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Anti‐tumor efficacy of a transcriptional replication‐competent adenovirus, Ad‐OC‐E1a, for osteosarcoma pulmonary metastasis
Author(s) -
Li Xiong,
Jung Chaeyong,
Liu YouHong,
Bae Kyunghee,
Zhang YanPing,
Zhang HongJi,
VanderPutten Dale,
Jeng MeeiHuey,
Gardner Thomas A.,
Kao Chinghai
Publication year - 2006
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.904
Subject(s) - cancer research , osteosarcoma , metastasis , cell culture , biology , cancer , medicine , genetics
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 RNA 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 SAOS‐2LM7, which indicated that adenovirus E1a was under strict control by the OC promoter. Ad‐OC‐E1a 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. Copyright © 2006 John Wiley & Sons, Ltd.