Adenoviral E4orf3 and E4orf6 Proteins, But Not E1B55K, Increase Killing of Cancer Cells by Radiotherapy in vivo

Journal Article · Mon Nov 15 00:00:00 EST 2010 · International Journal of Radiation Oncology, Biology and Physics

DOI:https://doi.org/10.1016/j.ijrobp.2010.05.037· OSTI ID:21438058

Liikanen, Ilkka; Dias, Joao D; Nokisalmi, Petri; Sloniecka, Marta; Kangasniemi, Lotta; Rajecki, Mari ^[1]; Dobner, Thomas ^[2]; Tenhunen, Mikko ^[3]; Kanerva, Anna ^[1]; Pesonen, Sari ^[1]; Hemminki, Akseli ^[1]

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1. Cancer Gene Therapy Group, Molecular Cancer Biology Program and Transplantation Laboratory and Haartman Institute and Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki (Finland)
2. Heinrich Pette Institute for Experimental Virology and Immunology, Hamburg (Germany)
3. Department of Oncology, Helsinki University Central Hospital, Helsinki (Finland)

Purpose: Radiotherapy is widely used for treatment of many tumor types, but it can damage normal tissues. It has been proposed that cancer cells can be selectively sensitized to radiation by adenovirus replication or by using radiosensitizing transgenes. Adenoviral proteins E1B55K, E4orf3, and E4orf6 play a role in radiosensitization, by targeting the Mre11, Rad50, and NBS1 complex (MRN) and inhibiting DNA double-strand break (DSB) repair. We hypothesize that combined with irradiation, these adenoviral proteins increase cell killing through the impairment of DSB repair. Methods and Materials: We assessed the radiosensitizing/additive potential of replication-deficient adenoviruses expressing E1B55K, E4orf3, and E4orf6 proteins. Combination treatments with low-dose external photon beam radiotherapy were studied in prostate cancer (PC-3MM2 and DU-145), breast cancer (M4A4-LM3), and head and neck cancer (UT-SCC8) cell lines. We further demonstrated radiosensitizing or additive effects in mice with PC-3MM2 tumors. Results: We show enhanced cell killing with adenovirus and radiation combination treatment. Co-infection with several of the viruses did not further increase cell killing, suggesting that both E4orf6 and E4orf3 are potent in MRN inhibition. Our results show that adenoviral proteins E4orf3 and E4orf6, but not E1B55K, are effective also in vivo. Enhanced cell killing was due to inhibition of DSB repair resulting in persistent double-strand DNA damage, indicated by elevated phospho-H2AX levels at 24 h after irradiation. Conclusions: This knowledge can be applied for improving the treatment of malignant tumors, such as prostate cancer, for development of more effective combination therapies and minimizing radiation doses and reducing side effects.

• OSTI ID: 21438058
• Journal Information: International Journal of Radiation Oncology, Biology and Physics, Vol. 78, Issue 4; Other Information: DOI: 10.1016/j.ijrobp.2010.05.037; PII: S0360-3016(10)00760-1; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0360-3016
• Country of Publication: United States
• Language: English

Related Subjects

62 RADIOLOGY AND NUCLEAR MEDICINE
ADENOVIRUS
CELL KILLING
DNA REPAIR
GENE THERAPY
IN VIVO
MAMMARY GLANDS
MICE
NEOPLASMS
PROSTATE
PROTEINS
RADIOSENSITIVITY
RADIOTHERAPY
STRAND BREAKS
ANIMALS
BIOLOGICAL RECOVERY
BIOLOGICAL REPAIR
BODY
DISEASES
DNA DAMAGES
GLANDS
MALE GENITALS
MAMMALS
MEDICINE
MICROORGANISMS
NUCLEAR MEDICINE
ONCOGENIC VIRUSES
ORGANIC COMPOUNDS
ORGANS
PARASITES
RADIOLOGY
REPAIR
RODENTS
SENSITIVITY
THERAPY
VERTEBRATES
VIRUSES