A Novel Method for Viral Gene Delivery in Solid Tumors

Wang, Yong; Liu, Shanling; Li, Chuan Yuan; Yuan, Fan

doi:10.1158/0008-5472.can-05-1112

Cited by 48 publications

(48 citation statements)

References 19 publications

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“…The dose-dependence of virus dissemination has also been observed in previous studies (12,14,24,25). No adenoviruses could be detected in normal tissues when the dose was <1 Â 10 7 pfu/tumor (9).…”

Section: Resultssupporting

confidence: 79%

“…These data provided further evidence to support the conclusion that virus dissemination was caused by infusion-induced convective transport in tumors (14,15). This information will be useful in the optimization of intratumoral infusion of viral vectors in cancer gene therapy.…”

Section: Resultssupporting

confidence: 61%

“…On the other hand, virus dissemination was observed clearly when the dose was >1 Â 10 9 pfu/tumor (10 -12). It has also been reported that some animals die within a short period after either systemic or intratumoral infusion of high-dose adenoviral vectors (12,14,24,25); and the death is likely to be due to acute immune response to adenoviruses in the systemic circulation and normal tissues (25 -28).…”

Section: Resultsmentioning

confidence: 99%

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Effects of rate, volume, and dose of intratumoral infusion on virus dissemination in local gene delivery

Wang¹,

Wang

et al. 2006

Molecular Cancer Therapeutics

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Recent studies have shown that up to 90% of viral vectors could disseminate to normal organs following intratumoral infusion. The amount of dissemination might be dependent on the infusion conditions. Therefore, we investigated the effects of infusion rate, volume, and dose on transgene expression in liver and tumor tissues after intratumoral infusion of an adenoviral vector encoding luciferase. Luciferase expression was determined through bioluminescence intensity measurement. We observed that the luciferase expression in the liver was independent of the infusion rate but increased with the infusion dose, whereas the luciferase expression in the tumor was a bell-shaped function of the infusion rate. The latter observation was consistent with the distribution pattern of Evans blue -labeled albumin after its solution was infused into tumors at the same infusion rates. We also observed that the infusion volume could affect luciferase expression in the tumor but not in the liver. These observations implied that virus dissemination was determined mainly by the infusion dose, whereas the amount of transgene expression in the tumor depended on the distribution volume of viral vectors in the tumor as well as the infusion dose. [Mol Cancer Ther 2006;5(2):362 -6]

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Section: Resultssupporting

confidence: 79%

Section: Resultssupporting

confidence: 61%

Section: Resultsmentioning

confidence: 99%

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Effects of rate, volume, and dose of intratumoral infusion on virus dissemination in local gene delivery

Wang¹,

Wang

et al. 2006

Molecular Cancer Therapeutics

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“…This biocompatible polymer dissolves in aqueous solution at 4 1C, but rapidly forms a gel upon shifting the temperature to 37 1C and can be used to effect slow release of lipophilic drugs and other small molecules as well as large particles such as viruses. 23,33,46 Overall exposure of the tumor mass to 4-OH-CPA was increased 3.9-fold by i.t. CPA delivery via the slow release polymer, as indicated by AUC, and antitumor activity was correspondingly enhanced, as indicated by early onset and more extensive tumor regression.…”

Section: Discussionmentioning

confidence: 99%

“…injection. 33 Intratumoral delivery of CPA using a 23% solution of F127 significantly increased the AUC of tumor-associated 4-OH-CPA when compared to i.t. injection without polymer, and significantly decreased the C max of 4-OH-CPA in both blood and liver ( Figure 4d vs Figure 4c; Table 1).…”

Section: Impact Of Intratumoral Cpa Delivery On 4-oh-cpa Pharmacokinementioning

confidence: 91%

Enhancement of intratumoral cyclophosphamide pharmacokinetics and antitumor activity in a P450 2B11-based cancer gene therapy model

Chen

Jounaïdi

et al. 2007

Cancer Gene Ther

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The therapeutic utility of cytochrome P450-based enzyme prodrug therapy is well established by preclinical studies and in initial clinical trials. The underlying premise of this gene therapy is that intratumoral P450 expression leads to in situ activation of anticancer P450 prodrugs, such as cyclophosphamide (CPA), with intratumoral accumulation of its activated 4-OH metabolite. In mice bearing 9L gliosarcomas expressing the CPA 4-hydroxylase P450 2B6, enhanced tumor apoptosis was observed 48 h after CPA treatment; however, intratumoral 4-OH-CPA levels were indistinguishable from those of P450-deficient tumors, indicating that the bulk of activated CPA is derived from hepatic metabolism. In contrast, in 9L tumors expressing P450 2B11, a low K m CPA 4-hydroxylase, intratumoral 4-OH-CPA levels were higher than in blood, liver and P450-deficient tumors. Intratumoral 4-OH-CPA increased dose-dependently, without saturation at 140 mg kg À1 CPA, suggesting restricted tumor cell permeation of the parent drug. To circumvent this problem, CPA was administered by direct intratumoral injection, which increased the maximum concentration and area under the curve of drug concentration Â time (AUC) of intratumoral 4-OH-CPA by 1.8-and 2.7-fold, respectively. An overall 3.9-fold increase in intratumoral 4-OH-CPA AUC, and in antitumor activity, was obtained when CPA release to systemic circulation was delayed using the slow-release polymer poloxamer 407 as vehicle for intratumoral CPA delivery. These findings highlight the advantage of gene therapy strategies that combine low K m P450 prodrug activation enzymes with slow, localized release of P450 prodrug substrates.

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Silk‐elastinlike protein polymers improve the efficacy of adenovirus thymidine kinase enzyme prodrug therapy of head and neck tumors

Greish

Frandsen

Scharff

et al. 2010

The Journal of Gene Medicine

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Background-Adenoviral directed enzyme prodrug therapy is a promising approach for head and neck cancer gene therapy. Challenges with this approach however are transient gene expression and dissemination of viruses to distant organs.Methods-We used recombinant silk-elastinlike protein copolymer (SELP) matrices for intratumoral delivery of adenoviruses containing both thymidine kinase-1, and luciferase genes in a nude mice model of JHU-022 head and neck tumor. Hydrogels made from two SELP analogues (47K and 815K) with similar silk to elastinlike block ratios but different block lengths were studied for intratumoral viral delivery. Tumor bearing mice were followed up for tumor progression and luciferase gene expression concomitantly for five weeks. Polymer's safety was evaluated through body weight change, blood count, liver and kidney functions in addition to gross and microscopic histological examination.Results-SELP 815K analogues efficiently controlled the duration and extent of transfection in tumors for up to 5 weeks with no detectable spread to the liver. About five-fold greater reduction in tumor volume was obtained with matrix-mediated delivery compared to intra-tumoral injection of adenoviruses in saline. SELP matrix proved safe in all injected mice compared to control group.Conclusion-SELP-controlled gene delivery approach could potentially improve the anticancer activity of virus-mediated gene therapy while limiting viral spread to normal organs.

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A Novel Method for Viral Gene Delivery in Solid Tumors

Cited by 48 publications

References 19 publications

Effects of rate, volume, and dose of intratumoral infusion on virus dissemination in local gene delivery

Effects of rate, volume, and dose of intratumoral infusion on virus dissemination in local gene delivery

Enhancement of intratumoral cyclophosphamide pharmacokinetics and antitumor activity in a P450 2B11-based cancer gene therapy model

Silk‐elastinlike protein polymers improve the efficacy of adenovirus thymidine kinase enzyme prodrug therapy of head and neck tumors

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