Combination therapy with conditionally replicating adenovirus and replication defective adenovirus

Choon Taek Lee, Kyung Ho Park, Kiyoshi Yanagisawa, Yasushi Adachi, Joyce E. Ohm, Sorena Nadaf, Mikhail M. Dikov, David T. Curiel, David P. Carbone

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Abstract

Low gene transfer rate is the most substantial hurdle in the practical application of gene therapy. One strategy to improve transfer efficiency is the use of a conditionally replicating adenovirus (CRAD) that can selectively replicate in tumor cells. We hypothesized that conventional E1-deleted adenoviruses (ad) can become replication-competent when cotransduced with a CRAD to selectively supply E1 in trans in tumors. The resulting selective production of large numbers of the E1-deleted ad within the tumor mass will increase the transduction efficiency. We used a CRAD (Δ24RGD) that produces a mutant E1 without the ability to bind retinoblastoma but retaining viral replication competence in cancer cells with a defective pRb/p16. Ad-lacZ, adenovirus-luciferase (ad-luc), and adenovirus insulin-like growth factor-1R/dominant-negative (ad-IGF-1R/dn; 482, 950) are E1-deleted replication-defective adenoviruses. The combination of CRAD and ad-lacZ increased the transduction efficiency of lacZ to 100% from 15% observed with ad-lacZ alone. Transfer of media of CRAD and ad-lacZ cotransduced cells induced the transfer of lacZ (media transferable bystander effect). Combination of CRAD and ad-IGF-1R/dn increased the production of truncated IGF-1R or soluble IGF-1R > 10 times compared with transduction with ad-IGF-1R/dn alone. Combined intratumoral injection of CRAD and ad-luc increased the luciferase expression about 70 times compared with ad-luc alone without substantial systemic spread. Combined intratumoral injection of CRAD and ad-IGF-1R/482 induced stronger growth suppression of established lung cancer xenografts than single injections. The combination of CRAD and E1-deleted ad induced tumor-specific replication of CRAD and E1-deleted ad and increased the transduction rate and therapeutic efficacy of these viruses in model tumors.

Original languageEnglish
Pages (from-to)6660-6665
Number of pages6
JournalCancer Research
Volume64
Issue number18
DOIs
StatePublished - 15 Sep 2004

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Adenoviridae
Therapeutics
Neoplasms
Luciferases
Efficiency
Injections
Bystander Effect

Cite this

Lee, C. T., Park, K. H., Yanagisawa, K., Adachi, Y., Ohm, J. E., Nadaf, S., ... Carbone, D. P. (2004). Combination therapy with conditionally replicating adenovirus and replication defective adenovirus. Cancer Research, 64(18), 6660-6665. https://doi.org/10.1158/0008-5472.CAN-04-1200
Lee, Choon Taek ; Park, Kyung Ho ; Yanagisawa, Kiyoshi ; Adachi, Yasushi ; Ohm, Joyce E. ; Nadaf, Sorena ; Dikov, Mikhail M. ; Curiel, David T. ; Carbone, David P. / Combination therapy with conditionally replicating adenovirus and replication defective adenovirus. In: Cancer Research. 2004 ; Vol. 64, No. 18. pp. 6660-6665.
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abstract = "Low gene transfer rate is the most substantial hurdle in the practical application of gene therapy. One strategy to improve transfer efficiency is the use of a conditionally replicating adenovirus (CRAD) that can selectively replicate in tumor cells. We hypothesized that conventional E1-deleted adenoviruses (ad) can become replication-competent when cotransduced with a CRAD to selectively supply E1 in trans in tumors. The resulting selective production of large numbers of the E1-deleted ad within the tumor mass will increase the transduction efficiency. We used a CRAD (Δ24RGD) that produces a mutant E1 without the ability to bind retinoblastoma but retaining viral replication competence in cancer cells with a defective pRb/p16. Ad-lacZ, adenovirus-luciferase (ad-luc), and adenovirus insulin-like growth factor-1R/dominant-negative (ad-IGF-1R/dn; 482, 950) are E1-deleted replication-defective adenoviruses. The combination of CRAD and ad-lacZ increased the transduction efficiency of lacZ to 100{\%} from 15{\%} observed with ad-lacZ alone. Transfer of media of CRAD and ad-lacZ cotransduced cells induced the transfer of lacZ (media transferable bystander effect). Combination of CRAD and ad-IGF-1R/dn increased the production of truncated IGF-1R or soluble IGF-1R > 10 times compared with transduction with ad-IGF-1R/dn alone. Combined intratumoral injection of CRAD and ad-luc increased the luciferase expression about 70 times compared with ad-luc alone without substantial systemic spread. Combined intratumoral injection of CRAD and ad-IGF-1R/482 induced stronger growth suppression of established lung cancer xenografts than single injections. The combination of CRAD and E1-deleted ad induced tumor-specific replication of CRAD and E1-deleted ad and increased the transduction rate and therapeutic efficacy of these viruses in model tumors.",
author = "Lee, {Choon Taek} and Park, {Kyung Ho} and Kiyoshi Yanagisawa and Yasushi Adachi and Ohm, {Joyce E.} and Sorena Nadaf and Dikov, {Mikhail M.} and Curiel, {David T.} and Carbone, {David P.}",
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Lee, CT, Park, KH, Yanagisawa, K, Adachi, Y, Ohm, JE, Nadaf, S, Dikov, MM, Curiel, DT & Carbone, DP 2004, 'Combination therapy with conditionally replicating adenovirus and replication defective adenovirus', Cancer Research, vol. 64, no. 18, pp. 6660-6665. https://doi.org/10.1158/0008-5472.CAN-04-1200

Combination therapy with conditionally replicating adenovirus and replication defective adenovirus. / Lee, Choon Taek; Park, Kyung Ho; Yanagisawa, Kiyoshi; Adachi, Yasushi; Ohm, Joyce E.; Nadaf, Sorena; Dikov, Mikhail M.; Curiel, David T.; Carbone, David P.

In: Cancer Research, Vol. 64, No. 18, 15.09.2004, p. 6660-6665.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Combination therapy with conditionally replicating adenovirus and replication defective adenovirus

AU - Lee, Choon Taek

AU - Park, Kyung Ho

AU - Yanagisawa, Kiyoshi

AU - Adachi, Yasushi

AU - Ohm, Joyce E.

AU - Nadaf, Sorena

AU - Dikov, Mikhail M.

AU - Curiel, David T.

AU - Carbone, David P.

PY - 2004/9/15

Y1 - 2004/9/15

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U2 - 10.1158/0008-5472.CAN-04-1200

DO - 10.1158/0008-5472.CAN-04-1200

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EP - 6665

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JF - Cancer Research

SN - 0008-5472

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