Radiation increases the activity of oncolytic adenovirus cancer gene therapy vectors that overexpress the ADP (E3-11.6K) protein

Tóth, Károly; Tarakanova, Vera L.; Doronin, Konstantin; Ward, Peter A.; Kuppuswamy, Mohan; Locke, J.; Dawson, J.E.; Kim, Han J.; Wold, William S.M.

doi:10.1038/sj.cgt.7700555

Cited by 34 publications

(31 citation statements)

References 30 publications

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“…Studies by others on the effects of irradiation on adenovirus replication in vitro have yielded conflicting results. Increases in viral burst size of the prostate cell -specific oncolytic adenoviruses CV706 and CG7870 in combination with irradiation have been reported (12,15), as well as decreases in viral DNA synthesis in irradiated cells infected with ADP-overexpressing oncolytic adenoviruses (26). For the E1-B -deleted oncolytic adenovirus dl1520 (ONYX-015), no significant effect of irradiation on virus replication was found (27), consistent with our results.…”

Section: Discussionsupporting

confidence: 90%

“…This more general mechanism of enhanced antitumor efficacy of oncolytic adenoviruses in combination with radiotherapy is presumed to be operative in s.c. tumor models as well. Indeed, we and others have shown the potentiating effect of irradiation on the antitumor activity of various oncolytic adenoviruses in a variety of s.c. xenografts (10,12,13,15,26,27). Again, both increases (12) and decreases (13) in intratumoral adenovirus replication in irradiated tumors were reported.…”

Section: Discussionmentioning

confidence: 99%

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Differential Effects of Combined Ad5-Δ24RGD and Radiation Therapy in In vitro versus In vivo Models of Malignant Glioma

Lamfers

Idema

Bosscher

et al. 2007

Clinical Cancer Research

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Purpose: The integrin-targeted conditionally replicating adenovirus Ad5-D24RGD has been shown to possess strong oncolytic activity in experimental tumors and is currently being developed toward phase I clinical evaluation for ovarian cancer and malignant glioma. Previously, we reported that combination therapy of Ad5-D24RGD with irradiation led to synergistic antitumor activity in s.c. glioma xenografts. In the current study, the underlying mechanism of action to this synergy was studied and the effects of combined therapy were assessed in an orthotopic glioma model. Experimental Design and Results: Sequencing studies in U-87 monolayers showed that delivery of irradiation before Ad5-D24RGD infection led to a greater oncolytic effect than simultaneous delivery or infection before irradiation. This effect was not due to enhanced virus production or release. Experiments using a luciferase-encoding vector revealed a small increase in transgene expression in irradiated cells. In tumor spheroids, combination therapy was more effective than Ad5-D24RGD or irradiation alone. Staining of spheroid sections showed improved penetration of virus to the core of irradiated spheroids. Mice bearing intracranial tumors received a combination of Ad5-D24RGD with 1 Â 5 Gy total body irradiation or with 2 Â 6 Gy whole brain irradiation. In contrast to the in vitro data and reported results in s.c. tumors, addition of radiotherapy did not significantly enhance the antitumor effect of Ad5-D24RGD. Conclusions: Combined treatment with Ad5-D24RGD and irradiation shows enhanced antitumor activity in vitro and in s.c. tumors, but not in an orthotopic glioma model. These differential results underscore the significance of the selected tumor model in assessing the effects of combination therapies with oncolytic adenoviruses.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Differential Effects of Combined Ad5-Δ24RGD and Radiation Therapy in In vitro versus In vivo Models of Malignant Glioma

Lamfers

Idema

Bosscher

et al. 2007

Clinical Cancer Research

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“…However, docetaxel in combination with Xvir03 causes increased growth delay of DU145 xenograft compared with treatment with either docetaxel or virus alone. Considering the fact that Xvir03 does not express the adenoviral death protein (50) and E1A proteins suggests that it should be possible to design adenoviral mutants that are even more effective in achieving enhanced antitumor effects in combination with chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the Multidrug-Resistant Phenotype by Targeting YB-1 with a Conditionally Oncolytic Adenovirus: Implications for Combinatorial Treatment Regimen with Chemotherapeutic Agents

et al. 2006

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Bearing in mind the limited success of available treatment modalities for the therapy of multidrug-resistant tumor cells, alternative and complementary strategies need to be developed. It is known that the transcriptional activation of genes, such as MDR1 and MRP1, which play a major role in the development of a multidrug-resistant phenotype in tumor cells, involves the Y-box protein YB-1. Thus, YB-1 is a promising target for new therapeutic approaches to defeat multidrug resistance. In addition, it has been reported previously that YB-1 is an important factor in adenoviral replication because it activates transcription from the adenoviral E2-late promoter. Here, we report that an oncolytic adenovirus, named Xvir03, expressing the viral proteins E1B55k and E4orf6, leads to nuclear translocation of YB-1 and in consequence to viral replication and cell lysis in vitro and in vivo. Moreover, we show that Xvir03 down-regulates the expression of MDR1 and MRP1, indicating that recruiting YB-1 to the adenoviral E2-late promoter for viral replication is responsible for this effect. Thus, nuclear translocation of YB-1 by Xvir03 leads to resensitization of tumor cells to cytotoxic drugs. These data reveal a link between chemotherapy and virotherapy based on the cellular transcription factor YB-1 and provide the basis for formulating a model for a novel combined therapy regimen named Mutually Synergistic

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“…Malignant tumors that express adenoviral proteins may become more sensitive to treatment with DNA-damaging agents such as radiation in vivo. Toth et al 20 have recently reported that the combination of radiation plus oncolytic adenovirus suppresses the growth of A549 lung adenocarcinoma xenografts in nude mice more efficiently than either radiation alone or oncolytic vector alone. Our current findings with CG7870 clearly show that the virotherapy and radiation combination significantly improves both cytotoxicity and virus burst size in vitro as well as efficacy in the xenograft tumor model in vivo, but without a concomitant increase in toxicity.…”

Section: Discussionmentioning

confidence: 99%

Oncolytic adenovirus CG7870 in combination with radiation demonstrates synergistic enhancements of antitumor efficacy without loss of specificity

Dilley

Reddy

et al. 2005

Cancer Gene Ther

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Conditionally replicating adenoviruses that selectively replicate in tumor cells, but not in normal cells, are being explored as virotherapeutic agents for cancer. A prostate-specific oncolytic adenovirus, CG7870 is currently being evaluated in phase 1/2 clinical trials for the treatment of prostate cancer. To decrease the effective dose and further increase the therapeutic efficacy of CG7870, the combination of virotherapy with radiation therapy was explored in this study. CG7870 is an oncolytic adenovirus in which tumor-specific promoters are driving the expression of E1A and E1B proteins. The effects of combined treatment with CG7870 and radiation on cultured cells were determined in cytotoxicity and virus yield assays. The antitumor efficacy of CG7870 (1 Â 10 7 particles/mm 3 of tumor), 10 Gy of local radiation or both was evaluated in established subcutaneous LNCaP xenografts in nude mice. In vitro, the dual agent treatment resulted in synergistically enhanced potency at suboptimal doses of radiation and virus. Virus yield in irradiated cells increased relative to yield in nonirradiated cells without compromising the specificity of the vector for its target cell types. In vivo, CG7870 treatment alone suppressed tumor growth and extended tumor nonprogression time. The average tumor-volume of the groups treated with CG7870 only and radiation only was 121 and 126% of baseline, respectively, 39 days after treatment. The average tumor-volume of the combination group was 34% of baseline 39 days after a single dose of treatment. No significant body weight loss was observed in any treatment group. There was a significant drop in serum level of prostate-specific antigen (PSA) in the combination group compared to the group treated with either agent alone. In mice treated with CG7870 only or radiation only, serum PSA levels changed to 26 and 383% of baseline, respectively, by study day 46. In contrast, PSA levels in mice treated with CG7870 plus radiation decreased to less than 11% of baseline by study day 46. Histological analysis of tumor sections collected from the combination group revealed enhanced necrosis and more apoptotic cells. Combination of CG7870 with radiotherapy significantly increased antitumor efficacy compared to either agent alone. These results suggest that CG7870 in combination with radiation has improved antitumor efficacy at lower doses and with no additional side effects.

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Radiation increases the activity of oncolytic adenovirus cancer gene therapy vectors that overexpress the ADP (E3-11.6K) protein

Cited by 34 publications

References 30 publications

Differential Effects of Combined Ad5-Δ24RGD and Radiation Therapy in In vitro versus In vivo Models of Malignant Glioma

Differential Effects of Combined Ad5-Δ24RGD and Radiation Therapy in In vitro versus In vivo Models of Malignant Glioma

Inhibition of the Multidrug-Resistant Phenotype by Targeting YB-1 with a Conditionally Oncolytic Adenovirus: Implications for Combinatorial Treatment Regimen with Chemotherapeutic Agents

Oncolytic adenovirus CG7870 in combination with radiation demonstrates synergistic enhancements of antitumor efficacy without loss of specificity

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