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Inducible gene expression in tumors colonized by modified oncolytic vaccinia virus strains.

Journal of virology (2014-07-25)
Jochen Stritzker, Sascha Huppertz, Qian Zhang, Ulrike Geissinger, Barbara Härtl, Ivaylo Gentschev, Aladar A Szalay
ABSTRACT

Exogenous gene induction of therapeutic, diagnostic, and safety mechanisms could be a considerable improvement in oncolytic virotherapy. Here, we introduced a doxycycline-inducible promoter system (comprised of a tetracycline repressor, several promoter constructs, and a tet operator sequence) into oncolytic recombinant vaccinia viruses (rVACV), which were further characterized in detail. Experiments in cell cultures as well as in tumor-bearing mice were analyzed to determine the role of the inducible-system components. To accomplish this, we took advantage of the optical reporter construct, which resulted in the production of click-beetle luciferase as well as a red fluorescent protein. The results indicated that each of the system components could be used to optimize the induction rates and had an influence on the background expression levels. Depending on the given gene to be induced in rVACV-colonized tumors of patients, we discuss the doxycycline-inducible promoter system adjustment and further optimization. Oncolytic virotherapy of cancer can greatly benefit from the expression of heterologous genes. It is reasonable that some of those heterologous gene products could have detrimental effects either on the cancer patient or on the oncolytic virus itself if they are expressed at the wrong time or if the expression levels are too high. Therefore, exogenous control of gene expression levels by administration of a nontoxic inducer will have positive effects on the safety as well as the therapeutic outcome of oncolytic virotherapy. In addition, it paves the way for the introduction of new therapeutic genes into the genome of oncolytic viruses that could not have been tested otherwise.

MATERIALS
Product Number
Brand
Product Description

Supelco
Doxycycline hyclate, Pharmaceutical Secondary Standard; Certified Reference Material
Supelco
Doxycycline hyclate, VETRANAL®, analytical standard
Sigma-Aldrich
Doxycycline hyclate
Doxycycline hyclate, European Pharmacopoeia (EP) Reference Standard
USP
Doxycycline hyclate, United States Pharmacopeia (USP) Reference Standard
Sigma-Aldrich
Doxycycline monohydrate