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Review
. 2009 Jul;109(7):3125-40.
doi: 10.1021/cr900048k.

Pharmacologic and chemical adjuvants in tumor virotherapy

Christopher Alvarez-Breckenridge  1 , Balveen Kaur, E Antonio Chiocca
Affiliations
Review

Pharmacologic and chemical adjuvants in tumor virotherapy

Christopher Alvarez-Breckenridge et al. Chem Rev. 2009 Jul.
No abstract available

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Figures

Figure 1
Figure 1
(a) The host response to OV therapy represents a unique interplay between host factors that have the capacity to both limit viral efficacy and elicit enhanced tumor killing. For instance, the inflammatory cytokine milieu following viral infection can consist of tumor necrosis factor (TNF)-α, which has the capacity to culminate in tumor regression, while inducible nitric oxide synthase (iNOS) and interferon (IFN)-γ are potent antiviral mediators. Similarly, CD8 cytotoxic T cells have the ability to selectively recognize and lyse tumor cells via a CD8-dependent mechanism. However, natural killer (NK) cells are among the rapid responders to viral infection that attempt to limit viral spread. (b) Due to the dichotomous nature of virus elicited host responses, continuing efforts are needed to clarify the contribution of components of the tumor microenvironment that both limit and enhance viral replication and spread. As the most critical factors are elucidated, they must be translated into pharmacological targets that can be paired with OVs to result in additive or synergistic tumor cell killing. In order to meet this objective, extensive studies will need to determine appropriate quantities of virus and drug along with proper dosing schedules that result in tumor clearance and limited host toxicity.
Figure 2
Figure 2
Viral infection elicits a variety of antiviral cellular responses. Following viral infection, viral pathogen-associated molecular patterns are detected through both TLR and RIG pathways as described in the text. Following the activation of each pathway, signals are relayed to interferon regulatory factors and NF-κB, leading to their translocation from the cytoplasm into the nucleus. Upon arrival in the nucleus, they activate the transcription of a variety of antiviral mediators that limit viral replication and spread.
Figure 3
Figure 3
(A) Viral inoculation results in the infection of cancer cells and surrounding non-neoplastic tissue; however, only cancerous cells will support active viral replication. Just hours following viral inoculation, the tumor microenvironment undergoes a series of dynamic changes (B) that create a barrier for efficient viral replication and spread: (i) an angiogenic response with vasodilation and leakage of inflammatory cellular responders; (ii) elaboration of inflammatory cytokines that create an environment that is limiting for viral replication; (iii) the recruitment and activation of cells from the innate immune system; (iv) components of the ECM create an environment with high interstitial pressure that limits viral dissemination between individual cancer cells. If these responses to viral infection are not addressed, viral clearance will be seen within days of viral administration with limited tumor killing (C); however, each component of the host responses also provides a drug target that can be used to enhance OV efficacy using cotherapy. By tailoring OV therapy with pharmacologic agents, viral replication and spread can be enhanced with increased tumor killing (D).
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