Cancer Suicide Gene Therapy

Dear Colleagues,

Nonbiological- and biological-based forms of nucleic acid delivery vehicles lending themselves to directed enzyme prodrug therapy (DEPT) comprise the modalities for mediating suicide gene therapy (SGT), which entails the homing of a transgene-enclosing vector (i.e., a delivery vehicle), which encodes a foreign prodrug-activating enzyme to targeted tumor cells to achieve site-specific sensitization. In principle, bio-orthogonal enzyme presentation after its cancer cell-type-specific delivery and expression affords targeted localized conversion of a subsequently administered cognate prodrug substrate into an active therapeutic metabolite, wherein such a metabolite exerts tumor cell cytotoxicity. As cancers have cell-type-specific promoters, catalysis can be predisposed to transpire in only such targeted malignant/diseased tissue. Accordingly, such a strategy allows for circumventing dose-limiting systemic cytotoxicity to noncancerous cells and preventing iatrogenic disease that may otherwise be confronted.

One well-characterized DEPT modality for mediating SGT is the canonical G-/V-DEPT nitroreductase (NTR)-CB1954 bipartite system, which capitalizes on an E. coli-derived transgene, nfsB, and a latent nitroaromatic moiety-based prodrug (CB1954) for activating and subsequently killing only those malignant cancer cells in which the transgene has been expressed. nsfB encodes a biorthogonal NAD(P)H cofactor-preferred Type I NTR (i.e., an oxygen-insensitive NTR) that affords bioreduction in nitroaromatic moiety-based prodrugs to their active form (i.e., a reactive nitroso intermediate) under normoxic conditions (pO₂ = 20 %). Running counter to this process, a Type II NTR cannot similarly do so because Type II NTRs are oxygen-sensitive, thereby affording the reactive nitroso intermediate only under hypoxic conditions (pO₂ ≤ 2.0 %).

To date, all NTR-triggerable pro-reporters (i.e., biorthogonal enzyme-reactive substrates that relay critical intracellular information upon undergoing such catalytic activity) that have been designed for visualizing/quantifying such intracellular biophysics/mechanics effectively function under only hypoxic conditions in in vitro/in vivo settings, which affords the identification of (i) presumably the convoluted collective activity of both Type I and II NTRs (though, to date, no reports in the scientific literature appear to have undertaken efforts to shed light on this question), or (ii) presumably Type II NTR activity due to being upregulated within cancer cells undergoing necrosis that is afforded by a hypoxic environment. Thus, necrotic/intratumoral tissue (from a radial perspective) conditions/state are opposite to those of progressive/metastasic cancer tissue, which operates at normoxic conditions and can only display Type I NTR activity. As such, there is no readily available means capable of affording direct confirmation/visualization of the extent of nsfB delivery, its transcription, its expression, and/or its presentation. Moreover, all other nonbiological- and biological-based forms of transgene-enclosing vectors, with each having their own preferred cognate prodrug counterpart, also encounter these limitations/obstacles.

Given all the difficulties/limitations associated with implementing G-/V-DEPT and the many other forms of DEPT for SGT, the purpose and scope of this Special Issue is to serve as a forum to facilitate the communication of new research findings and sound insights derived thereof obtained from conventional and innovative investigative efforts arising from noteworthy research initiatives that peer into providing/establishing the means for (I) detecting, (ii) measuring, (iii) visualizing (directly), (iv) tracking, and/or (v) any combination thereof, of transgene delivery efficiency, transcript production efficacy (including any post-transcriptional spliced variants), translation of any such RNA into a nascent form of the bio-orthogonal enzyme as well as post-translational modifications rendering the presentation of the transgene-based enzyme into its mature active state.

Dr. Kenneth S. Hettie
Guest Editor

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• directed enzyme prodrug therapy (DEPT)
• suicide gene therapy (SGT)
• gene-/virus-directed enzyme prodrug therapy (G-/V-DEPT)
• nitroreductase (NTR)
• hypoxia
• transgene tracking