An investigation of adverse effects caused by the injection of high-dose TNFα-expressing adenovirus vector into established murine melanoma

Okada, Yoshinori; Okada, Naoki; Mizuguchi, Hiroyuki; Hayakawa, Tetsuo; Mayumi, Tadanori; Mizuno, Nobuyasu

doi:10.1038/sj.gt.3301876

Cited by 21 publications

(13 citation statements)

References 23 publications

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“…In fact, we found that about 1% of AdRGD that was carefully injected into B16BL6 tumor leaked from tumors into systemic circulation, although AdRGD could reduce systemic vector dissemination by its superior gene transduction to melanoma as compared with conventional Ad. 18 In the present study, we attempted to construct a specialized AdRGD and optimized its applicability to the HSVtk/ GCV treatment for melanoma by using Tyr (melanomaspecific) or TERT (tumor-specific) promoter. C57BL/6 mice were intravenously injected with each AdRGD at the indicated PFU in 100-ml PBS.…”

Section: Discussionmentioning

confidence: 99%

“…18 Therefore, analysis of AdRGD biodistribution after the intratumoral injection is important for predicting and suppressing adverse effects of HSVtk/GCV treatment. We measured luciferase activity of B16BL6 tumors and six major organs (liver, spleen, kidney, heart, lung, and brain) in mice 2 days after intratumoral injection with AdRGD-CMV/Luc, AdRGD-Tyr/Luc, or AdRGD-TERT/Luc at 10 6 -10 9 PFU (Table 1).…”

Section: Distribution Of Transgene Expression In Mice After Intratumomentioning

confidence: 99%

“…However, we also found that AdRGD leaked from the injected tumor site into systemic circulation even if we carefully injected small volumes of AdRGD, and that a large fraction of the leaked AdRGD accumulated in the liver. 18 A major drawback of universal CMV promoterbased suicide gene therapy for cancer is the lack of selectivity for tumor cells in transgene expression accompanied by high probability for toxicity in normal healthy tissue. [19][20][21] Therefore, the ability to restrict gene expression to tumor cells is essential for assuring the safety of suicide gene therapy.…”

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confidence: 99%

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Transcriptional targeting of RGD fiber-mutant adenovirus vectors can improve the safety of suicide gene therapy for murine melanoma

Okada

Mizuguchi

et al. 2005

Cancer Gene Ther

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Since RGD fiber-mutant adenovirus vector (AdRGD), which contains an av-integrin tropism, is highly efficient in gene transduction to melanoma, the AdRGD-mediated herpes simplex virus thymidine kinase (HSVtk)/ganciclovir (GCV) system is an attractive approach for melanoma treatment. However, the intratumoral injection of AdRGD causes limited transgene expression in healthy normal tissue, due to unwanted vector spread. Herein, we describe our attempt to overcome this limitation related to the safety of HSVtk/GCV treatment by using AdRGD carrying either melanoma-specific tyrosinase (Tyr) promoter or tumor-specific telomerase reverse transcriptase (TERT) promoter instead of universal cytomegalovirus promoter. Our in vitro study revealed that Tyr promoterregulated AdRGD exhibited high transgene expression specificity for melanoma cells, and that TERT promoter-regulated AdRGD could induce efficient gene expression in tumor cells, but was relatively quiescent in normal cells. Anti-B16BL6 melanoma effects in mice injected intratumorally with AdRGD-Tyr/HSVtk or AdRGD-TERT/HSVtk, after which GCV was injected intraperitoneally for 10 days, were comparable to those in mice injected with AdRGD-CMV/HSVtk at 10 times less vector dosage. On the other hand, AdRGD-Tyr/HSVtk and AdRGD-TERT/HSVtk did not induce severe adverse effects even when they were intravenously injected into mice at 10 9 plaque-forming units (PFU), whereas mice injected with AdRGD-CMV/HSVtk at 10 8 PFU exhibited body weight reduction and serum level increase of biochemical enzymes for hepatotoxicity. These results indicate that AdRGD combined with transcriptional regulation using Tyr or TERT promoter is a potentially useful and safe vector system for suicide gene therapy for melanoma.

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Section: Discussionmentioning

confidence: 99%

Section: Distribution Of Transgene Expression In Mice After Intratumomentioning

confidence: 99%

mentioning

confidence: 99%

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Transcriptional targeting of RGD fiber-mutant adenovirus vectors can improve the safety of suicide gene therapy for murine melanoma

Okada

Mizuguchi

et al. 2005

Cancer Gene Ther

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“…Figure 1. Blood was collected at the indicated post-injection time points (6,24,48,72 and 96 h post-injection). Total DNA, including Ad vector DNA, was isolated from the blood, and the Ad vector DNA contents were measured by quantitative TaqMan PCR assay, as previously described.…”

Section: Spleen and Nasal Cavitymentioning

confidence: 99%

“…When Ad vectors carry a transgene that exerts cytotoxic effects on transduced cells, Ad vector-mediated hepatic transduction leads to severe hepatotoxicity. [5][6][7] In contrast, human species B Ad serotype 35 (Ad35) vectors, which our group and several others have developed, [8][9][10][11] possess attractive properties that can overcome the drawbacks of conventional Ad5 vectors. First, Ad35 vector-mediated transduction is not hampered by anti-Ad5 antibodies, because Ad35 belongs to a different species (species B) than Ad5 (species C).…”

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confidence: 99%

Adenovirus serotype 35 vector-mediated transduction following direct administration into organs of nonhuman primates

Sakurai

Akitomo

et al. 2008

Gene Ther

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Adenovirus (Ad) serotype 35 (Ad35) vectors have attracted remarkable attention as alternatives to conventional Ad serotype 5 (Ad5) vectors. In a previous study, we showed that intravenously administered Ad35 vectors exhibited a safer profile than Ad5 vectors in cynomolgus monkeys, which ubiquitously express CD46, an Ad35 receptor, in a pattern similar to that in humans. However, the Ad35 vectors poorly transduced the organs. In this study, we examined the transduction properties of Ad35 vectors after local administration into organs of cynomolgus monkeys. The vectors transduced different types of cells depending on the organ. Hepatocytes and microglia were mainly transduced after the vectors were injected into the liver and cerebrum, respectively. Injection of the vectors into the femoral muscle resulted in the transduction of cells that appeared to be fibroblasts and/or macrophages. Conjunctival epithelial cells showed transgene expression following infusion into the vitreous body of the eyeball. Transgene expression was limited to areas around the injection points in most of the organs. In contrast, Ad35 vector-mediated transgene expression was not detected in any of the organs not injected with Ad35 vectors. These results suggest that Ad35 vectors are suitable for gene delivery by direct administration to organs.

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Death Ligands Designed to Kill: Development and Application of Targeted Cancer Therapeutics Based on Proapoptotic TNF Family Ligands

Gerspach

Wajant

Pfizenmaier

2009

Results and Problems in Cell Differentiation

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The identification of molecular markers associated with cancer development or progression, opened a new era in the development of therapeutics. The successful introduction of a few low molecular weight chemicals and recombinant protein therapeutics with targeted actions into clinical practice have raised great expectations to broadly improve cancer therapy with respect to both overall clinical responses and tolerability. Targeting the apoptotic machinery of malignant cells is an attractive concept to combat cancer, which is currently exploited for the proapoptotic members of the TNF ligand family at various stages of preclinical and clinical development. This review summarizes recent progress in this rapidly progressing field of "biologic" therapies targeting the death receptors of TNF, CD95L, and TRAIL by means of its cognate protein ligands, receptor specific antibodies, and gene therapeutic approaches. Preclinical data on newly derived variants and fusion proteins based on these death ligands, designed to act in a tumor restricted manner, thereby preventing a systemic, potentially harmful action, will also be discussed.

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An investigation of adverse effects caused by the injection of high-dose TNFα-expressing adenovirus vector into established murine melanoma

Cited by 21 publications

References 23 publications

Transcriptional targeting of RGD fiber-mutant adenovirus vectors can improve the safety of suicide gene therapy for murine melanoma

Transcriptional targeting of RGD fiber-mutant adenovirus vectors can improve the safety of suicide gene therapy for murine melanoma

Adenovirus serotype 35 vector-mediated transduction following direct administration into organs of nonhuman primates

Death Ligands Designed to Kill: Development and Application of Targeted Cancer Therapeutics Based on Proapoptotic TNF Family Ligands

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