Elsevier

Biochemical Pharmacology

Volume 90, Issue 2, 15 July 2014, Pages 97-106
Biochemical Pharmacology

Commentary
Association of oncolytic adenoviruses with chemotherapies: An overview and future directions

https://doi.org/10.1016/j.bcp.2014.05.003Get rights and content

Abstract

Oncolytic adenoviruses have been used in different preclinical and clinical studies, showing their capacity to kill tumor cells without major adverse events. However, these studies also underline the limitations of this approach. The efficacy of oncolytic adenoviruses is hampered by their limited ability to transduce some tumor types, their lack of selectivity, and their poor dissemination within tumors. In addition, the host immune response may limit oncolytic adenovirus efficacy. Combining oncolytic adenoviruses with chemotherapeutics constitutes an appealing strategy to increase their potency. The first part of this review describes the molecular basis of oncolytic adenoviruses, their use in preclinical studies and clinical trials, their limitations, and strategies to circumvent these limitations. The second part will focus on studies combining oncolytic adenoviruses with chemotherapeutic drugs, including standard chemotherapeutic drugs, molecularly targeted drugs, and other drugs that have been combined with oncolytic adenoviruses. Finally, based on these studies, we describe future directions and general rules that could be followed to identify chemotherapeutic drugs displaying additive/synergistic effects when combined with oncolytic adenoviruses.

Section snippets

Organization of adenovirus genome

Adenoviruses constitute a large family of non-enveloped DNA virus that infect different hosts from fish to mammals. Among these viruses, human Ad serotype 5 is the best characterized in term of pathogenesis, molecular biology and protein functions. Ad entry into a target cell is followed by viral gene transcription. The first region to be transcribed, E1, is divided into E1A and E1B sub-regions [2]. E1A encodes 13S, 12S, 11S, 10S and 9S mRNA, leading to the production of 289R, 243R, 217R, 171R

Principles

Chemotherapeutic drugs are widely used to treat cancers and constitute powerful weapons against tumor development [17], [18]. These compounds are classified into two different families corresponding to standard chemotherapeutic drugs and molecular-targeted drugs [17], [18]. The first family includes mitotic inhibitors, antibiotics, anti-metabolites, platine salts, alkylating agents, and topoisomerase inhibitors. Drugs from this family interact with DNA to form covalent links with DNA strands to

Future directions

As discussed in the previous paragraphs, many studies have investigated the potential of CRAd–chemotherapeutic drug combination. Among classical chemotherapeutic drugs, those belonging to the mitotic inhibitor (paclitaxel, docetaxel), antibiotic (doxorubicin), and topoisomerase inhibitor (mitoxantrone) families showed a synergistic or additive response with CRAd (Table 1). Among targeted chemotherapeutic drugs, mTOR inhibitors as well as HDACi were able to act in synergy with CRAd to inhibit

Conflict of interest

The authors have no competing financial interests to declare.

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