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Conditionally Replicating Adenovirus Expressing TIMP2 Increases Survival in a Mouse Model of Disseminated Ovarian Cancer

Yang SW, Chanda D, Cody JJ, Rivera AA, Waehler R, Siegal GP, Douglas JT, Ponnazhagan S - PLoS ONE (2011)

Bottom Line: The median survival for the PBS cohort was 33 days; for Ad-ΔE1-TIMP2, 39 days; for Ad5/3-CXCR4, 52.5 days; and for Ad5/3-CXCR4-TIMP2, 63 days.The TIMP2-armed CRAd delayed tumor growth and significantly increased survival when compared to the unarmed CRAd.This therapeutic effect was confirmed to be mediated through inhibition of MMP9.

Affiliation: Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama, United States of America.

ABSTRACT

Ovarian cancer remains difficult to treat mainly due to presentation of the disease at an advanced stage. Conditionally-replicating adenoviruses (CRAds) are promising anti-cancer agents that selectively kill the tumor cells. The present study evaluated the efficacy of a novel CRAd (Ad5/3-CXCR4-TIMP2) containing the CXCR4 promoter for selective viral replication in cancer cells together with TIMP2 as a therapeutic transgene, targeting the matrix metalloproteases (MMPs) in a murine orthotopic model of disseminated ovarian cancer. An orthotopic model of ovarian cancer was established in athymic nude mice by intraperitonal injection of the human ovarian cancer cell line, SKOV3-Luc, expressing luciferase. Upon confirmation of peritoneal dissemination of the cells by non-invasive imaging, mice were randomly divided into four treatment groups: PBS, Ad-ΔE1-TIMP2, Ad5/3-CXCR4, and Ad5/3-CXCR4-TIMP2. All mice were imaged weekly to monitor tumor growth and were sacrificed upon reaching any of the predefined endpoints, including high tumor burden and significant weight loss along with clinical evidence of pain and distress. Survival analysis was performed using the Log-rank test. The median survival for the PBS cohort was 33 days; for Ad-ΔE1-TIMP2, 39 days; for Ad5/3-CXCR4, 52.5 days; and for Ad5/3-CXCR4-TIMP2, 63 days. The TIMP2-armed CRAd delayed tumor growth and significantly increased survival when compared to the unarmed CRAd. This therapeutic effect was confirmed to be mediated through inhibition of MMP9. Results of the in vivo study support the translational potential of Ad5/3-CXCR4-TIMP2 for treatment of human patients with advanced ovarian cancer.

MMP-9 expression in excised epithelial ovarian tumor.At the time of sacrifice of mice due to tumor burden, tumors were collected from indicated treatment groups and examined for expression of MMP-9 by immunohistochemistry.
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pone-0025131-g005: MMP-9 expression in excised epithelial ovarian tumor.At the time of sacrifice of mice due to tumor burden, tumors were collected from indicated treatment groups and examined for expression of MMP-9 by immunohistochemistry.

Mentions: TIMP2 is a known inhibitor of MMP2 and MMP9. Hence, staining for active MMP2 and MMP9 was performed to determine if the levels were affected. Results of this analysis indicated that tumors from groups treated with PBS, Ad5/3-CXCR4, and Ad-ΔE1-TIMP2, all exhibited high levels of active MMP2. In contrast, tumors from the group treated with Ad5/3-CXCR4-TIMP2 had very low levels of MMP2. An identical pattern was also detected in MMP9 expression by immunohistochemistry. Groups treated with PBS, Ad5/3-CXCR4, and Ad-ΔE1-TIMP2, all exhibited immunoreactivity for active MMP9. In contrast, tumors from the group treated with Ad5/3-CXCR4-TIMP2 had very low levels of active MMP9 expression (Fig. 5). These data suggest that TIMP2 secreted by the armed CRAd was also effective in inhibiting MMP2 and MMP9 activities.

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Conditionally Replicating Adenovirus Expressing TIMP2 Increases Survival in a Mouse Model of Disseminated Ovarian Cancer

Yang SW, Chanda D, Cody JJ, Rivera AA, Waehler R, Siegal GP, Douglas JT, Ponnazhagan S - PLoS ONE (2011)

MMP-9 expression in excised epithelial ovarian tumor.At the time of sacrifice of mice due to tumor burden, tumors were collected from indicated treatment groups and examined for expression of MMP-9 by immunohistochemistry.
© Copyright Policy
pone-0025131-g005: MMP-9 expression in excised epithelial ovarian tumor.At the time of sacrifice of mice due to tumor burden, tumors were collected from indicated treatment groups and examined for expression of MMP-9 by immunohistochemistry.
Mentions: TIMP2 is a known inhibitor of MMP2 and MMP9. Hence, staining for active MMP2 and MMP9 was performed to determine if the levels were affected. Results of this analysis indicated that tumors from groups treated with PBS, Ad5/3-CXCR4, and Ad-ΔE1-TIMP2, all exhibited high levels of active MMP2. In contrast, tumors from the group treated with Ad5/3-CXCR4-TIMP2 had very low levels of MMP2. An identical pattern was also detected in MMP9 expression by immunohistochemistry. Groups treated with PBS, Ad5/3-CXCR4, and Ad-ΔE1-TIMP2, all exhibited immunoreactivity for active MMP9. In contrast, tumors from the group treated with Ad5/3-CXCR4-TIMP2 had very low levels of active MMP9 expression (Fig. 5). These data suggest that TIMP2 secreted by the armed CRAd was also effective in inhibiting MMP2 and MMP9 activities.

Bottom Line: The median survival for the PBS cohort was 33 days; for Ad-ΔE1-TIMP2, 39 days; for Ad5/3-CXCR4, 52.5 days; and for Ad5/3-CXCR4-TIMP2, 63 days.The TIMP2-armed CRAd delayed tumor growth and significantly increased survival when compared to the unarmed CRAd.This therapeutic effect was confirmed to be mediated through inhibition of MMP9.

Affiliation: Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama, United States of America.

ABSTRACT

Ovarian cancer remains difficult to treat mainly due to presentation of the disease at an advanced stage. Conditionally-replicating adenoviruses (CRAds) are promising anti-cancer agents that selectively kill the tumor cells. The present study evaluated the efficacy of a novel CRAd (Ad5/3-CXCR4-TIMP2) containing the CXCR4 promoter for selective viral replication in cancer cells together with TIMP2 as a therapeutic transgene, targeting the matrix metalloproteases (MMPs) in a murine orthotopic model of disseminated ovarian cancer. An orthotopic model of ovarian cancer was established in athymic nude mice by intraperitonal injection of the human ovarian cancer cell line, SKOV3-Luc, expressing luciferase. Upon confirmation of peritoneal dissemination of the cells by non-invasive imaging, mice were randomly divided into four treatment groups: PBS, Ad-ΔE1-TIMP2, Ad5/3-CXCR4, and Ad5/3-CXCR4-TIMP2. All mice were imaged weekly to monitor tumor growth and were sacrificed upon reaching any of the predefined endpoints, including high tumor burden and significant weight loss along with clinical evidence of pain and distress. Survival analysis was performed using the Log-rank test. The median survival for the PBS cohort was 33 days; for Ad-ΔE1-TIMP2, 39 days; for Ad5/3-CXCR4, 52.5 days; and for Ad5/3-CXCR4-TIMP2, 63 days. The TIMP2-armed CRAd delayed tumor growth and significantly increased survival when compared to the unarmed CRAd. This therapeutic effect was confirmed to be mediated through inhibition of MMP9. Results of the in vivo study support the translational potential of Ad5/3-CXCR4-TIMP2 for treatment of human patients with advanced ovarian cancer.

View Similar Images In: Results  - Collection
View Article: MedlinePlus - PubMed Central -  PubMed
Show All Figures - Show MeSH
getmorefigures.php?pmc=3192051&rFormat=json&query=null&req=5