Fas ligand delivery by a prostate-restricted replicative adenovirus enhances safety and antitumor efficacy

Xiong Li, You Hong Liu, Yan Ping Zhang, Shaobo Zhang, Xinzhu Pu, Thomas Gardner, Meei Huey Jeng, Chinghai Kao

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Purpose: Recent studies showed that Fas ligand (FasL) induced apoptosis in tumor cells and suppressed the immune response in several types of tumors. However, the toxicity of FasL limited further administration. This study delivered FasL in prostate cancer cells using an improved prostate-restricted replicative adenovirus (PRRA), thereby improving the antitumor effect while decreasing systemic toxicity. Experimental Design: We designed a FasL-armed PRRA, called AdIU3, by placing adenoviral E1a and E4 genes, FasL cDNA, and E1b gene under the control of two individual PSES enhancers. Tissue-specific viral replication and FasL expression were analyzed, and the tumor killing effect of AdIU3 was investigated both in vitro and in vivo using androgen-independent CWR22rv s.c. models via local administration and bone models via systemic administration. The safety of systemic administration of AdIU3 was evaluated. AdCMVFasL, in which FasL was controlled by a universal cytomegalovirus (CMV) promoter, was used as a control. Results: AdIU3 enhanced FasL expression in prostate-specific antigen (PSA)/prostate-specific membrane antigen (PSMA)-positive cells but not in PSA/PMSA-negative cells. It induced apoptosis and killed PSA/PMSA-positive prostate cancer cells but spared normal human fibroblasts, hepatocytes, and negative cells. The increase in killing activity was confirmed to result in part from a bystander killing effect. Furthermore, AdIU3 was more effective than a plain PRRA in inhibiting the growth of androgen-independent prostate cancer xenografts and bone tumor formation. Importantly, systemic administration of AdIU3 resulted in undetectable toxicity, whereas the same doses of AdCMVFasL killed all mice due to multiviscera failure in 16 h. Conclusions: AdIU3 decreased the toxicity of FasL by controlling its expression with PSES, with greatly enhanced prostate cancer antitumor efficacy. The results suggested that toxic antitumor factors can be delivered safely by a PRRA.

Original languageEnglish
Pages (from-to)5463-5473
Number of pages11
JournalClinical Cancer Research
Volume13
Issue number18
DOIs
StatePublished - Sep 15 2007

Fingerprint

Fas Ligand Protein
Adenoviridae
Prostate
Safety
Prostatic Neoplasms
Prostate-Specific Antigen
Androgens
Neoplasms
Apoptosis
Bystander Effect
Bone Neoplasms
Poisons
Cytomegalovirus
Heterografts
Osteogenesis
Genes
Hepatocytes
Research Design
Complementary DNA
Fibroblasts

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Fas ligand delivery by a prostate-restricted replicative adenovirus enhances safety and antitumor efficacy. / Li, Xiong; Liu, You Hong; Zhang, Yan Ping; Zhang, Shaobo; Pu, Xinzhu; Gardner, Thomas; Jeng, Meei Huey; Kao, Chinghai.

In: Clinical Cancer Research, Vol. 13, No. 18, 15.09.2007, p. 5463-5473.

Research output: Contribution to journalArticle

Li, Xiong ; Liu, You Hong ; Zhang, Yan Ping ; Zhang, Shaobo ; Pu, Xinzhu ; Gardner, Thomas ; Jeng, Meei Huey ; Kao, Chinghai. / Fas ligand delivery by a prostate-restricted replicative adenovirus enhances safety and antitumor efficacy. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 18. pp. 5463-5473.
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abstract = "Purpose: Recent studies showed that Fas ligand (FasL) induced apoptosis in tumor cells and suppressed the immune response in several types of tumors. However, the toxicity of FasL limited further administration. This study delivered FasL in prostate cancer cells using an improved prostate-restricted replicative adenovirus (PRRA), thereby improving the antitumor effect while decreasing systemic toxicity. Experimental Design: We designed a FasL-armed PRRA, called AdIU3, by placing adenoviral E1a and E4 genes, FasL cDNA, and E1b gene under the control of two individual PSES enhancers. Tissue-specific viral replication and FasL expression were analyzed, and the tumor killing effect of AdIU3 was investigated both in vitro and in vivo using androgen-independent CWR22rv s.c. models via local administration and bone models via systemic administration. The safety of systemic administration of AdIU3 was evaluated. AdCMVFasL, in which FasL was controlled by a universal cytomegalovirus (CMV) promoter, was used as a control. Results: AdIU3 enhanced FasL expression in prostate-specific antigen (PSA)/prostate-specific membrane antigen (PSMA)-positive cells but not in PSA/PMSA-negative cells. It induced apoptosis and killed PSA/PMSA-positive prostate cancer cells but spared normal human fibroblasts, hepatocytes, and negative cells. The increase in killing activity was confirmed to result in part from a bystander killing effect. Furthermore, AdIU3 was more effective than a plain PRRA in inhibiting the growth of androgen-independent prostate cancer xenografts and bone tumor formation. Importantly, systemic administration of AdIU3 resulted in undetectable toxicity, whereas the same doses of AdCMVFasL killed all mice due to multiviscera failure in 16 h. Conclusions: AdIU3 decreased the toxicity of FasL by controlling its expression with PSES, with greatly enhanced prostate cancer antitumor efficacy. The results suggested that toxic antitumor factors can be delivered safely by a PRRA.",
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AU - Liu, You Hong

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AU - Zhang, Shaobo

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AU - Gardner, Thomas

AU - Jeng, Meei Huey

AU - Kao, Chinghai

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