to bone marrow and osteotropic tumors. OC is also known to express in cell lines with bone metastasis feathers. Gene therapy strategies with the OC promoter directing the replication of adenovirus in a tumor-specific manner are a potential modality for OSPM therapy. Methods: We detected OC mRNA expression by R NA in situ hybridization in OSA and OSPM samples from patients, and tested OC promoter transcriptional activity in OSA and non-OSA cell lines. Then we used a transcriptional replication-competent adenovirus, Ad-OC-E1a, to treat OSPM, and evaluated its tumor-specific replication and killing activities in vitro as well as anti-OSPM efficacy in vivo via systemic delivery. Results: OC mRNA was detected in all types of OSA tissues, including OSPM tissues. The transcriptional activity of the OC promoter was much higher in a OSPM cell line SAOS-2LM7 and primary OSA cell line MG63 than in non-OSA cell lines, including cell lines from breast cancer, colon cancer, and liver cancer. Ad-OC-E1a expressed E1a protein only in MG63 and SAGS-2LM7, which indicated that adenovirus E1a was under strict control by the OC promoter. Ad-OC-E1la demonstrated killing and viral replication activity close to wild-type adenovirus levels in MG63 and SAOS-2LM7, but the killing and viral replication activities were attenuated significantly in cells expressing low OC transcriptional activity. To test whether Ad-OC-E1a could be used to target human OSPM in vivo, SAOS-2LM7 pulmonary metastasis models in nude mice were induced and treated by tail-vein injection with Ad-OC-E1a. Compared to tumor nodules in the lung in groups treated with PBS or control virus, the quantity of metastasized tumor nodules decreased significantly. Adenovirus-infected cells were stained immunohistochemically only inside and around the OSPM nodules but spared normal lung tissue and other organs. Conclusions: These data demonstrated that OC promoter could direct adenovirus replication by controlling the E1a gene to target human OSPM in a tumor-specific manner, providing an efficient tool to develop a feasible therapeutic modality for OSPM.",
keywords = "Adenovirus, Gene therapy, Osteocalcin promoter, Osteosarcoma, Pulmonary metastasis, Targeting",
author = "Xiong Li and Chaeyong Jung and Liu, {You Hong} and Bae, {Kyung Hee} and Zhang, {Yan Ping} and Zhang, {Hong Ji} and Dale VanderPutten and Jeng, {Meei Huey} and Thomas Gardner and Chinghai Kao",
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AU - Li, Xiong

AU - Jung, Chaeyong

AU - Liu, You Hong

AU - Bae, Kyung Hee

AU - Zhang, Yan Ping

AU - Zhang, Hong Ji

AU - VanderPutten, Dale

AU - Jeng, Meei Huey

AU - Gardner, Thomas

AU - Kao, Chinghai

PY - 2006/6

Y1 - 2006/6

N2 - Background: Osteosarcoma (OSA) is the most frequent type of primary malignant bone tumor and is apt to occur in children and young adults. Pulmonary metastasis (OSPM) is the major reason for its fatal outcome. Osteocalcin (OC) is a major noncollagenous bone protein whose, expression is limited almost exclusively to bone marrow and osteotropic tumors. OC is also known to express in cell lines with bone metastasis feathers. Gene therapy strategies with the OC promoter directing the replication of adenovirus in a tumor-specific manner are a potential modality for OSPM therapy. Methods: We detected OC mRNA expression by R NA in situ hybridization in OSA and OSPM samples from patients, and tested OC promoter transcriptional activity in OSA and non-OSA cell lines. Then we used a transcriptional replication-competent adenovirus, Ad-OC-E1a, to treat OSPM, and evaluated its tumor-specific replication and killing activities in vitro as well as anti-OSPM efficacy in vivo via systemic delivery. Results: OC mRNA was detected in all types of OSA tissues, including OSPM tissues. The transcriptional activity of the OC promoter was much higher in a OSPM cell line SAOS-2LM7 and primary OSA cell line MG63 than in non-OSA cell lines, including cell lines from breast cancer, colon cancer, and liver cancer. Ad-OC-E1a expressed E1a protein only in MG63 and SAGS-2LM7, which indicated that adenovirus E1a was under strict control by the OC promoter. Ad-OC-E1la demonstrated killing and viral replication activity close to wild-type adenovirus levels in MG63 and SAOS-2LM7, but the killing and viral replication activities were attenuated significantly in cells expressing low OC transcriptional activity. To test whether Ad-OC-E1a could be used to target human OSPM in vivo, SAOS-2LM7 pulmonary metastasis models in nude mice were induced and treated by tail-vein injection with Ad-OC-E1a. Compared to tumor nodules in the lung in groups treated with PBS or control virus, the quantity of metastasized tumor nodules decreased significantly. Adenovirus-infected cells were stained immunohistochemically only inside and around the OSPM nodules but spared normal lung tissue and other organs. Conclusions: These data demonstrated that OC promoter could direct adenovirus replication by controlling the E1a gene to target human OSPM in a tumor-specific manner, providing an efficient tool to develop a feasible therapeutic modality for OSPM.

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KW - Adenovirus

KW - Gene therapy

KW - Osteocalcin promoter

KW - Osteosarcoma

KW - Pulmonary metastasis

KW - Targeting

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