Perspective
As a relatively recently identified alkylating
(methylating) agent, temozolomide (TMZ) has become a focus of
attention, most notably in malignant glioma and melanoma treatment
(1,2). Resistance to TMZ occurs following
prolonged treatment and therefore poses a major therapeutic
challenge. A key mechanism of the resistance to TMZ is the
overexpression of O6-methylguanine-DNA methyl
transferase (MGMT) (3). MGMT
repairs the TMZ-induced DNA lesion, O6MeG, by removing
the methyl group from guanine to a cysteine residue (4). Suppressing MGMT activity, therefore,
could enhance the cytotoxicity of TMZ against melanoma and
glioblastoma multiforme (4).
In previous years, we have focused our research on
oncolytic virotherapy. Oncolytic viruses exhibit selective
replication and lysis in tumor cells, while also amplifying the
expression and functions of therapeutic gene in the tumor
microenvironment (5). Two main
strategies are used for oncolytic adenovirus generation. One
strategy is the deletion of the viral element that is required for
replication of the virus in normal cells, but is dispensable in
tumor cells, such as ONYX-015 or ZD55 with E1B-55K gene deletion
(6,7). The other strategy is the use of a
tumor-specific promoter to drive the gene that is required for
viral replication (8). In clinical
trials, the E1B 55-kDa-deleted oncolytic virus, ONYX-015, or the
ONYX-015 derivative, H101, have exhibited encouraging anticancer
activity when combined with chemotherapy (9).
RNA interference (RNAi) technology is able to
downregulate targeted genes and has been evaluated as a potential
therapeutic strategy in human cancer therapy (10). The knockdown of DNA repair genes by
small interfering RNA (siRNA) and virally delivered short hairpin
RNA (shRNA), can sensitize various cancer cells to chemotherapeutic
agents in vitro (11). A
previous study has shown that the use of siRNA to transiently
transfect nasopharyngeal carcinoma cells and glioma cells results
in the inhibition of MGMT gene expression and increased sensitivity
to bis-chloroethylnitrosourea (12). Similarly, a study by Kato et
al (13) revealed that the
transduction of TMZ-resistant glioma cells with a LipoTrust™
liposome, which contains siRNA to inhibit MGMT gene expression,
enhanced the sensitivity of the glioma cells to TMZ.
Zheng et al (14,15)
focused on the production of several shRNA constructs using an
oncolytic virus for delivery. Examples of these constructs included
siRNAs against Ki67 and hTERT, which were observed to act as
antiproliferative and apoptotic inducers in cancer cells. shRNA
delivery via armed oncolytic viruses has potential for enhancing
antitumor efficacy as a consequence of synergism between viral
replication and oncolysis and shRNA antitumor responses (11). When conveying shRNA, oncolytic
viruses are expected to effect a marked reduction in the tumor MGMT
level, which should result in an increase in the cytotoxicity of
TMZ (Fig. 1).
We hypothesize that the effects of the oncolytic
virus-mediated RNAi of MGMT activity may enhance the cytotoxicity
of TMZ in tumors for the following reasons: Firstly, the use of
armed oncolytic viruses to deliver shRNA combines the advantages of
gene therapy and virotherapy. The inserted shRNA can target the DNA
repair protein, MGMT, in tumor cells and multiply by several 100-
to several 1,000-fold in parallel with viral replication. The
oncolytic adenovirus-armed shRNA targeting MGMT also offers the
advantage of enhancing shRNA-mediated antitumor responses through
its intrinsic oncolytic activity (10). Secondly, as a delivery agent that
couples shRNA expression with viral replication, oncolytic
adenoviruses can minimize the effects of off-target activity in
normal cells, and facilitate, sustain and regenerate shRNA
expression within the tumor microenvironment (15). Thirdly, as oncolytic adenovirus
vectors and chemotherapeutic agents act by different mechanisms,
there is a synergistic or additive effect rather than
cross-resistance on the death of tumor cells (5).
The combination of these advantages and
possibilities suggest that using oncolytic adenoviruses to deliver
therapeutic shRNA targeting MGMT protein may be a powerful
technique for overcoming resistance to TMZ in human cancers. This
may result in a significantly enhanced antitumor outcome through
MGMT-knockdown and viral oncolysis.
Acknowledgements
This study was supported by a grant from the
National Natural Science Foundation of China (grant no.
81372916).
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