Oncolytic viruses and DNA-repair machinery: overcoming ...

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Oncolytic viruses and DNA-repair machinery: overcoming chemoresistance of gliomas Hong Jiang†, Marta M Alonso, Candelaria Gomez-Manzano, Yuji Piao and Juan Fueyo

CONTENTS Mechanistic analysis of resistance to temozolomide in gliomas Inactivation of DNA repair: a way to overcome chemoresistance by oncolytic adenoviruses Taking advantage of DNA repair: a way to increase oncolysis by herpes viruses Combination of oncolytic viruses and DNA-damaging chemotherapy drugs Expert commentary

The current standard of care for malignant gliomas is surgical resection and radiotherapy followed by extended adjuvant treatment with the alkylating agent temozolomide. Temozolomide causes DNA damage, which induces cell death. Through changes in the DNA-repair machinery, glioma cells develop resistance to temozolomide, compromising the therapeutic effect of the drug. Oncolytic viruses, such as herpes simplex viruses and adenoviruses, are being introduced into clinical trials as a new treatment for this malignancy. Biological studies have revealed that these viruses use mechanisms to either inactivate (adenovirus) or take advantage of (herpes simplex virus) the cellular DNA-repair machinery to achieve productive replication. Adenoviruses express proteins from the early genes to either downregulate the damage-repair enzyme, O6-methylguanine-DNA methyltransferase, or degrade poly (ADP-ribose) polymerase or the Mre11-Rad50-NBS1 complex, which detects DNA strand breaks. Temozolomide enhances herpes simplex virus oncolysis by upregulating the DNA repair-related genes growth arrest DNA damage 34 and ribonucleotide reductase. The interactions between viruses and the DNA-repair machinery suggest that a combined temozolomide and viral therapy will overcome the limitations of a single therapy by diminishing chemoresistance or enhancing oncolysis. This hypothesis has been supported by promising findings from preclinical and clinical studies.

Five-year view

Expert Rev. Anticancer Ther. 6(11), 1585–1592 (2006)

Key issues

The prognosis of glioma patients is poor; less than 3% of glioblastoma patients are still alive 5 years after diagnosis [1]. Malignant gliomas show high levels of resistance to conventional therapies (i.e., surgery, radiation and chemotherapy) [2]. For decades, no substantial improvements have been observed in the clinical outcomes of newly diagnosed patients with glioblastoma multiforme [2]. A recent randomized study demonstrated that the addition of temozolomide to radiotherapy for patients with newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity, but the improvement in the 2-year survival rate remains suboptimal [3]. The resistance of gliomas to the therapeutic effect of temozolomide is due to changes in the DNA-repair machinery that

References Affiliations

†

Author for correspondence University of Texas MD Anderson Cancer Center, Department of Neuro-Oncology, 1515 Holcombe Blvd, Box 1002, Houston, Texas 77030, USA Tel.: +1 713 834 6251 Fax: +1 713 834 6230 [email protected] KEYWORDS: adenovirus, chemotherapy, DNA repair, herpes simplex virus, oncolytic virus, temozolomide

www.future-drugs.com

10.1586/14737140.6.11.1585

allow cancer cells to avoid DNA damages, such as the double-strand breaks (DSBs) in DNA that trigger a cellular response, resulting in cell death [4–6]. Interference with the DNA-repair machinery was found to sensitize cancer cells to temozolomide [7,8]. Oncolytic viruses are a promising alternative therapeutic agent for gliomas. The replication-competent oncolytic viruses selectively lyse tumors by targeting abnormalities in cancer cells [9]. During viral infection, the extraordinary amount of exogenous viral DNA mimics the damaged DNA with DSBs that are processed by the cellular DNA-repair machinery [10]. However, unlike the DNAdamaging agents, viruses have a mechanism that inactivates or manipulates the DNArepair system for the viruses’ benefit [10]. Since combination therapy with agents that act

© 2006 Future Drugs Ltd

ISSN 1473-7140

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Jiang, Alonso, Gomez-Manzano, Piao & Fueyo

through different mechanisms make the emergence of treatment-resistant disease less likely, treatment with oncolytic viruses and DNA-damaging agents, such as temozolomide, may result in a better therapeutic effect in gliomas. In this review, we analyze the mechanism of resistance to temozolomide in gliomas. We then discuss the interactions between viral proteins and cellular DNA-repair machinery and their relevance to overcoming chemoresistance in gliomas. Since there is no evidence showing RNA viruses (i.e., the measles virus) interacting with DNA-repair machinery, we focus on adenoviruses and herpes viruses, which are both DNA viruses. Finally, we briefly summarize the preclinical and clinical findings of oncolytic virus and DNA-damaging agent combination therapies. Mechanistic analysis of resistance to temozolomide in gliomas

Temozolomide, an oral alkylating agent, was approved by the US FDA for the treatment of newly diagnosed glioblastoma in 2005 on the basis of a Phase III randomized, multicenter trial in which patients with newly diagnosed glioblastoma, who were treated with temozolomide plus radiotherapy, survived for a median of 14.6 months compared with 12.1 months for patients who underwent radiotherapy alone [3]. At a nonacidic pH, temozolomide spontaneously converts into its active metabolite, 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide, a DNA-alkylating agent that methylates guanine at the O6 and N7 positions and adenine at the N3 position [11,12]. O6-methylguanine is not itself lethal to cells, but when paired with thymine, it triggers mismatch DNA repair, a three-step process that involves mismatched base removal by N-methylpurine-DNA glycosylase [13], strand cleavage by apurinic/apyrimidic endonuclease and strand-break recruitment of poly (ADP-ribose) polymerase (PARP), a nick sensor that targets the DNA-repair synthetic machinery to damaged DNA [13]. However, if repair fails to keep pace with DNA damage, repetitive rounds of mismatch repair (MMR) create single-strand DNA breaks that activate serine/threonine kinase ATR (ataxia-telangiectasia mutated [ATM] and Rad3-related) during S phase [14]. If ATR activation fails to arrest the cell cycle, in MMR proficient cells, singlestrand breaks are converted into DSBs in subsequent S phases; these breaks activate the serine/threonine kinase, ATM. Activated ATM promotes cell-cycle arrest and apoptosis [14]. Unfortunately, many gliomas are resistant to temozolomide, primarily because they express the DNA-repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). MGMT, which is expressed by 20% of gliomas, facilitates temozolomide resistance by removing the alkyl adduct from the O6 position of guanine before MMR begins [8,15]. MGMT-mediated temozolomide resistance can be partially overcome by simultaneous treatment with O6-benzylguanine, an MGMT inhibitor that is nontoxic and has been demonstrated, in Phase I clinical trials, to be capable of enhancing the temozolomide responsiveness of MGMT-expressing gliomas [16]. In addition, temozolomide induces a substantial proportion of DNA damage that is repaired by the base excision repair (BER) pathway. At least some temozolomide-induced toxicity is

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caused by unrepaired BER intermediates (owing to incomplete repair), and the intrinsic cellular resistance to temozolomide is due, in part, to robust repair of temozolomide-induced DNA lesions by the BER pathway [4]. PARP, a zinc finger DNA-binding enzyme, detects and signals DNA strand breaks generated during BER and other repair pathways [17,18]. As evidence of the involvement of PARP in temozolomide resistance, Cheng and colleagues reported that a PARP inhibitor, INO-1001, reversed temozolomide resistance in a DNA MMR-deficient malignant glioma xenograft [8]. Tumors can acquire resistance to alkylating agents by loss of MMR activity [19]. This phenomenon is caused directly by impairing the ability of the cell to detect DNA damage and activate apoptosis, and indirectly by increasing the mutation rate throughout the genome [19]. The cellular MMR pathway, which involves human MutL homolog (hMLH)1, mutS homolog (MSH)2 and MSH6, detects and repairs DNA frame shift replication errors and regulates recombination events [20,21]. Tumor cells are able to cope with DNA damage caused by chemotherapy as long as the MMR process is disabled [20]. Although a statistically significant increase in survival has been reported with extended adjuvant treatment with temozolomide after surgical resection and radiotherapy [3], nearly all gliomas recur and become insensitive to further treatment with this class of agents [21]. In gliomas recurrent after the treatment, studies revealed inactivating somatic mutations of the MMR gene MSH6, which heterodimerizes with MSH2 recognizing double-stranded DNA mismatches [21,22]. This evidence suggests that when MSH6 is inactivated in gliomas, the function of alkylating agents changes from induction of tumor cell death to promotion of neoplastic progression [21]. The available preclinical data suggest that tumors that contain a substantial fraction of MMR-deficient cells will demonstrate reduced responsiveness to specific drugs. The challenge now is to assess the clinical significance of the presence of deficient cells in tumors and develop drugs that retain activity against MMR-deficient cells [19]. Inactivation of DNA repair: a way to overcome chemoresistance by oncolytic adenoviruses

The adenoviruses are a family of double-stranded DNA viruses [23]. The linear adenovirus genome has doublestranded DNA termini that presumably represent targets for cellular DNA DSB repair (DSBR): homologous recombination and nonhomologous end joining [10]. The cellular DNArepair machinery can function as an obstacle to adenovirus infection, and viral proteins can inactivate cellular repair pathways to overcome this barrier [10]. The first indication that the adenoviral genome could be a substrate for DSBR arose from the observation that infection with a virus-harboring deletion of the open reading frames within the early region E4 resulted in the formation of large concatemers of viral DNA [24]. In contrast, a wild-type adenovirus with an E4 region that encodes viral factors can prevent viral concatemerization and DSBR [24]. Further studies identified two sets

Expert Rev. Anticancer Ther. 6(11), (2006)

Oncolytic viruses and chemoresistance of glioma

of human proteins that were required for concatemer formaDifferent from the interference of cellular DNA-repair tion: members of the nonhomologous end-joining repair machinery by viral proteins, another possible mechanism to machinery DNA-dependent protein kinase catalytic subunit enhance the therapeutic effect with temozolomide and onco(DNA-PKcs) and ligase IV [25,26], and the conserved multi- lytic adenoviruses could be that the cellular response to temoprotein Mre11, Rad50 and NBS1 (MRN) complex [26]. The zolomide induces early lysis of the infected cells to release MRN complex is thought to be a central player in the human adenoviral particles. Thus, the viruses can expand faster within DNA-damage response and may act as part of the machinery the cancer cell population. The interactions of oncolytic adenoviruses, cellular DNA-repair machinery and temozolomide’s that senses DSBs [27]. A functional redundancy exists for the E4orf3 and E4orf6 potential effect on glioma cells are elucidated in FIGURE 1. proteins during virus infection, and either is sufficient for efficient viral DNA replication and prevention of concatemer for- Taking advantage of DNA repair: a way to increase oncolysis mation [28]. Both E4orf3 and E4orf6 interact with the adeno- by herpes viruses virus E1b55K protein independently and lead to its The genome of herpes simplex virus (HSV) is a large linear dourelocalization into the nucleus [23]. Both E4orf3 and E4orf6 ble-stranded DNA molecule consisting of a long and a short have also been suggested to interact physically with DNA-PKcs, region flanked by large inverted repeats [32]. After HSV-1 infecand this may contribute to their effect on virus concatemerization of non-neuronal cells, replication and subsequent death of tion [25]. The MRN complex appears to be a common target for the host cell usually occurs [32]. By contrast, when HSV-1 infects E4orf3 and E4orf6. The E4orf3 protein disrupts a nuclear sensory neurons, replication is limited and the virus can estabstructure called the promyelocytic leukemia (PML) oncogenic lish latency, in which it remains for the lifetime of the host. The domain (POD or ND10) and this is accompanied by redistribu- latent virus may be reactivated by DNA-damaging agents and tion of the MRN complex [26]. Members of the MRN complex stress [32]. are most likely substrates of the ubiquitin ligase recruited by After infection, the incoming genome is thought to circuE1b55K/E4orf6, and E1b55K has been shown to interact with larize and, as this process does not depend on de novo protein the MRN complex [29]. End joining of E4-deleted viral genomes synthesis from the virus, it is assumed that the end joining is suggests that the virus elicits a cellular DNA-damage response. It was determined that degradation of Mre11 by Temozolomide E1b55K/E4orf6 proteins prevents ATM and ATR signaling in wild-type O6-meG, N7-meG or N3-meA infections [29]. The studies indicated a Survival BER requirement for the MRN complex in ATM and ATR signaling in response to DNA repair adenovirus infection, and degradation of Base mismatch DBR the MRN complex abrogated the ATMFutile MMR MMR dependent G2/M checkpoint in response ATM G2/M arrest to irradiation [29]. In the case of temozoloDSB mide treatment, blocking ATM and ATR Failure of signaling by oncolytic adenoviruses should DNA repair MRN PARP severely impair the ability of the cancer MGMT Cleavage Cell death Degradation cells to recover from the damaged DNA, resulting in the synergistic induction of Transcription E4 or f3 and E3 E4 or f6–E1b55K cell death. Early viral release In addition to inhibition of the detection p300 E1A of DSBs in DNA, there are other indications Fast spread of Oncolytic that adenoviruses can interfere with the viral infection adenovirus DNA-repair machinery in host cells. It was Expert Review of Anticancer Therapy reported that overexpression of adenovirus E1A, which binds CBP/p300, strongly Figure 1. Oncolytic adenoviruses interfere with DNA-repair pathways to sensitize the cells to cell inhibited both basal and TSA-inducible death induced by temozolomide. The viruses express early genes to suppress the repair of the lesions MGMT promoter activity, whereas a mutant caused by temozolomide. E1A binds with p300 to inhibit the transcription of MGMT for removal of methyl E1A, defective in binding CBP/p300, did group from O6meG. E3–11.6K induces cleavage of PARP. The MRN complex is a sensor of double-strand not [30]. In another study, it was demon- breaks. The E4 products and E1b55K reorganize and degrade the members of the MRN complex. strated that infection of the cell with an ade- ATM: Ataxia-telangiectasia mutated;6BER: Base excision repair; DBR: Direct base repair; DSB: Double-strand break; MGMT: O -methylguanine DNA methyltransferase; MMR: Mismatch repair; novirus overexpressing the E3–11.6K MRN: Mre11–Rad50–NBS1; O6meG: O6-methylguanine; PARP: Poly (ADP-ribose) polymerase. protein led to cleavage of PARP [31].


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HSV-1 infection [41]. The formation or stability of concatemers and complex Survival branched structures observed during HSV1 infection [44] may require the Mre11 complex and the cellular DNA-damage DNA repair DSB response machinery [41]. In situations in which the ability of HSV-1 to induce a DNA repair DNA–PKcs MRN ATM G2/M arrest DNA-damage response was compromised (in cells with mutant Mre11 or ATM), sigDegradation nificant defects in viral replication were RR GADD34 observed [41]. This situation is parallel to Increased ICP0 that occurring after HSV-1 infection of viral neurons, in which the virus is unable to replication Cell death elicit a DNA-damage response [41]. It has d nce been suggested that the delay in viral Enha sis ly onco Oncolytic HSV-1 growth in the absence of DNA-repair proteins may be due to a reduced ability to Expert Review of Anticancer Therapy form stable replication structures in a Figure 2. Temozolomide induces a DNA-repair response in the glioma cells to facilitate the timely manner [41]. In the absence of a replication of oncolytic HSV-1, resulting in increased oncolysis. The DNA double-strand breaks damage response, the integrity of the replicaused by temozolomide activate ATM pathways that upregulate the genes needed for DNA repair and cation fork or replication intermediates synthesis, such as RR and probably GADD34. The products of the genes are used by the viruses for a may be compromised, leading to deficienproductive replication. cies in viral replication and contributing to ATM: Ataxia-telangiectasia mutated; DSB: Double-strand break; DNA-PKcs: DNA-dependent protein kinase catalytic subunit; GADD: Growth arrest DNA damage; HSV: Herpes simplex virus; ICP: Infected cell the establishment of latency [41]. polypeptide; MRN: Mre11–Rad50–NBS1 complex; RR: Ribonucleotide reductase. Initial studies revealed the connections between DNA-repair response and the facilitated by cellular proteins [33–35]. Until recently, it was synergism of oncolytic HSVs and DNA-damaging agents generally accepted that a circular DNA molecule provided (FIGURE 2) [6,45,46]. Cisplatin was shown to induce growth arrest the template for HSV replication [32]. This premise has been DNA damage (GADD)34 upregulation and potentiate challenged by the proposal that the immediate early gene- NV1066, a replication-competent oncolytic HSV-1 attenuated infected cell polypeptide (ICP)0 controls the configuration by a deletion in the gene γ134.5, in the treatment of malignant of the viral genome inside the host cell and that the preferred pleural mesothelioma [46]. In another study, the same researchtemplate for replication is actually a linear molecule [36]. ers demonstrated significant synergism between the DNA ICP0 is a promiscuous activator of viral transcription that is cross-linking agent mitomycin C and the oncolytic HSV-1 required for the efficient initiation of the viral lytic cascade G207, and that induction of GADD34 selectively restores the and reactivation from latency [37]. ICP0 is also an E3 ubiqui- virulent phenotype of the deleted gene in G207 [45]. G207 hartin ligase that induces degradation of the catalytic subunit of bors deletions of both copies of neurovirulence gene γ134.5 the DNA-PKcs and other cellular proteins associated with and an inactivating mutation of UL39, which encodes ICP6, PML bodies [38–40]. the large subunit of HSV RR [47]. As a result of these mutaIn contrast to the adenovirus, it appears that HSV may actu- tions, G207 selectively replicates in and lyses dividing cells, ally induce a DNA-damage response [10]. The cellular DNA- possibly since dividing cells express mammalian RR and repair machinery may also play a role in circularization of the GADD34. In particular, mammalian RR generates deoxyriboviral genome during latency, and this is prevented during pro- nucleotides in place of HSV RR, and the GADD34 carboxyl ductive replication by ICP0-induced degradation of DNA- terminus substitutes for the homologous region of γ134.5 [48]. PKcs [36]. In these ways, the virus may manipulate the cellular These gene products have yet to be fully characterized, but DNA-damage response for its own benefit. Wild-type HSV-1 they may regulate the cell cycle [49,50]. infection resulted in activation of the host cell’s DNA-damage Recently, it was reported that temozolomide exhibited machinery, characterized by ATM activation and signaling to strong synergy with G207 through induction of GADD34 proteins involved in the cellular DNA-damage response [41]. and RR expression in malignant glioma cells [6]. Mice with For example, the activity of ribonucleotide reductase (RR) was intracranial gliomas survived longer after combination therupregulated after DNA-damage via the ATM pathway [42,43]. apy (100% survival at 90 days) than after single-agent therThis is an interesting contrast to adenovirus, in which the apy (median survival, 46 and 48 days with G207 and temotreatments, respectively) repair machinery represents an obstacle for productive zolomide [6]. Therefore, infection [10]. Specific DNA-repair proteins or a DNA-damage temozolomide-induced DNA-repair pathways vary with response environment are generally beneficial for productive MGMT expression and enhance HSV-mediated oncolysis in Temozolomide

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Table 1. Examples of combination of oncolytic viruses with DNA-damaging chemotherapeutic agents. Virus

Chemotherapy drug

Tumor type

Phase

Ref.

ONYX-015

Cisplatin, 5-FU

Wide range of human tumor cells

Preclinical

[51]

ONYX-015

Cisplatin, 5-FU

Head and neck

Phase I/II

[52]

ONYX-015

Mitomycin C, doxorubicin, cisplatin

Sarcoma

Phase I/II

[53]

H101

Cisplatin, 5-FU

Squamous cell cancers

Phase III

[54]

G207

Cisplatin

Carcinoma

Preclinical

[55]

G207

Mitomycin C

Gastric cancer

Preclinical

[45]

G207

Temozolomide

Glioma

Preclinical

[6]

HSV-1716

Mitomycin C, cis-platinum II, methotrexate, or doxorubicin

Nonsmall cell lung cancer

Preclinical

[56]

NV1066

Cisplatin

Pleural mesothelioma

Preclinical

[46]

Adenovirus

HSV-1

5-FU: 5-fluorouracil; HSV: Herpes simplex virus.

glioma cells [6]. These findings unveil the potential of HSV to target cells that survive temozolomide treatment [6]. Whether oncolytic HSVs also have the ability to interfere with the repair of the DNA damage caused by temozolomide needs further investigation (FIGURE 2). Combination of oncolytic viruses and DNA-damaging chemotherapy drugs

Preclinical and clinical studies have demonstrated that viral therapy is well suited for combination with DNA-damaging chemotherapy (TABLE 1), although the rationale for the combination has not been completely established. The additive or synergistic mechanisms of combined therapies that have been observed in the clinical setting are also not yet entirely understood. Murine tumor model studies demonstrated that the E1B-55K-deleted oncolytic adenovirus ONYX-015 (dl1520) can be safely and effectively combined with cisplatin and 5fluorouracil (5-FU), and that efficient viral replication can still occur [51]. More importantly, evidence of the combination of adenoviral therapy and chemotherapy has resulted in favorable effects in multiple trials. Promising clinical data were found in a Phase II study of patients with recurrent head and neck cancer treated with intratumoral ONYX-015 and intravenous cisplatin and 5-FU [52]. In a Phase I/II study, ONYX-015, in combination with mitomycin C, doxorubicin and cisplatin, was found to be well tolerated in patients with advanced sarcoma, with no significant ONYX-015 toxicities [53]. The detection of viral DNA in post-treatment tumor specimens by in situ hybridization and detection of the ONYX-015 genome in the peripheral blood by quantitative PCR up to 7 days after the last viral dose, provide evidence for adenoviral replication [53]. Evidence of antitumor activity was found in one out of six patients [53]. In a Phase III randomized clinical


trial, an intratumoral injection of H101, an oncolytic adenovirus that is similar to ONYX-015, combined with cisplatin plus 5-FU-based chemotherapy were used to treat squamous cell cancer of the head and neck or the esophagus; response rates of nearly 80% were observed [54]. The intratumoral H101 injection demonstrated distinct efficacy and was relatively safe [54]. Currently, this is the most complete clinical trial of oncolytic adenoviral therapy, with the largest number of patients reported. In one study, the combination of G207 with cisplatin demonstrated improved efficacy [55]. The therapeutic effects of cisplatin and G207 in vivo were independent [55]. In cisplatin-sensitive tumors, combination therapy resulted in 100% cures, in contrast to 42% with G207, or 14% with cisplatin alone [55]. Another study showed the synergism between oncolytic HSVs and cisplatin or mitomycin C through upregulating the expression of GADD34 protein to functionally substitute for the γ134.5 gene [45,46]. Recently, Aghi and colleagues reported a similar synergistic mechanism between G207 and temozolomide in malignant glioma cells [6]. This is the only study that has focused on gliomas [6]. Another replication-selective HSV-1 ICP34.5 mutant (HSV-1716) has demonstrated additive to synergistic oncolytic effects both in vitro and in vivo against human non-small cell lung cancer cell lines when used in combination with each of four chemotherapeutic agents: mitomycin C, cis-platinum II, methotrexate or doxorubicin [56]. No antagonism was observed [56]. Expert commentary

The current standard of care for malignant glioma consists of extended adjuvant treatment with the alkylating agent temozolomide after surgical resection and radiotherapy [21]. In a randomized study of radiotherapy versus radiotherapy plus 1589


temozolomide followed by 6 months of adjuvant temozolomide in patients with newly diagnosed glioblastoma, the combination treatment group had a statistically significantly longer median survival duration (by 3 months) [3]. The 2-year survival rate was 26.5% in the combination treatment group compared with only 10.4% in the radiotherapy group [3]. New therapeutic regimens are urgently needed to optimize the antiglioma effect of temozolomide. Studies have revealed that changes in DNA-repair machinery contribute to the resistance to temozolomide [4–6] and the inhibitors blocking DNA repair enhanced the effect of temozolomide [16]. Although preclinical and clinical studies have demonstrated the benefit of combining oncolytic viruses with DNA-damaging agents, the mechanism remains unclear. Recently, Aghi and colleagues reported that temozolomide induced synergistic replication of oncolytic HSV in glioma cells through upregulating DNA repair-related genes GADD34 and RR [6]. Currently, no reports exist on the combination of temozolomide and oncolytic adenoviruses. However, on the basis of studies of the interactions between adenoviruses and the cellular DNA-repair machinery, there is a good chance that oncolytic adenoviruses will potentiate the effect of temozolomide in glioma cells. Partial experimental support for this hypothesis comes from the experience of combining E1B mutant oncolytic adenoviruses with cisplatin [51–54]. In addition, our unpublished study of the combination of temozolomide and

a tropism-enhanced E1A mutant oncolytic adenovirus Delta24-RGD has shown promising preliminary data to further support this hypothesis [57]. Moreover, since oncolytic viruses selectively replicate in cancer cells, the interference on DNArepair machinery should also demonstrate some cancer selectivity. Thus, oncolytic viruses may potentiate temozolomide more in cancer cells than in normal cells. On the other hand, the cellular response to temozolomide could delay the growth of the tumor volume and help the early release of the viruses so that the viruses expand faster in the tumor mass. Since temozolomide is a small molecule that diffuses more easily than the viruses within the tumor mass, it could reach tumor cells that are spared by viruses and thus complement the activity of the viruses. Five-year view

At molecular and cellular levels, how oncolytic viruses interfere with the DNA-repair machinery (FIGURES 1 & 2) and the effect on the cytotoxicity of temozolomide, and how temozolomideinduced DNA damage affects viral oncolysis need to be elucidated in glioma cells. In animal models, the effect of the combination on antiglioma activity and the kinetics of the effect need to be studied. The results of accumulating preclinical studies support the use of combining viral therapy and temozolomide in the treatment of gliomas; thus, there is no doubt it will be studied clinically in the near future.

Key issues • In 2005, temozolomide was approved by the US FDA for the treatment of newly diagnosed glioblastoma on the basis of the results of a randomized, multicenter, Phase III trial. Patients treated with temozolomide plus radiotherapy survived for a median of 14.6 months compared with 12.1 months for patients who underwent radiotherapy alone. • The resistance of gliomas to temozolomide is primarily due to the changes in the DNA-repair machinery that allow cancer cells to avoid cell death induced by damaged DNA. • The inhibitors of DNA repair potentiate the cytotoxicity of DNA-damaging agents in cancer cells. • Adenoviruses inactivate the DNA-repair machinery to facilitate efficient replication. • There is the potential to sensitize glioma cells to temozolomide interference DNA. • Herpes viruses induce a DNA-repair response to achieve productive replication. • Temozolomide works synergistically with oncolytic Herpes simplex virus-1 by increasing viral replication through upregulating DNA repair-related genes Growth arrest DNA damage (GADD34) and ribonucleotide reductase (RR). • Preclinical and clinical studies have found the combination of oncolytic viruses and DNA-damaging drugs to be effective against cancers. • In China, after a successful Phase III clinical trial, the first oncolytic viral therapy using an E1B mutant adenovirus has been approved for use in combination with cisplatin and 5-fluorouracil for patients with late-stage refractory nasopharyngeal cancer. References Papers of special note have been highlighted as: • of interest •• of considerable interest 1

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